Next Article in Journal
A Human and Rhesus Macaque Interferon-Stimulated Gene Screen Shows That Over-Expression of ARHGEF3/XPLN Inhibits Replication of Hepatitis C Virus and Other Flavivirids
Next Article in Special Issue
Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B
Previous Article in Journal
Serum SARS-CoV-2 Antigens for the Determination of COVID-19 Severity
Previous Article in Special Issue
Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Viruses
Volume 14
Issue 8
10.3390/v14081656
viruses-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Harnessing Human Papillomavirus’ Natural Tropism to Target Tumors

by
Rhonda C. Kines
1,* and
John T. Schiller
2
1
Aura Biosciences, Cambridge, MA 02140, USA
2
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Viruses 2022, 14(8), 1656; https://doi.org/10.3390/v14081656
Submission received: 1 July 2022 / Revised: 25 July 2022 / Accepted: 26 July 2022 / Published: 28 July 2022
(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)
Browse Figures
Versions Notes

Abstract

:
Human papillomaviruses (HPV) are small non-enveloped DNA tumor viruses established as the primary etiological agent for the development of cervical cancer. Decades of research have elucidated HPV’s primary attachment factor to be heparan sulfate proteoglycans (HSPG). Importantly, wounding and exposure of the epithelial basement membrane was found to be pivotal for efficient attachment and infection of HPV in vivo. Sulfation patterns on HSPG’s become modified at the site of wounds as they serve an important role promoting tissue healing, cell proliferation and neovascularization and it is these modifications recognized by HPV. Analogous HSPG modification patterns can be found on tumor cells as they too require the aforementioned processes to grow and metastasize. Although targeting tumor associated HSPG is not a novel concept, the use of HPV to target and treat tumors has only been realized in recent years. The work herein describes how decades of basic HPV research has culminated in the rational design of an HPV-based virus-like infrared light activated dye conjugate for the treatment of choroidal melanoma.

1. Introduction

There is a long and varied literature on the relationship of virus infection and cancer. Prominent examples include the determination of specific viruses as etiologic agents in specific cancers, the development of prophylactic vaccines to prevent these cancers, the initial identification and characterization of cellular oncoproteins and tumor suppressor proteins from studies of viral gene products, and the development of oncolytic virus-based cancer therapies. In this article we review a rather unique example of a virus/cancer relationship in which the characterization of the unusual early events in the HPV infection process involving tissue-associated and cellular proteoglycans have led to the finding of an unexpected tumor-specific tropism for the virus, and the exploitation of this knowledge to develop a potent and potentially broadly applicable treatment for cancers.

2. HPV Background

Papillomaviruses (PV) are small double-stranded DNA (dsDNA) viruses with a family with nearly 200 distinct types identified to date [1]. Papillomaviruses are not unique to humans having been found in over 50 animal species. The viral structure is composed of two proteins, L1 and L2, and it encapsidates a small ~8 kb genome encoding six “early” genes and the two “late” capsid genes. HPVs targets both cutaneous and mucosal basal epithelium and are regarded as the most prevalent sexually transmitted virus, although most infections are asymptomatic. HPVs are the primary etiological agent for several cancers, including almost all cervical cancers, and a substantial subset of anal, penile, vulvar, vaginal, and oropharyngeal tumors [2]. HPVs are grouped into “low risk” (LR) and “high risk” (HR) types loosely based on their presence in benign versus malignant disease. LR-HPV types such as types 1, 2, 6 and 11 can often be found in warts (common, genital, flat, verrucas, myrmecia), recurrent respiratory papillomatosis and lesions in individuals with epidermodysplasia verrucformis, though HR types have also been associated with these diseases in some cases [3,4,5,6]. A small group of 14 HPV types (16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 66 and 68) are classified as “high risk” based on their detection in HPV-associated cancers [2]. The viral oncoproteins E6 and E7 are the primary drivers of HPVs oncogenicity as they bind and effectively disable the tumor suppressor genes p53 and Rb, respectively [7,8,9]. Further, in addition to cancer, some studies have reported that HR-HPV infection can be detected in polyps (nasal and antrochoanal) and may impact both male and female fertility, though further exploration of these topics is warranted [10,11,12,13,14,15,16,17,18].
The study of HPV’s life cycle has met with roadblocks such as difficulty in producing native virions in cultured cells and establishing model systems to interrogate the HPV life cycle. However, advances in recombinant protein expression systems have greatly improved the tools available to PV researchers. When expressed as recombinant proteins, the L1 and L2 capsid proteins self-assemble into empty virus-like particles (VLPs). Importantly, L1 can self-assemble in the absence of L2, and this discovery was the basis for the current L1-based HPV prophylactic vaccines, Cervarix (16, 18), Gardasil (6, 11, 16, 18), Gardasil 9 (6, 11, 16, 18, 31, 33, 45, 52, 58), and Cecolin (16, 18) [19,20,21,22]. The advancement of VLP technology also afforded researchers the ability to study the early events of HPV binding and entry, however, it was the development of pseudovirus (PsV) technology that greatly facilitated the study of HPV intracellular trafficking followed by nuclear gene delivery. PsV are composed of both the L1 and L2 structural proteins encapsidating a plasmid mimicking the size of the dsDNA viral genome referred to as a “pseudogenome”. In the most frequently employed method, they are generated in monolayer cultured cells by co-transfection of plasmid DNA expressing the L1 and L2 capsid proteins that is too large to self-package, along with a smaller 6–8 kb plasmid, often encoding a reporter gene such as red fluorescent protein or luciferase, using a mammalian 293TT cell production system [23]. As the capsid proteins are made, they self-assemble and preferentially package the reporter plasmid as it mimics the size of the viral genome [24]. The final product allows for not only the study of the early binding and entry events of the virus, but also intracellular trafficking followed by nuclear delivery of the encapsidated plasmid and gene expression as a surrogate for the initial stage of infection.

3. HPV Infection Mechanism

A lingering problem that had vexed researchers studying HPV infection in the laboratory was the observation that HPV was unable to infect the known target cells, primary keratinocytes, in vitro, and virus binding and infection of intact epithelium in vivo proved elusive [25,26,27]. However, cultured cell lines, as well as their extracellular matrix (ECM), were capable of being bound by the virion. Over time, it was determined that the virus preferentially recognized and attached to specific modifications on heparan sulfate proteoglycans (HSPG) expressed on the cell surface and within the ECM that are not present on primary cells in culture [28,29,30]. These observations, coupled with the in vivo discovery that wounding of the upper epithelial layer led to virus binding and infection [26,31], resulted in the development of the model of the early events of HPV infection.
HPV cannot bind the apical surface of epithelial cells of intact tissues, instead it first requires access and attachment to the acellular basement membrane (BM) situated below the basal epithelial layer, a unique initial step in its infection process. Wounding or physical disruption of the epithelium must occur to expose the BM, and only then can the virus attach and initiate the early events of infection (Figure 1). The exposed BM is home to several molecules engaged in a signaling and structural interplay within the ECM, though most important for HPV, are HSPG and chondroitin sulfate proteoglycans (CSPG) [32]. The sulfation patterns of the polysaccharide chains of these proteoglycans undergo modifications promoting the various processes important during wound healing such as recruitment of growth factors, cell proliferation, and angiogenesis [33]. It is these specific modifications which provide the “molecular address” recognized by HPV in the context of a wound. Upon virus attachment to the BM-resident HSPG, the N-terminus of the L2 capsid protein undergoes a proteolytic cleavage event by furin or a related proprotein convertase [25,34,35]. This cleavage in turn alters the physical conformation of the viral particle such that previously occluded regions of L1 become exposed, and the virus is only then able to bind the cell surface of newly populating and dividing epithelial cells as they encroach on the wounded area. The virus can then enter the cell by an ill-defined L1-specific receptor and traffic to the nucleus leading to a productive infection, or in the case of the PsV, release of the “pseudogenome” as a surrogate for the first stage of infection indicating successful entry and DNA delivery to the nucleus (“pseudoinfection”) [35].
The use of HSPGs as part of its life cycle is not unique to HPV. Several other viruses, bacteria, parasites, yeast and even prions have been reported to rely on HSPG as minor or major factors in their binding and entry process (Table 1; reviewed in [36,37,38]. However, unlike HPVs, these microbes primarily bind directly to cell surfaces in vivo. As such, HSPGs are considered plausible targets in the prevention of infection and disease (e.g., heparin, heparin and HSPG mimetics and anti-syndecan 3; reviewed in Cagno et al. [37].

4. Proteoglycans

Proteoglycans (PG) are complex molecules found ubiquitously across species and at their most basic are composed of a protein core with one or more covalently linked glycosaminoglycan (GAG) chains. They are important meditators of cell growth and tissue maintenance as they provide a scaffold to facilitate the local modulation and retention of growth factors, chemokines, cytokines and adhesion molecules, all key players in wound healing. Common GAGs are heparan sulfate (HS), chondroitin sulfate (CS), keratin sulfate (KS), dermatan sulfate (DS) and hyaluronic acid (HA). They have long polysaccharide chains composed of repeating disaccharide units of hexuronic acid (e.g., glucuronic acid (GlcA), iduronic acid (IdoA)) and hexosamine (e.g., N-acetyl glucosamine (GlcNAc)) (Figure 2A) [92,93,94]. The length, along with the sulfation and acetylation patterns on these chains, can vary thereby dictating the binding activity of the GAG and providing a functional “signature” of sorts. Remodeling of GAGs is dictated by environmental factors and often relies on localized enzymatic activity, primarily by sheddases such as matrix metalloproteinases (MMP), heparanase and sulfotransferases (Figure 2B) [95,96]. The modifications stemming from the remodeling process can, for example, enrich for growth factors such as basic fibroblast growth factor (FGF2) whose role in wound healing serves to activate fibroblasts and vascular endothelial cells enabling wound closure [33].
Through the years, a detailed view of the specific interaction of HPV with HSPGs has been elucidated, both in vitro and in vivo. HSPGs can exist as cell surface associated molecules (glypicans and syndecans) or secreted (perlecans) and, though some may exist on the cell surface, they can also be released following cleavage by heparanases and MMP to regulate the microenvironment. Importantly, it is within the wound healing milieu of the exposed BM that the modified HSPGs are present and provide the necessary recognition patterns for HPV attachment. Interestingly, even the basolateral surfaces of keratinocytes in wounded tissue are devoid of HPV-binding HSPGs stressing the importance of basement membrane exposure as the initial requirement for HPV attachment [26].
Using biochemical approaches, it was found that the HSPG modification patterns that HPV preferentially targets involve N-sulfated glucosamine, followed by 6-O GalNAc and 2-O GlcA/IdoA sulfation [30,32]. CSPG have also been implicated as an additional attachment factor for HPV under certain binding conditions and this recognition also relies upon 6-O sulfation of GalNAc [97]. Collectively these findings demonstrate the importance of the specific modification patterns that HPV relies upon to initiate its infectious process. HPV is not the only pathogen to rely on particular sulfation patterns for attachment and infection, for example herpes simplex virus type 1 (HSV-1) gD protein preferentially binds 3-O HS [58]; the capsid protein, pORF2 of hepatitis E virus (HEV) relies on 6-O sulfated syndecans for attachment to liver cells [46], and human cytomegalovirus (HCMV) associates with long, heavily sulfated HS chains exhibiting a preference for 6-O and 2-O sulfation [53].

5. HSPGs and Cancer

The importance of HSPGs in cancer progression cannot be understated as they play a profound role in all aspects of cancer biology from tumorigenesis to angiogenesis and metastasis. Much like the wound healing roles of modified HSPGs, tumors too require similar properties for growth factor recruitment and vascularization [98,99,100]. The sulfation patterns and chain lengths of proteoglycans can be modified within the tumor milieu by N-deacetylase/N-sulfotransferases (NDSTs), O-sulfotransferases (HS2ST1, HS3STs, HS6STs), endosulfotransferases (SULF1 and SULF2), heparanases (HPSE), sheddases and sulfatases (Figure 2B) [99]. Expression of these enzymes becomes aberrant in the tumor microenvironment because they are key to promoting and sustaining a malignant state. N-sulfation and 2-O sulfation are important sulfation sites for FGF2 attachment and promotion of endothelial proliferation and organization. 6-O sulfation, tightly regulated by the sulfotransferases, SULF1 and SULF2, is key to the stabilization of the ternary ligand-receptor complexes for both FGF2-FGFR1 and vascular endothelial growth factor (VEGF) and VEGFR, vital regulators of proliferation and angiogenesis [101,102,103,104,105,106]. 3-O GlcN sulfation is a rarely observed modification controlled by heparan sulfate 3-O sulfotransferase which has several isoforms. 3-O sulfation, and its associated sulfotransferase have been associated with increased tumorgenicity in several cancer models such as lung, pancreatic and leukemia [107,108,109].
Heparanases play a significant role in the controlling the length of HSPG chains such as those found on syndecan-1, freeing bound growth factors such as FGF2 and VEGF, thereby converting autocrine growth factor signaling within the environment to a paracrine one, promoting blood vessel formation and invasion [110,111]. Heparanase-mediated remodeling has also been associated with the epithelial to mesenchymal transition, a key feature in tumorigenesis and establishment of a pro-metastatic state attributed to increases in FGF2 and TGF-β signaling [99,112,113]. Reduction in heparanase expression as well as prevention of HSPG expression on tumor cells has been shown to reduce tumorgenicity in vivo, highlighting their importance in retaining a malignant phenotype as well as making them attractive targets for therapeutics [114,115,116].

6. Proteoglycans as Targets for Tumor Therapy

As tumors are heavily dependent upon GAGs and their respective modifying enzymes, these conserved molecules can serve as both therapeutic targets as well as biomarkers for disease staging and progression. Highly active heparinases can lead to shedding and release of GAGs along with their attached cargo, such as growth factors, resulting in more aggressive tumor growth. Shed syndecans have been demonstrated to be plausible biomarkers for predicting cancer progression in some studies, namely elevated serum levels of syndecan-1 are associated with a poor prognosis in bladder cancer, cervical cancer, and colon cancer, among others [117,118,119,120,121]. Kalscheuer et al. [122] demonstrated an association with upregulated levels of perlecan and poor prognosis in triple-negative breast cancer.
The near ubiquitous use of varyingly modified proteoglycans by tumors affords researchers a wealth of cancer specific therapeutic targets. The observation that soluble heparin, which commonly serves as an anti-thrombotic drug, reduced tumor burden and metastasis was the start of the exploitation of proteoglycans for tumor therapy [123]. Now, heparin and heparan sulfate mimetics such as Muparfostat (heparinase competitor), Necuparinib (reduces MMP activity), and Roneparstat (heparinase competitor) are in various stages of clinical development in an attempt to impact tumor growth and spread (Table 2). GAG targeted peptides (e.g., Arginylglycylaspartic acid (RGD motif)), nanoparticles, antibodies and modified pathogens carrying toxic payloads and more recently CAR-T cells, are also in various stages of clinical development (Table 2) [124,125,126].
The tumor ECM can serve as a sink or barrier inhibiting translocation of oncolytic viruses or other viruses targeting tumors thereby preventing broader tumor distribution. To overcome this, tumor targeting viruses can be engineered to express genes for ECM degrading enzymes such as hyaluronidase, chondroitinase and MMPs which can facilitate the localized breakdown of tumor ECM resulting in enhanced spread of the oncolytic virus [127,128]. For these aforementioned reasons, targeting the GAG modifying enzymes or the tumor associated proteoglycans is a burgeoning field of tumor therapy.

7. HPV Capsids as a Tumor Therapeutic

The similarity between the HSPG modifications found on tumors and those on exposed basement membranes makes HPV and attractive tool for tumor-directed therapy. HPV capsids were found to bind a wide variety of human tumor types in a screen of the NCI-60 panel of human tumor cell lines, particularly epithelial derived cancers such as ovarian, lung and breast [171]. Using biochemical assays to decipher HPVs tumor binding characteristics in vitro, it was noted that heparinase treatment of tumor cells abrogated HPVs binding ability and the same basement membrane-associated HSPG N-, 6-O and 2-O sulfation patterns were responsible for HPV tumor targeting. This HSPG targeting was verified in vivo using i-carrageenan, a heavily sulfated polysaccharide, to inhibit HPVs binding and infection of human tumor cells. Importantly, the HPV capsids did not detectably bind the apical surfaces of a wide variety of intact tissues [171]. In considering the use of HPV as a cancer therapeutic, it is important to note that the VLP can be easily modified to carry a “payload” such as a dye without altering its tumor targeting ability. In addition to modifications to the VLP itself, using pseudovirus technology, the virus can specifically deliver nucleic acids to tumor cells resulting in locally expressed genes within the tumor microenvironment minimizing off-target or systemic effects [171,172,173].
In addition to their tumor specific HSPG targeting capability, the 55 nm HPV VLP fits into a particular niche of nano sized particles that preferentially collect in tumors due to leaky vasculature. As tumors grow, their interior becomes hypoxic forcing the tumor to undergo neovascularization, but in most cases, these newly generated blood vessels are disorganized and porous, allowing for preferential extravasation of particles of 40–120 nm to passively accumulate within the tumor, an observation referred to as the EPR effect (enhanced permeabilization and retention) [174,175]. With its size and tropism for tumors, the HPV VLP is a natural vehicle for cancer therapeutics that may be exploited in many ways.

7.1. Gene Delivery

While the HPV PsV has proven a useful tool for studying the early stages of HPV binding, it also affords researchers a useful vector for gene delivery to tumors. In initial studies involving intravenous delivery of HPV PsV packaging reporter plasmids, spontaneous and orthotopically implanted tumors in syngeneic and xenograft murine models of bladder, ovarian, and lung cancer were specifically transduced [171,172,173]. Importantly, there were no off-target gene transduction events detected, indicating that the tumor targeting was specific. In the human NCI-H460 non-small cell lung cancer orthotopic tumor model, PsV infection (as noted by transduction of the firefly luciferase gene) was observed in a subset of animals in regions other than the lungs. Upon microscopic assessment, it was determined that intravenous delivery of HPV PsV had targeted metastatic tumors in lymph nodes, kidneys, and ovaries [171]. Using HPV PsV to target orthotopic ovarian and bladder tumors, Hung et al. [172] and Hojeij et al. [173] demonstrated delivery of a gene for thymidine kinase (TK), a commonly used “suicide” gene that activates the prodrug ganciclovir. Both groups reported an impact on tumor growth and tumor burden specific to the animals receiving the TK gene delivered by HPV PsV followed by ganciclovir treatment. However, a potential limitation of this approach is that HPVs complete their infectious process only in actively dividing cells, and tumors generally have a subpopulation of quiescent cells. This constraint might be less critical if the PsV were used in an adjuvant capacity, for example to deliver immune modulatory genes to a tumor or to express cytokines and chemokines to generate a chemoattracting gradient to enhance recruitment of immune cells to the tumor milieu.

7.2. HPV Virus-like Particles as Drug Conjugates

A second general strategy to overcome the infection limitation of HPVs is to deliver drugs that only require capsid binding, which occurs similarly in dividing and nondividing tumor cells. The most advance example of this approach is AU-011 (belzupacap sarotalocan), a virus-like drug conjugate (VDC) composed of a modified HPV16 VLP (L1 and L2 capsid proteins) conjugated with the phthalocyanine photosensitizing dye, IRDye700DX [176,177]. The L1 amino acid sequence has been modified to reduce interaction with pre-existing neutralizing antibodies, but this modification has no impact on the tumor associated HSPG targeting. When bound to tumor cells and photoactivated by 689–690 nm near-infrared (NIR) light, AU-011 releases reactive oxygen species and causes physical disruption of the tumor cell membrane resulting in rapid and acute, necrotic cell death (Figure 3). Using in vitro mixed cell assays in which human tumor cells were combined with HSPG deficient cells (pGSA-745) and exposed to AU-011 followed by NIR light treatment, extensive cytotoxicity for the tumor cells was observed, while simultaneously sparing the HSPG negative cells. AU-011 mediated tumor cytotoxicity also leads to the release of tumor neoantigens, and damage associated molecular patterns (DAMPs), such as ATP, cell-free DNA, HMGB-1, and the subcellular re-localization of ER proteins HSP70 and calreticulin to the surface of the cell, resulting in a potently immunogenic tumor milieu capable of stimulating cell-mediated anti-tumor immunity (Figure 3) [178].
In vivo murine syngeneic tumor models, TC-1 and MB49-luciferase have been used to better understand AU-011’s efficacy and its potential to generate anti-tumor immunity. A single intravenous administration followed by NIR exposure of the tumor resulted in >50% complete response rates with animals remaining tumor free up to 100 days post-treatment. Tumor-free animals were re-challenged with corresponding tumor cells and again >50% were protected from tumor outgrowth indicating that a long-term anti-tumor immune response had been induced. When AU-011 was combined with checkpoint inhibitors, anti-CTLA-4 or anti-PD-1, tumor-free survival rates were increased to 100% and 75%, respectively, and >70% of tumor-free animals were protected from tumor re-challenge after 100 days. Induction of both CD4+ and CD8+ anti-tumor T cells was a key contributing factor to AU-011’s efficacy, both at the time of treatment, and for maintaining long-term protection [178].
Inherent in their nature, VLPs will bind and be taken up by antigen presenting cells of the hosts immune system. In human peripheral blood lymphocytes, the VLPs avidly bind neutrophils, monocytes, macrophages, dendritic cells and B cells, but not T or NK cells [179]. Within a tumor resides suppressive populations of these cells, such as tumor associated macrophage (TAM) and myeloid-derived suppressor cells (MDSC), primarily serving to shield the tumor from host immune responses. AU-011 can bind and kill these cells within the tumor microenvironment, lending further credence to its ability to generate a potent immunogenic tumor microenvironment [178].
AU-011 is currently being assessed for it use as a first-line treatment for choroidal melanoma, a disease with minimal early interventions [180]. Pre-clinical data demonstrated that intravitreal or suprachoroidal injection into the eyes of rabbits bearing choroidal melanoma tumors resulted in AU-011 tumor distribution and dose dependent efficacy upon NIR treatment (as measured by tumor necrosis and tumor control) [177,181,182]. A Phase 1/2b dose escalation study (Clinical Trial #NCT03052127) examining intravitreal administration of AU-011 to patients with small primary choroidal melanomas resulted in minimal adverse events, with inflammation and increases in intraocular pressure being the most common, though not unexpected due to AU-011′s potent immune stimulatory capabilities and mechanism of action. Importantly, there were no dose limiting toxicities observed and, for those patients experiencing inflammation or intraocular pressure, symptoms could be managed with steroids and ocular hypertensives. Interim data suggests ≥55% tumor control across all dosing groups including a subtherapeutic dose and regimen and ≥87% vision preservation at the time of interim analysis (12-month median follow-up) [182]. Vision preservation is critical as current standard of care for choroidal melanoma is typically radiotherapy such as plaque brachytherapy which often results in vision loss as a result of complications such as retinopathy, cataracts and neovascular glaucoma [180]. An additional Phase 2 safety and efficacy trial is underway (Clinical Trial #NCT04417530) to deliver AU-011 directly into the suprachoroidal space of the eye with the idea of directly localizing the drug within the tumor compartment rather than relying on it to distribute throughout the vitreous and cross the retina and retinal pigment epithelium (RPE) to bind to the tumor after intravitreal injection. Future studies are planned to examine the use of AU-011 to treat other cancers that metastasize to the choroid as well as to examine its applicability for treatment of non-muscle invasive bladder cancer.

8. Conclusions

The use of viruses and nanocarriers is an expanding field in cancer therapy seeking to deliver sensitizing drugs (phototherapy, thermotherapy, ultrasound), chemotherapeutics, immune stimulators, or cytotoxic genes. While advances in targeted tumor therapies have revolutionized cancer research in the past 20 years, many rely on personalized therapy (T cells) or tumor-type restricted surface ligands (CAR-T, mAbs). Tumor associated modified proteoglycans provide a target that can be found on a breadth of cancer types. Unlike HPV capsids that possess natural targeting capabilities, proteoglycan targeted nanoparticle therapies require modifications with ligands, targeting peptides or scFv that recognizes the particularly modified tumor proteoglycans to deliver their payload. The HPV capsid binding studies revealed an unanticipated commonality of HSPG-specific modifications across many cancer types. Therefore, a clear advantage HPV has over many other supramolecular candidates is that it does not require any modification to preferentially recognize tumors, making it a broadly applicable biologic for cancer therapy, both in terms of the type of payload it can deliver and the types of cancers it can target.

9. Patents

RCK-US Patent 9,855,347 B2 (issued) for virion-derived nanospheres for selective delivery of therapeutic and diagnostic agents to cancer cells; U.S. Patent 10,117,947 B2 (pending) for virus-like particle conjugates for diagnosis and treatment of tumors; WO/2018/191363 (pending) for targeted combination therapy. JTS-US Patent 10,117,947 B2 (issued, licensed, and with royalties paid from Aura Biosciences); US Patent 10,188,751 B2 (issued, licensed, and with royalties paid from Aura Biosciences); US Patent 8,990,290 B2 (issued, licensed, and with royalties paid from Aura Biosciences).

Author Contributions

Writing and review of the manuscript—R.C.K. and J.T.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

R.C.K.—employee of Aura Biosciences; patents; J.T.S.—patents. Authors and Aura Biosciences declare that they have no competing interest.

References

  1. Bernard, H.-U.; Burk, R.D.; Chen, Z.; van Doorslaer, K.; Hausen, H.Z.; de Villiers, E.-M. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010, 401, 70–79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. de Martel, C.; Plummer, M.; Vignat, J.; Franceschi, S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int. J. Cancer 2017, 141, 664–670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Burd, E.M. Human Papillomavirus and Cervical Cancer. Clin. Microbiol. Rev. 2003, 16, 637–646. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Gillison, M.L.; Alemany, L.; Snijders, P.J.; Chaturvedi, A.; Steinberg, B.M.; Schwartz, S.; Castellsagué, X. Human papillomavirus and diseases of the upper airway: Head and neck cancer and respiratory papillomatosis. Vaccine 2012, 30 (Suppl. 5), F34–F54. [Google Scholar] [CrossRef] [PubMed]
  5. Egawa, N.; Doorbar, J. The low-risk papillomaviruses. Virus Res. 2017, 231, 119–127. [Google Scholar] [CrossRef] [PubMed]
  6. Fortes, H.R.; von Ranke, F.M.; Escuissato, D.L.; Araujo Neto, C.A.; Zanetti, G.; Hochhegger, B.; Souza, C.A.; Marchiori, E. Recurrent respiratory papillomatosis: A state-of-the-art review. Respir. Med. 2017, 126, 116–121. [Google Scholar] [CrossRef] [Green Version]
  7. Dyson, N.; Howley, P.M.; Munger, K.; Harlow, E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989, 243, 934–937. [Google Scholar] [CrossRef]
  8. Hawley-Nelson, P.; Vousden, K.H.; Hubbert, N.L.; Lowy, D.R.; Schiller, J.T. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 1989, 8, 3905–3910. [Google Scholar] [CrossRef]
  9. Scheffner, M.; Werness, B.A.; Huibregtse, J.M.; Levine, A.J.; and Howley, P.M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990, 63, 1129–1136. [Google Scholar] [CrossRef]
  10. Conde-Ferráez, L.; Chan May Ade, A.; Carrillo-Martínez, J.R.; Ayora-Talavera, G.; González-Losa Mdel, R. Human papillomavirus infection and spontaneous abortion: A case-control study performed in Mexico. Eur. J. Obstet. Gynecol. Reprod. Biol. 2013, 170, 468–473. [Google Scholar] [CrossRef]
  11. Knör, M.; Tziridis, K.; Agaimy, A.; Zenk, J.; Wendler, O. Human papillomavirus (HPV) prevalence in nasal and antrochoanal polyps and association with clinical data. PLoS ONE 2015, 10, e0141722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Ambühl, L.M.; Baandrup, U.; Dybkær, K.; Blaakær, J.; Uldbjerg, N.; Sørensen, S. Human papillomavirus infection as a possible cause of spontaneous abortion and spontaneous preterm Delivery. Infect. Dis. Obstet. Gynecol. 2016, 2016, 3086036. [Google Scholar] [CrossRef] [Green Version]
  13. Ambühl, L.M.M.; Leonhard, A.K.; Widen Zakhary, C.; Jørgensen, A.; Blaakaer, J.; Dybkaer, K.; Baandrup, U.; Uldbjerg, N.; Sørensen, S. Human papillomavirus infects placental trophoblast and Hofbauer cells, but appears not to play a causal role in miscarriage and preterm labor. Acta Obstet. Gynecol. Scand. 2017, 96, 1188–1196. [Google Scholar] [CrossRef] [Green Version]
  14. Xiong, Y.Q.; Mo, Y.; Luo, Q.M.; Huo, S.T.; He, W.Q.; Chen, Q. The risk of human papillomavirus infection for spontaneous abortion, spontaneous preterm birth, and pregnancy rate of assisted reproductive technologies: A systematic review and meta-analysis. Gynecol. Obstet. Investig. 2018, 83, 417–427. [Google Scholar] [CrossRef]
  15. Jeršovienė, V.; Gudlevičienė, Ž.; Rimienė, J.; Butkauskas, D. Human papillomavirus and infertility. Medicina 2019, 55, 377. [Google Scholar] [CrossRef] [Green Version]
  16. Tognon, M.; Tagliapietra, A.; Magagnoli, F.; Mazziotta, C.; Oton-Gonzalez, L.; Lanzillotti, C.; Vesce, F.; Contini, C.; Rotondo, J.C.; Martini, F. Investigation on spontaneous abortion and human papillomavirus infection. Vaccines 2020, 8, 473. [Google Scholar] [CrossRef] [PubMed]
  17. Muscianisi, F.; De Toni, L.; Giorato, G.; Carosso, A.; Foresta, C.; Garolla, A. Is HPV the novel target in male idiopathic infertility? A systematic review of the literature. Front. Endocrinol. 2021, 12, 643539. [Google Scholar] [CrossRef]
  18. Oton-Gonzalez, L.; Rotondo, J.C.; Cerritelli, L.; Malagutti, N.; Lanzillotti, C.; Bononi, I.; Ciorba, A.; Bianchini, C.; Mazziotta, C.; De Mattei, M.; et al. Association between oncogenic human papillomavirus type 16 and Killian polyp. Infect. Agent Cancer 2021, 16, 3. [Google Scholar] [CrossRef]
  19. Zhou, J.; Sun, X.Y.; Stenzel, D.J.; Frazer, I.H. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991, 185, 251–257. [Google Scholar] [CrossRef]
  20. Kirnbauer, R.; Booy, F.; Cheng, N.; Lowy, D.R.; Schiller, J.T. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc. Natl. Acad. Sci. USA 1992, 89, 12180–12184. [Google Scholar] [CrossRef] [Green Version]
  21. Kirnbauer, R.; Taub, J.; Greenstone, H.; Roden, R.; Dürst, M.; Gissmann, L.; Lowy, D.R.; Schiller, J.T. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles. J. Virol. 1993, 67, 6929–6936. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Rose, R.C.; Bonnez, W.; Reichman, R.C.; Garcea, R.L. Expression of human papillomavirus type 11 L1 protein in insect cells: In vivo and in vitro assembly of viruslike particles. J. Virol. 1993, 67, 1936–1944. [Google Scholar] [CrossRef] [Green Version]
  23. Buck, C.B.; Pastrana, D.V.; Lowy, D.R.; Schiller, J.T. Efficient intracellular assembly of papillomaviral vectors. J. Virol. 2004, 78, 751–757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Cerqueira, C.; Pang, Y.Y.; Day, P.M.; Thompson, C.D.; Buck, C.B.; Lowy, D.R.; Schiller, J.T. A Cell-Free Assembly System for Generating Infectious Human Papillomavirus 16 Capsids Implicates a Size Discrimination Mechanism for Preferential Viral Genome Packaging. J. Virol. 2016, 90, 1096–1107. [Google Scholar] [CrossRef] [Green Version]
  25. Day, P.M.; Lowy, D.R.; Schiller, J.T. Heparan sulfate-independent cell binding and infection with furin-precleaved papillomavirus capsids. J. Virol. 2008, 82, 12565–12568. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Roberts, J.N.; Buck, C.B.; Thompson, C.D.; Kines, R.; Bernardo, M.; Choyke, P.L.; Lowy, D.R.; Schiller, J.T. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat. Med. 2007, 13, 857–861. [Google Scholar] [CrossRef] [Green Version]
  27. Griffin, L.M.; Cicchini, L.; Pyeon, D. Human papillomavirus infection is inhibited by host autophagy in primary human keratinocytes. Virology 2013, 437, 12–19. [Google Scholar] [CrossRef] [Green Version]
  28. Joyce, J.G.; Tung, J.S.; Przysiecki, C.T.; Cook, J.C.; Lehman, E.D.; Sands, J.A.; Jansen, K.U.; Keller, P.M. The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes. J. Biol. Chem. 1999, 274, 5810–5822. [Google Scholar] [CrossRef] [Green Version]
  29. Giroglou, T.; Florin, L.; Schäfer, F.; Streeck, R.E.; Sapp, M. Human papillomavirus infection requires cell surface heparan sulfate. J. Virol. 2001, 75, 1565–1570. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Knappe, M.; Bodevin, S.; Selinka, H.C.; Spillmann, D.; Streeck, R.E.; Chen, X.S.; Lindahl, U.; Sapp, M. Surface-exposed amino acid residues of HPV16 L1 protein mediating interaction with cell surface heparan sulfate. J. Biol. Chem. 2007, 282, 27913–27922. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Cladel, N.M.; Hu, J.; Balogh, K.; Mejia, A.; Christensen, N.D. Wounding prior to challenge substantially improves infectivity of cottontail rabbit papillomavirus and allows for standardization of infection. J. Virol. Methods 2008, 148, 34–39. [Google Scholar] [CrossRef] [Green Version]
  32. Johnson, K.M.; Kines, R.C.; Roberts, J.N.; Lowy, D.R.; Schiller, J.T.; Day, P.M. Role of heparan sulfate in attachment to and infection of the murine female genital tract by human papillomavirus. J. Virol. 2009, 83, 2067–2074. [Google Scholar] [CrossRef] [Green Version]
  33. Olczyk, P.; Mencner, Ł.; Komosinska-Vassev, K. Diverse Roles of Heparan Sulfate and Heparin in Wound Repair. Biomed. Res. Int. 2015, 2015, 549417. [Google Scholar] [CrossRef] [Green Version]
  34. Richards, R.M.; Lowy, D.R.; Schiller, J.T.; Day, P.M. Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc. Natl. Acad. Sci. USA 2006, 103, 1522–1527. [Google Scholar] [CrossRef] [Green Version]
  35. Kines, R.C.; Thompson, C.D.; Lowy, D.R.; Schiller, J.T.; Day, P.M. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc. Natl. Acad. Sci. USA 2009, 106, 20458–20463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Bartlett, A.H.; Park, P.W. Heparan sulfate proteoglycans in infection. In Glycans in Diseases and Therapeutics; Springer: Berlin/Heidelberg, Germany, 2011; pp. 31–62. [Google Scholar] [CrossRef]
  37. Cagno, V.; Tseligka, E.D.; Jones, S.T.; Tapparel, C. Heparan sulfate proteoglycans and viral attachment: True receptors or adaptation bias? Viruses 2019, 11, 596. [Google Scholar] [CrossRef] [Green Version]
  38. De Pasquale, V.; Quiccione, M.S.; Tafuri, S.; Avallone, L.; Pavone, L.M. Heparan sulfate proteoglycans in viral infection and treatment: A special focus on SARS-CoV-2. Int. J. Mol. Sci. 2021, 22, 6574. [Google Scholar] [CrossRef]
  39. Dechecchi, M.C.; Tamanini, A.; Bonizzato, A.; Cabrini, G. Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions. Virology 2000, 268, 382–390. [Google Scholar] [CrossRef] [Green Version]
  40. Dechecchi, M.C.; Melotti, P.; Bonizzato, A.; Santacatterina, M.; Chilosi, M.; Cabrini, G. Heparan sulfate glycosaminoglycans are receptors sufficient to mediate the initial binding of adenovirus types 2 and 5. J. Virol. 2001, 75, 8772–8780. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Chen, Y.; Maguire, T.; Hileman, R.E.; Fromm, J.R.; Esko, J.D.; Linhardt, R.J.; Marks, R.M. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nat. Med. 1997, 3, 866–871. [Google Scholar] [CrossRef] [PubMed]
  42. Schulze, A.; Gripon, P.; Urban, S. Hepatitis B virus infection initiates with a large surface protein–dependent binding to heparan sulfate proteoglycans. Hepatology 2007, 46, 1759–1768. [Google Scholar] [CrossRef]
  43. Leistner, C.M.; Gruen-Bernhard, S.; Glebe, D. Role of glycosaminoglycans for binding and infection of hepatitis B virus. Cell Microbiol. 2008, 10, 122–133. [Google Scholar] [CrossRef] [PubMed]
  44. Barth, H.; Schafer, C.; Adah, M.I.; Zhang, F.; Linhardt, R.J.; Toyoda, H.; Kinoshita-Toyoda, A.; Toida, T.; Van Kuppevelt, T.H.; Depla, E.; et al. Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. J. Biol. Chem. 2003, 278, 41003–41012. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Barth, H.; Schnober, E.K.; Zhang, F.; Linhardt, R.J.; Depla, E.; Boson, B.; Cosset, F.L.; Patel, A.H.; Blum, H.E.; Baumert, T.F. Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction. J. Virol. 2006, 80, 10579–10590. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Kalia, M.; Chandra, V.; Rahman, S.A.; Sehgal, D.; Jameel, S. Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection. J. Virol. 2009, 83, 12714–12724. [Google Scholar] [CrossRef] [Green Version]
  47. Patel, M.; Yanagishita, M.; Roderiquez, G.; Bou-Habib, D.C.; Oravecz, T.; Hascall, V.C.; Norcross, M.A. Cell-surface heparan sulfate proteoglycan mediates HIV-1 infection of T-cell lines. AIDS Res. Hum. Retrovir. 1993, 9, 167–174. [Google Scholar] [CrossRef]
  48. Tyagi, M.; Rusnati, M.; Presta, M.; Giacca, M. Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. J. Biol. Chem. 2001, 276, 3254–3261. [Google Scholar] [CrossRef] [Green Version]
  49. Vivès, R.R.; Imberty, A.; Sattentau, Q.J.; Lortat-Jacob, H. Heparan sulfate targets the HIV-1 envelope glycoprotein gp120 coreceptor binding site. J. Biol. Chem. 2005, 280, 21353–21357. [Google Scholar] [CrossRef] [Green Version]
  50. Pomin, V.H.; Bezerra, F.F.; Soares, P.A.G. Sulfated Glycans in HIV Infection and Therapy. Curr. Pharm. Des. 2017, 23, 3405–3414. [Google Scholar] [CrossRef]
  51. Compton, T.; Nowlin, D.M.; Cooper, N.R. Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology 1993, 193, 834–841. [Google Scholar] [CrossRef]
  52. Boyle, K.A.; Compton, T. Receptor-binding properties of a soluble form of human cytomegalovirus glycoprotein B. J. Virol. 1998, 72, 1826–1833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Mitra, D.; Hasan, M.H.; Bates, J.T.; Bierdeman, M.A.; Ederer, D.R.; Parmar, R.C.; Fassero, L.A.; Liang, Q.; Qiu, H.; Tiwari, V.; et al. The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus entry into host cells. PLoS Pathog. 2021, 17, e1009803. [Google Scholar] [CrossRef] [PubMed]
  54. WuDunn, D.; Spear, P.G. Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J. Virol. 1989, 63, 52–58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Shieh, M.T.; WuDunn, D.; Montgomery, R.I.; Esko, J.D.; Spear, P.G. Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J. Cell Biol. 1992, 116, 1273–1281. [Google Scholar] [CrossRef]
  56. Tal-Singer, R.; Peng, C.; Ponce De Leon, M.; Abrams, W.R.; Banfield, B.W.; Tufaro, F.; Cohen, G.H.; Eisenberg, R.J. Interaction of herpes simplex virus glycoprotein gC with mammalian cell surface molecules. J. Virol. 1995, 69, 4471–4483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Feyzi, E.; Trybala, E.; Bergström, T.; Lindahl, U.; Spillmann, D. Structural requirement of heparan sulfate for interaction with herpes simplex virus type 1 virions and isolated glycoprotein C. J. Biol. Chem. 1997, 272, 24850–24857. [Google Scholar] [CrossRef] [Green Version]
  58. Shukla, D.; Liu, J.; Blaiklock, P.; Shworak, N.W.; Bai, X.; Esko, J.D.; Cohen, G.H.; Eisenberg, R.J.; Rosenberg, R.D.; Spear, P.G. A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry. Cell 1999, 99, 13–22. [Google Scholar] [CrossRef] [Green Version]
  59. Shukla, D.; Spear, P.G. Herpesviruses and heparan sulfate: An intimate relationship in aid of viral entry. J. Clin. Investig. 2001, 108, 503–510. [Google Scholar] [CrossRef]
  60. Williams, R.K.; Straus, S.E. Specificity and affinity of binding of herpes simplex virus type 2 glycoprotein B to glycosaminoglycans. J. Virol. 1997, 71, 1375–1380. [Google Scholar] [CrossRef] [Green Version]
  61. Gerber, S.I.; Belval, B.J.; Herold, B.C. Differences in the role of glycoprotein C of HSV-1 and HSV-2 in viral binding may contribute to serotype differences in cell tropism. Virology 1995, 214, 29–39. [Google Scholar] [CrossRef] [Green Version]
  62. Schowalter, R.M.; Pastrana, D.V.; Buck, C.B. Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry. PLoS Pathog. 2011, 7, e1002161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Bayer, N.J.; Januliene, D.; Zocher, G.; Stehle, T.; Moeller, A.; Blaum, B.S. Structure of merkel cell polyomavirus capsid and interaction with its glycosaminoglycan attachment receptor. J. Virol. 2020, 94, e01664-19. [Google Scholar] [CrossRef]
  64. Clausen, T.M.; Sandoval, D.R.; Spliid, C.B.; Pihl, J.; Perrett, H.R.; Painter, C.D.; Narayanan, A.; Majowicz, S.A.; Kwong, E.M.; McVicar, R.N.; et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell 2020, 183, 1043–1057.e1015. [Google Scholar] [CrossRef]
  65. Liu, L.; Chopra, P.; Li, X.; Bouwman, K.M.; Tompkins, S.M.; Wolfert, M.A.; de Vries, R.P.; Boons, G.-J. Heparan sulfate proteoglycans as attachment factor for SARS-CoV-2. ACS Cent. Sci. 2021, 7, 1009–1018. [Google Scholar] [CrossRef]
  66. Jacquet, A.; Haumont, M.; Chellun, D.; Massaer, M.; Tufaro, F.; Bollen, A.; Jacobs, P. The varicella zoster virus glycoprotein B (gB) plays a role in virus binding to cell surface heparan sulfate proteoglycans. Virus Res. 1998, 53, 197–207. [Google Scholar] [CrossRef]
  67. Weiland, M.E.; Palm, J.E.; Griffiths, W.J.; McCaffery, J.M.; Svärd, S.G. Characterisation of alpha-1 giardin: An immunodominant Giardia lamblia annexin with glycosaminoglycan-binding activity. Int. J. Parasitol. 2003, 33, 1341–1351. [Google Scholar] [CrossRef]
  68. Frevert, U.; Sinnis, P.; Cerami, C.; Shreffler, W.; Takacs, B.; Nussenzweig, V. Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes. J. Exp. Med. 1993, 177, 1287–1298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Fried, M.; Duffy, P.E. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 1996, 272, 1502–1504. [Google Scholar] [CrossRef] [PubMed]
  70. Kobayashi, K.; Kato, K.; Sugi, T.; Takemae, H.; Pandey, K.; Gong, H.; Tohya, Y.; Akashi, H. Plasmodium falciparum BAEBL binds to heparan sulfate proteoglycans on the human erythrocyte surface. J. Biol. Chem. 2010, 285, 1716–1725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Ortega-Barria, E.; Boothroyd, J.C. A Toxoplasma lectin-like activity specific for sulfated polysaccharides is involved in host cell infection. J. Biol. Chem. 1999, 274, 1267–1276. [Google Scholar] [CrossRef] [Green Version]
  72. Carruthers, V.B.; Håkansson, S.; Giddings, O.K.; Sibley, L.D. Toxoplasma gondii uses sulfated proteoglycans for substrate and host cell attachment. Infect. Immun. 2000, 68, 4005–4011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Jacquet, A.; Coulon, L.; De Nève, J.; Daminet, V.; Haumont, M.; Garcia, L.; Bollen, A.; Jurado, M.; Biemans, R. The surface antigen SAG3 mediates the attachment of Toxoplasma gondii to cell-surface proteoglycans. Mol. Biochem. Parasitol. 2001, 116, 35–44. [Google Scholar] [CrossRef]
  74. Azzouz, N.; Kamena, F.; Laurino, P.; Kikkeri, R.; Mercier, C.; Cesbron-Delauw, M.-F.; Dubremetz, J.-F.; De Cola, L.; Seeberger, P.H. Toxoplasma gondii secretory proteins bind to sulfated heparin structures. Glycobiology 2012, 23, 106–120. [Google Scholar] [CrossRef] [Green Version]
  75. Ortega-Barria, E.; Pereira, M.E. A novel T. cruzi heparin-binding protein promotes fibroblast adhesion and penetration of engineered bacteria and trypanosomes into mammalian cells. Cell 1991, 67, 411–421. [Google Scholar] [CrossRef]
  76. Oliveira, F.O., Jr.; Alves, C.R.; Calvet, C.M.; Toma, L.; Bouças, R.I.; Nader, H.B.; Castro Côrtes, L.M.; Krieger, M.A.; Meirelles Mde, N.; Souza Pereira, M.C. Trypanosoma cruzi heparin-binding proteins and the nature of the host cell heparan sulfate-binding domain. Microb. Pathog. 2008, 44, 329–338. [Google Scholar] [CrossRef] [PubMed]
  77. Bambino-Medeiros, R.; Oliveira, F.O.; Calvet, C.M.; Vicente, D.; Toma, L.; Krieger, M.A.; Meirelles, M.N.; Pereira, M.C. Involvement of host cell heparan sulfate proteoglycan in Trypanosoma cruzi amastigote attachment and invasion. Parasitology 2011, 138, 593–601. [Google Scholar] [CrossRef] [PubMed]
  78. Hannah, J.H.; Menozzi, F.D.; Renauld, G.; Locht, C.; Brennan, M.J. Sulfated glycoconjugate receptors for the Bordetella pertussis adhesin filamentous hemagglutinin (FHA) and mapping of the heparin-binding domain on FHA. Infect. Immun. 1994, 62, 5010–5019. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Utt, M.; Wadström, T. Identification of heparan sulphate binding surface proteins of Helicobacter pylori: Inhibition of heparan sulphate binding with sulphated carbohydrate polymers. J. Med. Microbiol. 1997, 46, 541–546. [Google Scholar] [CrossRef]
  80. Utt, M.; Danielsson, B.; Wadström, T. Helicobacter pylori vacuolating cytotoxin binding to a putative cell surface receptor, heparan sulfate, studied by surface plasmon resonance. FEMS Immunol. Med. Microbiol. 2001, 30, 109–113. [Google Scholar] [CrossRef]
  81. Alvarez-Domínguez, C.; Vázquez-Boland, J.A.; Carrasco-Marín, E.; López-Mato, P.; Leyva-Cobián, F. Host cell heparan sulfate proteoglycans mediate attachment and entry of Listeria monocytogenes, and the listerial surface protein ActA is involved in heparan sulfate receptor recognition. Infect. Immun. 1997, 65, 78–88. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Menozzi, F.D.; Rouse, J.H.; Alavi, M.; Laude-Sharp, M.; Muller, J.; Bischoff, R.; Brennan, M.J.; Locht, C. Identification of a heparin-binding hemagglutinin present in mycobacteria. J. Exp. Med. 1996, 184, 993–1001. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Chen, T.; Belland, R.J.; Wilson, J.; Swanson, J. Adherence of pilus- Opa+ gonococci to epithelial cells in vitro involves heparan sulfate. J. Exp. Med. 1995, 182, 511–517. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. van Putten, J.P.; Paul, S.M. Binding of syndecan-like cell surface proteoglycan receptors is required for Neisseria gonorrhoeae entry into human mucosal cells. EMBO J. 1995, 14, 2144–2154. [Google Scholar] [CrossRef]
  85. Klotz, S.A.; Smith, R.L. Glycosaminoglycans inhibit Candida albicans adherence to extracellular matrix proteins. FEMS Microbiol. Lett. 1992, 78, 205–208. [Google Scholar] [CrossRef]
  86. Hoffman, M.P.; Haidaris, C.G. Identification and characterization of a Candida albicans-binding proteoglycan secreted from rat submandibular salivary glands. Infect. Immun. 1994, 62, 828–836. [Google Scholar] [CrossRef] [Green Version]
  87. Ordiales, H.; Vázquez-López, F.; Pevida, M.; Vázquez-Losada, B.; Vázquez, F.; Quirós, L.M.; Martín, C. Glycosaminoglycans are involved in the adhesion of Candida albicans and Malassezia species to keratinocytes but not to dermal fibroblasts. Actas Dermo-Sifiliográficas 2021, 112, 619–624. [Google Scholar] [CrossRef]
  88. Caughey, B.; Raymond, G.J. Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. J. Virol. 1993, 67, 643–650. [Google Scholar] [CrossRef] [Green Version]
  89. Hundt, C.; Peyrin, J.M.; Haïk, S.; Gauczynski, S.; Leucht, C.; Rieger, R.; Riley, M.L.; Deslys, J.P.; Dormont, D.; Lasmézas, C.I.; et al. Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptor. EMBO J. 2001, 20, 5876–5886. [Google Scholar] [CrossRef]
  90. Wong, C.; Xiong, L.W.; Horiuchi, M.; Raymond, L.; Wehrly, K.; Chesebro, B.; Caughey, B. Sulfated glycans and elevated temperature stimulate PrP(Sc)-dependent cell-free formation of protease-resistant prion protein. EMBO J. 2001, 20, 377–386. [Google Scholar] [CrossRef] [Green Version]
  91. Ben-Zaken, O.; Tzaban, S.; Tal, Y.; Horonchik, L.; Esko, J.D.; Vlodavsky, I.; Taraboulos, A. Cellular heparan sulfate participates in the metabolism of prions. J. Biol. Chem. 2003, 278, 40041–40049. [Google Scholar] [CrossRef] [Green Version]
  92. Bishop, J.R.; Schuksz, M.; Esko, J.D. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 2007, 446, 1030–1037. [Google Scholar] [CrossRef]
  93. Sarrazin, S.; Lamanna, W.C.; Esko, J.D. Heparan sulfate proteoglycans. In Cold Spring Harb Perspect Biol; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, USA, 2011; Volume 3, p. a004952. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Merry, C.L.R.; Lindahl, U.; Couchman, J.; Esko, J.D. Proteoglycans and sulfated glycosaminoglycans. In Essentials of Glycobiology; Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Mohnen, D., Kinoshita, T., Packer, N.H., Prestegard, J.H., et al., Eds.; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, USA, 2022; pp. 217–232. [Google Scholar]
  95. Kaltenbach, D.D.; Jaishankar, D.; Hao, M.; Beer, J.C.; Volin, M.V.; Desai, U.R.; Tiwari, V. Sulfotransferase and Heparanase: Remodeling engines in promoting virus infection and disease development. Front. Pharmacol. 2018, 9, 1315. [Google Scholar] [CrossRef] [Green Version]
  96. De Pasquale, V.; Pavone, L.M. Heparan sulfate proteoglycans: The sweet side of development turns sour in mucopolysaccharidoses. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 165539. [Google Scholar] [CrossRef]
  97. Fons, N.R.; Kines, R.C.; Thompson, C.D.; Day, P.M.; Lowy, D.R.; Schiller, J.T. Chondroitin sulfate proteoglycans are de facto cellular receptors for human papillomavirus 16 under high serum conditions. J. Virol. 2022, 96, e0185721. [Google Scholar] [CrossRef]
  98. Fuster, M.M.; Esko, J.D. The sweet and sour of cancer: Glycans as novel therapeutic targets. Nat. Rev. Cancer 2005, 5, 526–542. [Google Scholar] [CrossRef] [PubMed]
  99. Hammond, E.; Khurana, A.; Shridhar, V.; Dredge, K. The role of heparanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumor microenvironment and opportunities for novel cancer therapeutics. Front. Oncol. 2014, 4, 195. [Google Scholar] [CrossRef]
  100. Nagarajan, A.; Malvi, P.; Wajapeyee, N. Heparan sulfate and heparan sulfate proteoglycans in cancer initiation and progression. Front. Endocrinol. 2018, 9, 483. [Google Scholar] [CrossRef]
  101. Jayson, G.C.; Lyon, M.; Paraskeva, C.; Turnbull, J.E.; Deakin, J.A.; Gallagher, J.T. Heparan sulfate undergoes specific structural changes during the progression from human colon adenoma to carcinoma in vitro. J. Biol. Chem. 1998, 273, 51–57. [Google Scholar] [CrossRef] [Green Version]
  102. Weyers, A.; Yang, B.; Yoon, D.S.; Park, J.H.; Zhang, F.; Lee, K.B.; Linhardt, R.J. A structural analysis of glycosaminoglycans from lethal and nonlethal breast cancer tissues: Toward a novel class of theragnostics for personalized medicine in oncology? Omics 2012, 16, 79–89. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Fernández-Vega, I.; García, O.; Crespo, A.; Castañón, S.; Menéndez, P.; Astudillo, A.; Quirós, L.M. Specific genes involved in synthesis and editing of heparan sulfate proteoglycans show altered expression patterns in breast cancer. BMC Cancer 2013, 13, 24. [Google Scholar] [CrossRef] [Green Version]
  104. Fernández-Vega, I.; García-Suárez, O.; García, B.; Crespo, A.; Astudillo, A.; Quirós, L.M. Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character. BMC Cancer 2015, 15, 742. [Google Scholar] [CrossRef] [Green Version]
  105. Suhovskih, A.V.; Domanitskaya, N.V.; Tsidulko, A.Y.; Prudnikova, T.Y.; Kashuba, V.I.; Grigorieva, E.V. Tissue-specificity of heparan sulfate biosynthetic machinery in cancer. Cell Adh. Migr. 2015, 9, 452–459. [Google Scholar] [CrossRef] [Green Version]
  106. Rangel, M.P.; de Sá, V.K.; Prieto, T.; Martins, J.R.M.; Olivieri, E.R.; Carraro, D.; Takagaki, T.; Capelozzi, V.L. Biomolecular analysis of matrix proteoglycans as biomarkers in non small cell lung cancer. Glycoconj. J. 2018, 35, 233–242. [Google Scholar] [CrossRef]
  107. Denys, A.; Allain, F. The emerging roles of heparan sulfate 3-O-sulfotransferases in cancer. Front. Oncol. 2019, 9, 507. [Google Scholar] [CrossRef] [Green Version]
  108. Elgundi, Z.; Papanicolaou, M.; Major, G.; Cox, T.R.; Melrose, J.; Whitelock, J.M.; Farrugia, B.L. Cancer Metastasis: The role of the extracellular matrix and the heparan sulfate proteoglycan perlecan. Front. Oncol. 2020, 9, 1482. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Marques, C.; Reis, C.A.; Vivès, R.R.; Magalhães, A. Heparan sulfate biosynthesis and sulfation profiles as modulators of cancer signalling and progression. Front. Oncol. 2021, 11, 778752. [Google Scholar] [CrossRef]
  110. Vlodavsky, I.; Friedmann, Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J. Clin. Investig. 2001, 108, 341–347. [Google Scholar] [CrossRef]
  111. Ramani, V.C.; Purushothaman, A.; Stewart, M.D.; Thompson, C.A.; Vlodavsky, I.; Au, J.L.; Sanderson, R.D. The heparanase/syndecan-1 axis in cancer: Mechanisms and therapies. FEBS J. 2013, 280, 2294–2306. [Google Scholar] [CrossRef] [Green Version]
  112. Masola, V.; Zaza, G.; Secchi, M.F.; Gambaro, G.; Lupo, A.; Onisto, M. Heparanase is a key player in renal fibrosis by regulating TGF-β expression and activity. Biochim. Biophys. Acta 2014, 1843, 2122–2128. [Google Scholar] [CrossRef] [PubMed]
  113. Secchi, M.F.; Masola, V.; Zaza, G.; Lupo, A.; Gambaro, G.; Onisto, M. Recent data concerning heparanase: Focus on fibrosis, inflammation and cancer. Biomol. Concepts 2015, 6, 415–421. [Google Scholar] [CrossRef]
  114. Esko, J.D.; Rostand, K.S.; Weinke, J.L. Tumor Formation Dependent on Proteoglycan Biosynthesis. Science 1988, 241, 1092–1096. [Google Scholar] [CrossRef]
  115. Liu, D.; Shriver, Z.; Venkataraman, G.; Shabrawi, Y.E.; Sasisekharan, R. Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis. Proc. Nat. Acad. Sci. USA 2002, 99, 568–573. [Google Scholar] [CrossRef] [Green Version]
  116. Liu, X.; Zhou, Z.-H.; Li, W.; Zhang, S.-K.; Li, J.; Zhou, M.-J.; Song, J.-W. Heparanase promotes tumor growth and liver metastasis of colorectal cancer cells by activating the p38/MMP1 axis. Front. Oncol. 2019, 9, 216. [Google Scholar] [CrossRef]
  117. Wang, X.; Zuo, D.; Chen, Y.; Li, W.; Liu, R.; He, Y.; Ren, L.; Zhou, L.; Deng, T.; Wang, X.; et al. Shed Syndecan-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer. Br. J. Cancer 2014, 111, 1965–1976. [Google Scholar] [CrossRef]
  118. Olah, C.; Tschirdewahn, S.; Hoffmann, M.J.; Krafft, U.; Hadaschik, B.; Nyirady, P.; Szendröi, A.; Módos, O.; Csizmarik, A.; Kovalszky, I.; et al. Soluble syndecan-1 levels are associated with survival in platinum-treated bladder cancer patients. Diagnostics 2020, 10, 864. [Google Scholar] [CrossRef]
  119. Rangarajan, S.; Richter, J.R.; Richter, R.P.; Bandari, S.K.; Tripathi, K.; Vlodavsky, I.; Sanderson, R.D. Heparanase-enhanced shedding of syndecan-1 and its role in driving disease pathogenesis and progression. J. Histochem. Cytochem. 2020, 68, 823–840. [Google Scholar] [CrossRef]
  120. Czarnowski, D. Syndecans in cancer: A review of function, expression, prognostic value, and therapeutic significance. Cancer Treat. Res. Commun. 2021, 27, 100312. [Google Scholar] [CrossRef]
  121. Hilgers, K.; Ibrahim, S.A.; Kiesel, L.; Greve, B.; Espinoza-Sánchez, N.A.; Götte, M. Differential impact of membrane-bound and soluble forms of the prognostic marker syndecan-1 on the invasiveness, migration, apoptosis, and proliferation of cervical cancer cells. Front. Oncol. 2022, 12, 803899. [Google Scholar] [CrossRef] [PubMed]
  122. Kalscheuer, S.; Khanna, V.; Kim, H.; Li, S.; Sachdev, D.; DeCarlo, A.; Yang, D.; Panyam, J. Discovery of HSPG2 (perlecan) as a therapeutic target in triple negative breast cancer. Sci. Rep. 2019, 9, 12492. [Google Scholar] [CrossRef]
  123. Folkman, J.; Langer, R.; Linhardt, R.J.; Haudenschild, C.; Taylor, S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 1983, 221, 719–725. [Google Scholar] [CrossRef] [PubMed]
  124. Askari Rizvi, S.F.; Zhang, H. Emerging trends of receptor-mediated tumor targeting peptides: A review with perspective from molecular imaging modalities. Eur. J. Med. Chem. 2021, 221, 113538. [Google Scholar] [CrossRef]
  125. Berdiaki, A.; Neagu, M.; Giatagana, E.-M.; Kuskov, A.; Tsatsakis, A.M.; Tzanakakis, G.N.; Nikitovic, D. Glycosaminoglycans: Carriers and targets for tailored anti-cancer therapy. Biomolecules 2021, 11, 395. [Google Scholar] [CrossRef]
  126. Bloise, N.; Okkeh, M.; Restivo, E.; Della Pina, C.; Visai, L. Targeting the “Sweet Side” of tumor with glycan-binding molecules conjugated-nanoparticles: Implications in cancer therapy and diagnosis. Nanomaterials 2021, 11, 289. [Google Scholar] [CrossRef] [PubMed]
  127. McKee, T.D.; Grandi, P.; Mok, W.; Alexandrakis, G.; Insin, N.; Zimmer, J.P.; Bawendi, M.G.; Boucher, Y.; Breakefield, X.O.; Jain, R.K. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 2006, 66, 2509–2513. [Google Scholar] [CrossRef] [Green Version]
  128. Farrera-Sal, M.; Moreno, R.; Mato-Berciano, A.; Maliandi, M.V.; Bazan-Peregrino, M.; Alemany, R. Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation. Mol. Ther. Oncolytics 2021, 22, 27–35. [Google Scholar] [CrossRef]
  129. Gao, W.; Tang, Z.; Zhang, Y.F.; Feng, M.; Qian, M.; Dimitrov, D.S.; Ho, M. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat. Commun. 2015, 6, 6536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  130. Wang, C.; Gao, W.; Feng, M.; Pastan, I.; Ho, M. Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy. Oncotarget 2017, 8, 32450–32460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Zhu, A.X.; Gold, P.J.; El-Khoueiry, A.B.; Abrams, T.A.; Morikawa, H.; Ohishi, N.; Ohtomo, T.; Philip, P.A. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 2013, 19, 920–928. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Abou-Alfa, G.K.; Puig, O.; Daniele, B.; Kudo, M.; Merle, P.; Park, J.W.; Ross, P.; Peron, J.M.; Ebert, O.; Chan, S.; et al. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J. Hepatol. 2016, 65, 289–295. [Google Scholar] [CrossRef]
  133. Zhang, Y.-F.; Ho, M. Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma. Sci. Rep. 2016, 6, 33878. [Google Scholar] [CrossRef] [Green Version]
  134. Fu, Y.; Urban, D.J.; Nani, R.R.; Zhang, Y.-F.; Li, N.; Fu, H.; Shah, H.; Gorka, A.P.; Guha, R.; Chen, L.; et al. Glypican-3-Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma. Hepatology 2019, 70, 563–576. [Google Scholar] [CrossRef]
  135. Hanaoka, H.; Nagaya, T.; Sato, K.; Nakamura, Y.; Watanabe, R.; Harada, T.; Gao, W.; Feng, M.; Phung, Y.; Kim, I.; et al. Glypican-3 targeted human heavy chain antibody as a drug carrier for hepatocellular carcinoma therapy. Mol. Pharm. 2015, 12, 2151–2157. [Google Scholar] [CrossRef]
  136. Liu, X.; Gao, F.; Jiang, L.; Jia, M.; Ao, L.; Lu, M.; Gou, L.; Ho, M.; Jia, S.; Chen, F.; et al. 32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma. J. Transl. Med. 2020, 18, 295. [Google Scholar] [CrossRef]
  137. Ishiguro, T.; Sano, Y.; Komatsu, S.I.; Kamata-Sakurai, M.; Kaneko, A.; Kinoshita, Y.; Shiraiwa, H.; Azuma, Y.; Tsunenari, T.; Kayukawa, Y.; et al. An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors. Sci. Transl. Med. 2017, 9, eaal4291. [Google Scholar] [CrossRef] [Green Version]
  138. Pan, J.; Li, N.; Renn, A.; Zhu, H.; Chen, L.; Shen, M.; Hall, M.D.; Qian, M.; Pastan, I.; Ho, M. GPC1-targeted immunotoxins inhibit pancreatic tumor growth in mice via depletion of short-lived GPC1 and downregulation of Wnt signaling. Mol. Can. Ther. 2022, 21, 960–973. [Google Scholar] [CrossRef] [PubMed]
  139. Li, N.; Fu, H.; Hewitt, S.M.; Dimitrov, D.S.; Ho, M. Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma. Proc. Nat. Acad. Sci. USA 2017, 114, E6623–E6631. [Google Scholar] [CrossRef] [Green Version]
  140. Gao, H.; Li, K.; Tu, H.; Pan, X.; Jiang, H.; Shi, B.; Kong, J.; Wang, H.; Yang, S.; Gu, J.; et al. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res 2014, 20, 6418–6428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Jiang, Z.; Jiang, X.; Chen, S.; Lai, Y.; Wei, X.; Li, B.; Lin, S.; Wang, S.; Wu, Q.; Liang, Q.; et al. Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front. Immunol. 2017, 7, 690. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Li, D.; Li, N.; Zhang, Y.F.; Fu, H.; Feng, M.; Schneider, D.; Su, L.; Wu, X.; Zhou, J.; Mackay, S.; et al. Persistent polyfunctional chimeric antigen receptor T cells that target glypican 3 eliminate orthotopic hepatocellular carcinomas in mice. Gastroenterology 2020, 158, 2250–2265.e2220. [Google Scholar] [CrossRef]
  143. Shi, D.; Shi, Y.; Kaseb, A.O.; Qi, X.; Zhang, Y.; Chi, J.; Lu, Q.; Gao, H.; Jiang, H.; Wang, H.; et al. Chimeric antigen receptor-glypican-3 T-Cell therapy for advanced hepatocellular carcinoma: Results of phase I trials. Clin. Cancer Res. 2020, 26, 3979–3989. [Google Scholar] [CrossRef]
  144. Elson-Schwab, L.; Garner, O.B.; Schuksz, M.; Crawford, B.E.; Esko, J.D.; Tor, Y. Guanidinylated neomycin delivers large, bioactive cargo into cells through a heparan sulfate-dependent pathway. J. Biol. Chem. 2007, 282, 13585–13591. [Google Scholar] [CrossRef] [Green Version]
  145. Rapraeger, A.C.; Ell, B.J.; Roy, M.; Li, X.; Morrison, O.R.; Thomas, G.M.; Beauvais, D.M. Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between αVβ3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis. FEBS J. 2013, 280, 2194–2206. [Google Scholar] [CrossRef] [Green Version]
  146. Melo, C.M.; Wang, H.; Fujimura, K.; Strnadel, J.; Meneghetti, M.C.Z.; Nader, H.B.; Klemke, R.L.; Pinhal, M.A.S. The heparan sulfate binding peptide in tumor progression of triple-negative breast cancer. Front. Oncol. 2021, 11, 697626. [Google Scholar] [CrossRef]
  147. Brunetti, J.; Pillozzi, S.; Falciani, C.; Depau, L.; Tenori, E.; Scali, S.; Lozzi, L.; Pini, A.; Arcangeli, A.; Menichetti, S.; et al. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug. Sci. Rep. 2015, 5, 17736. [Google Scholar] [CrossRef]
  148. Brunetti, J.; Depau, L.; Falciani, C.; Gentile, M.; Mandarini, E.; Riolo, G.; Lupetti, P.; Pini, A.; Bracci, L. Insights into the role of sulfated glycans in cancer cell adhesion and migration through use of branched peptide probe. Sci. Rep. 2016, 6, 27174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Brunetti, J.; Riolo, G.; Depau, L.; Mandarini, E.; Bernini, A.; Karousou, E.; Passi, A.; Pini, A.; Bracci, L.; Falciani, C. Unraveling heparan sulfate proteoglycan binding motif for cancer cell selectivity. Front. Oncol. 2019, 9, 843. [Google Scholar] [CrossRef]
  150. Zheng, X.; Gai, X.; Han, S.; Moser, C.D.; Hu, C.; Shire, A.M.; Floyd, R.A.; Roberts, L.R. The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer 2013, 52, 225–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Hossain, M.M.; Hosono-Fukao, T.; Tang, R.; Sugaya, N.; van Kuppevelt, T.H.; Jenniskens, G.J.; Kimata, K.; Rosen, S.D.; Uchimura, K. Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology 2010, 20, 175–186. [Google Scholar] [CrossRef] [Green Version]
  152. Chen, P.J.; Lee, P.H.; Han, K.H.; Fan, J.; Cheung, T.T.; Hu, R.H.; Paik, S.W.; Lee, W.C.; Chau, G.Y.; Jeng, L.B.; et al. A phase III trial of muparfostat (PI-88) as adjuvant therapy in patients with hepatitis virus related hepatocellular carcinoma (HV-HCC) after resection. Ann. Oncol. 2017, 28, v213. [Google Scholar] [CrossRef]
  153. Marchetti, D.; Reiland, J.; Erwin, B.; Roy, M. Inhibition of heparanase activity and heparanase-induced angiogenesis by suramin analogues. Int. J. Cancer 2003, 104, 167–174. [Google Scholar] [CrossRef] [PubMed]
  154. Dredge, K.; Hammond, E.; Davis, K.; Li, C.P.; Liu, L.; Johnstone, K.; Handley, P.; Wimmer, N.; Gonda, T.J.; Gautam, A.; et al. The PG500 series: Novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy. Investig. New Drugs 2010, 28, 276–283. [Google Scholar] [CrossRef] [Green Version]
  155. Dredge, K.; Hammond, E.; Handley, P.; Gonda, T.J.; Smith, M.T.; Vincent, C.; Brandt, R.; Ferro, V.; Bytheway, I. PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. Br. J. Cancer 2011, 104, 635–642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Hammond, E.; Handley, P.; Dredge, K.; Bytheway, I. Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues. FEBS Open Bio. 2013, 3, 346–351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Zhou, H.; Roy, S.; Cochran, E.; Zouaoui, R.; Chu, C.L.; Duffner, J.; Zhao, G.; Smith, S.; Galcheva-Gargova, Z.; Karlgren, J.; et al. M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis. PLoS ONE 2011, 6, e21106. [Google Scholar] [CrossRef] [Green Version]
  158. Ritchie, J.P.; Ramani, V.C.; Ren, Y.; Naggi, A.; Torri, G.; Casu, B.; Penco, S.; Pisano, C.; Carminati, P.; Tortoreto, M.; et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin. Cancer Res. 2011, 17, 1382–1393. [Google Scholar] [CrossRef] [Green Version]
  159. Raman, K.; Ninomiya, M.; Nguyen, T.K.N.; Tsuzuki, Y.; Koketsu, M.; Kuberan, B. Novel glycosaminoglycan biosynthetic inhibitors affect tumor-associated angiogenesis. Biochem. Biophys. Res. Commun. 2011, 404, 86–89. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Chua, J.S.; Kuberan, B. Synthetic Xylosides: Probing the glycosaminoglycan biosynthetic machinery for biomedical applications. Acc. Chem. Res. 2017, 50, 2693–2705. [Google Scholar] [CrossRef]
  161. Ranki, T.; Kanerva, A.; Ristimäki, A.; Hakkarainen, T.; Särkioja, M.; Kangasniemi, L.; Raki, M.; Laakkonen, P.; Goodison, S.; Hemminki, A. A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer. Gene Ther. 2007, 14, 58–67. [Google Scholar] [CrossRef] [Green Version]
  162. Yu, T.; Li, Y.; Gu, X.; Li, Q. Development of a hyaluronic acid-based nanocarrier incorporating doxorubicin and cisplatin as a pH-sensitive and CD44-targeted anti-breast cancer drug delivery system. Front. Pharmacol. 2020, 11, 532457. [Google Scholar] [CrossRef]
  163. Salanti, A.; Clausen, T.M.; Agerbæk, M.; Al Nakouzi, N.; Dahlbäck, M.; Oo, H.Z.; Lee, S.; Gustavsson, T.; Rich, J.R.; Hedberg, B.J.; et al. Targeting human cancer by a glycosaminoglycan binding malaria protein. Cancer Cell 2015, 28, 500–514. [Google Scholar] [CrossRef] [Green Version]
  164. Seiler, R.; Oo, H.Z.; Tortora, D.; Clausen, T.M.; Wang, C.K.; Kumar, G.; Pereira, M.A.; Ørum-Madsen, M.S.; Agerbæk, M.; Gustavsson, T.; et al. An oncofetal glycosaminoglycan modification provides therapeutic access to cisplatin-resistant bladder cancer. Eur. Urol. 2017, 72, 142–150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Feng, S.; Zhou, J.; Li, Z.; Appelman, H.D.; Zhao, L.; Zhu, J.; Wang, T.D. Sorafenib encapsulated in nanocarrier functionalized with glypican-3 specific peptide for targeted therapy of hepatocellular carcinoma. Colloids Surf. B Biointerfaces 2019, 184, 110498. [Google Scholar] [CrossRef] [PubMed]
  166. Kuo, P.H.; Teng, Y.H.; Cin, A.L.; Han, W.; Huang, P.W.; Wang, L.H.; Chou, Y.T.; Yang, J.L.; Tseng, Y.L.; Kao, M.; et al. Heparan sulfate targeting strategy for enhancing liposomal drug accumulation and facilitating deep distribution in tumors. Drug Deliv. 2020, 27, 542–555. [Google Scholar] [CrossRef]
  167. Park, J.O.; Stephen, Z.; Sun, C.; Veiseh, O.; Kievit, F.M.; Fang, C.; Leung, M.; Mok, H.; Zhang, M. Glypican-3 targeting of liver cancer cells using multifunctional nanoparticles. Mol. Imaging 2011, 10, 69–77. [Google Scholar] [CrossRef] [PubMed]
  168. Chen, C.-J.; Tsai, K.-C.; Kuo, P.-H.; Chang, P.-L.; Wang, W.-C.; Chuang, Y.-J.; Chang, M.D.-T. A heparan sulfate-binding cell penetrating peptide for tumor targeting and migration inhibition. Biomed. Res. Int. 2015, 2015, 237969. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Huang, X.; Fan, C.; Zhu, H.; Le, W.; Cui, S.; Chen, X.; Li, W.; Zhang, F.; Huang, Y.; Sh, D.; et al. Glypican-1-antibody-conjugated Gd-Au nanoclusters for FI/MRI dual-modal targeted detection of pancreatic cancer. Int. J. Nanomed. 2018, 13, 2585–2599. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Qiu, W.; Zhang, H.; Chen, X.; Song, L.; Cui, W.; Ren, S.; Wang, Y.; Guo, K.; Li, D.; Chen, R.; et al. A GPC1-targeted and gemcitabine-loaded biocompatible nanoplatform for pancreatic cancer multimodal imaging and therapy. Nanomedicine 2019, 14, 2339–2353. [Google Scholar] [CrossRef]
  171. Kines, R.C.; Cerio, R.J.; Roberts, J.N.; Thompson, C.D.; de Los Pinos, E.; Lowy, D.R.; Schiller, J.T. Human papillomavirus capsids preferentially bind and infect tumor cells. Int. J. Cancer 2016, 138, 901–911. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  172. Hung, C.-F.; Chiang, A.J.; Tsai, H.-H.; Pomper, M.G.; Kang, T.H.; Roden, R.R.; Wu, T.C. Ovarian cancer gene therapy using HPV-16 pseudovirion carrying the HSV-TK gene. PLoS ONE 2012, 7, e40983. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Hojeij, R.; Domingos-Pereira, S.; Nkosi, M.; Gharbi, D.; Derré, L.; Schiller, J.T.; Jichlinski, P.; Nardelli-Haefliger, D. Immunogenic human papillomavirus pseudovirus-mediated suicide-gene therapy for bladder cancer. Int. J. Mol. Sci. 2016, 17, 1125. [Google Scholar] [CrossRef] [PubMed]
  174. Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986, 46, 6387–6392. [Google Scholar] [PubMed]
  175. Tang, L.; Yang, X.; Yin, Q.; Cai, K.; Wang, H.; Chaudhury, I.; Yao, C.; Zhou, Q.; Kwon, M.; Hartman, J.A.; et al. Investigating the optimal size of anticancer nanomedicine. Proc. Nat. Acad. Sci. USA 2014, 111, 15344–15349. [Google Scholar] [CrossRef] [Green Version]
  176. Mitsunaga, M.; Ogawa, M.; Kosaka, N.; Rosenblum, L.T.; Choyke, P.L.; Kobayashi, H. Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat. Med. 2011, 17, 1685–1691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Kines, R.C.; Varsavsky, I.; Choudhary, S.; Bhattacharya, D.; Spring, S.; McLaughlin, R.; Kang, S.J.; Grossniklaus, H.E.; Vavvas, D.; Monks, S.; et al. An infrared dye-conjugated virus-like particle for the treatment of primary uveal melanoma. Mol. Cancer Ther. 2018, 17, 565–574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Kines, R.C.; Thompson, C.D.; Spring, S.; Li, Z.; de Los Pinos, E.; Monks, S.; Schiller, J.T. Virus-like particle-drug conjugates induce protective, long-lasting adaptive antitumor immunity in the absence of specifically targeted tumor antigens. Cancer Immunol. Res. 2021, 9, 693–706. [Google Scholar] [CrossRef]
  179. Lenz, P.; Thompson, C.D.; Day, P.M.; Bacot, S.M.; Lowy, D.R.; Schiller, J.T. Interaction of papillomavirus virus-like particles with human myeloid antigen-presenting cells. Clin. Immunol. 2003, 106, 231–237. [Google Scholar] [CrossRef]
  180. Jager, M.J.; Shields, C.L.; Cebulla, C.M.; Abdel-Rahman, M.H.; Grossniklaus, H.E.; Stern, M.-H.; Carvajal, R.D.; Belfort, R.N.; Jia, R.; Shields, J.A.; et al. Uveal melanoma. Nat. Rev. Dis. Primers 2020, 6, 24. [Google Scholar] [CrossRef]
  181. Savinainen, A.; Grossniklaus, H.; Kang, S.; Rasmussen, C.; Bentley, E.; Krakova, Y.; Struble, C.B.; Rich, C. Ocular distribution and efficacy after suprachoroidal injection of AU-011 for treatment of ocular melanoma. Investig. Ophthalmol. Vis. Sci. 2020, 61, 3615. [Google Scholar]
  182. Narvekar, A.; Rich, C.; Savinainen, A.; Kim, I.K. Nanoparticles for the Treatment of Uveal Melanoma. In Uveal Melanoma: Biology and Management; Bernicker, E.H., Ed.; Springer Nature: Cham, Switzerland, 2021; pp. 135–149. [Google Scholar]
Viruses 14 01656 g001 550
Figure 1. Mechanism of HPV attachment and infection. (A) HPV attaches to HSPG on the exposedbasement membrane (1). The L2 protein is then cleaved by furin (2) and the virion undergoes a conformation change (3) before attaching to a cell surface receptor (4). (B) depicts heparin inhibition of VLP attachment to basement membrane HSPG and (C) illustrates heparinase cleavage of glycosaminoglycan chains prevents HPV attachment. Human papillomavirus (HPV); heparan sulfate proteoglycan (HSPG); basement membrane (BM).
Figure 1. Mechanism of HPV attachment and infection. (A) HPV attaches to HSPG on the exposedbasement membrane (1). The L2 protein is then cleaved by furin (2) and the virion undergoes a conformation change (3) before attaching to a cell surface receptor (4). (B) depicts heparin inhibition of VLP attachment to basement membrane HSPG and (C) illustrates heparinase cleavage of glycosaminoglycan chains prevents HPV attachment. Human papillomavirus (HPV); heparan sulfate proteoglycan (HSPG); basement membrane (BM).
Viruses 14 01656 g001
Viruses 14 01656 g002 550
Figure 2. The structure and modifications of heparan sulfate proteoglycans (HSPG). (A) The general structure of an HSPG made up of a protein core and branched polysaccharide chains. (B) Examples of HSPG modifications such as sulfation patterns as well as remodeling by cleavage of the polysaccharide chains by heparinase or cleavage of the protein core by sheddases. N-sulfation (NS); heparan sulfate (HS); N-deacetylase/N-sulfotransferase (NDST); glucuronic acid epimerase (GLCE); O-sulfotransferases (HS2ST1, HS3ST, HS6ST); endosulfotransferases (SULF1, SULF2); heparanase (HPSE); matrix metalloproteinase (MMP).
Figure 2. The structure and modifications of heparan sulfate proteoglycans (HSPG). (A) The general structure of an HSPG made up of a protein core and branched polysaccharide chains. (B) Examples of HSPG modifications such as sulfation patterns as well as remodeling by cleavage of the polysaccharide chains by heparinase or cleavage of the protein core by sheddases. N-sulfation (NS); heparan sulfate (HS); N-deacetylase/N-sulfotransferase (NDST); glucuronic acid epimerase (GLCE); O-sulfotransferases (HS2ST1, HS3ST, HS6ST); endosulfotransferases (SULF1, SULF2); heparanase (HPSE); matrix metalloproteinase (MMP).
Viruses 14 01656 g002
Viruses 14 01656 g003 550
Figure 3. Mechanism of AU-011 (belzupacap sarotalocan) mediated tumor killing. AU-011 binds to the surface of tumor cells and is activated by near infrared light. The killed tumor cells release DAMPs and neoantigens into the local tumor milieu resulting in uptake by and activation of antigen presenting cells. Both CD4+ and CD8+ T cells are activated and are necessary for localized tumor control and long-term protection from tumor re-challenge. Virus-like drug conjugate (VDC); damage associated molecular patterns (DAMPs); antigen presenting cells (APC); major histocompatibility complex (MHC); T cell receptor (TCR).
Figure 3. Mechanism of AU-011 (belzupacap sarotalocan) mediated tumor killing. AU-011 binds to the surface of tumor cells and is activated by near infrared light. The killed tumor cells release DAMPs and neoantigens into the local tumor milieu resulting in uptake by and activation of antigen presenting cells. Both CD4+ and CD8+ T cells are activated and are necessary for localized tumor control and long-term protection from tumor re-challenge. Virus-like drug conjugate (VDC); damage associated molecular patterns (DAMPs); antigen presenting cells (APC); major histocompatibility complex (MHC); T cell receptor (TCR).
Viruses 14 01656 g003
Table
Table 1. Pathogens utilizing proteoglycans for host infection.
Table 1. Pathogens utilizing proteoglycans for host infection.
PathogenLigandReference
Viruses
Adenovirus (AdV)fiber[39,40]
Dengue virusenvelope[41]
Hepatitis B virus (HBV)L-envelope[42,43]
Hepatitis C virus (HCV)E2 envelope[44,45]
Hepatitis E virus (HEV)ORF2 capsid protein[46]
Human immunodeficiency virus (HIV) gp120, Tat[47,48,49,50]
Human cytomegalovirus (HMCV)gB[51,52,53]
Human papillomavirus (HPV)L1 capsid potein[28,30,32]
Herpes simplex virus type 1 (HSV-1)gB, gC, gD[54,55,56,57,58,59]
Herpes simplex virus type 2 (HSV-2)gB, gC[54,59,60,61]
Merkel cell polyomavirus (MCPyV)VP1[62,63]
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spike[64,65]
Varicella zoster virus (VZV)gB[59,66]
Parasites
Giardia lambliaAlpha-1 giardin[67]
Plasmodium falciparumBAEBL, VAR2CSA, CS[68,69,70]
Toxoplasma gondiiSAG3, ROP2, ROP4, GRA2, SAG1[71,72,73,74]
Trypanosoma cruziHeparin binding proteins (HBP)[75,76,77]
Bacteria
Bordatella pertussisFHA[78]
Helicobacter pyloriVacA[79,80]
Listeria monocytogenesActA[81]
Mycobacterium tuberculosisHA[82]
Neisseria gonorrhoaeaOpa[83,84]
Other
Candida albicansn.d.[85,86,87]
Malassezia spp.n.d.[87]
PrionPrP[88,89,90,91]
Table
Table 2. Proteoglycan targeted tumor therapies.
Table 2. Proteoglycan targeted tumor therapies.
NameTarget/MechanismReference
Antibodies
HN3PE38, PE24 conjugates targeting glypican-3[129,130]
GC33ADCC; targeting glypican-3[131,132]
YP7PE38, Duocarmycin, IRdye700DX conjugates; pyrrolobenzodiazepine dimer; targeting glypican-3[129,133,134,135]
32A9PE24 conjugates targeting glypican-3[136]
ERY974bi-specific antibody agains glypican-3 and CD3[137]
D4 (camel)PE38-conjugated camelid nanobody targeting glypican-1[138]
LH7PE38-conjugated human single domain anti-glypican-2[139]
CAR-T
GC33Glypican-3[140,141]
hYP7Glypican-3[142]
32A9Glypican-3[136]
Y035Glypican-3[143]
LH7Glypican-2[139]
Small molecule/peptide mimics/false substrates
Guanidinylated neomycin (Gneo)LMW HS binding peptide carrying saporin[144]
Synstatin (SSTN)92–119Peptide blocks syndecan-1/IGF1R complex-blocks integrin signaling and VEGFR2 activation[145]
RGWRGEKIGN peptideHS binding peptide blocks FGF2/HS binding[146]
NT4General heparin, HSPG, CSPG mimetic (tetra-branched polypeptide); interferes with cell migration; delivers paclitaxel[147,148,149]
OKN-007Sulfatase-2 inhibitor[150]
PI-88 (muparfostat)Heparanase inhibitor (heparin mimetic); interferes with VEGF, FGF1, FGF2 leading to reduction in angiogenesis and sulf1 and sulf2 activity[151,152]
Suramin analogsHeparanse inhibition; inhibits degradation of ECM and blocks angiogenic events by preventing release of FGF from ECM HS[153]
PG545HS mimetic; blocks heparanase activity; prevents growth factor release and activation [154,155,156]
M402 (neuparanib)HS mimetic; inhibits HS interactions and activity of VEGF, FGF2, SDF-1α, P-selectin, and heparanase[157]
SST0001 (roneparstat)Split heparin; inhibits heparanase, downregulates HGF, VEGF, and MMP-9 expression and suppresses angiogenesis[158]
XylosidesBlocks GAG biosynthesis[159,160]
Nanoparticles/Pathogens
Ad5 Fiber modified to bind HSPG (bypass CAR)[161]
hyaluronic acid micelle nanocarrierHyaluronic acid nanocarrier targeting CD44; incorporate doxorubicin and cisplatin[162]
rVAR2CSATargets oncofetal CS (CD44, CDPG4; syndecan-1); conjugated with diptheria toxin or hemiasterlin[163,164]
liposomesComposed of glypican-3 targeting peptide incorporating sorafenib; GAG binding peptide incorporating doxorubicin[165,166]
metal conjugatesHSPG targeted peptide and glypican-3 antibody delivering Fe3O4 for imaging; Gold nanocluster with gadolinum conjugated to anti-glypican-1; Gold nanocages incorporating gemcetabine conjugated to anti-glypican-1 for theranostics[167,168,169,170]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Kines, R.C.; Schiller, J.T. Harnessing Human Papillomavirus’ Natural Tropism to Target Tumors. Viruses 2022, 14, 1656. https://doi.org/10.3390/v14081656

AMA Style

Kines RC, Schiller JT. Harnessing Human Papillomavirus’ Natural Tropism to Target Tumors. Viruses. 2022; 14(8):1656. https://doi.org/10.3390/v14081656

Chicago/Turabian Style

Kines, Rhonda C., and John T. Schiller. 2022. "Harnessing Human Papillomavirus’ Natural Tropism to Target Tumors" Viruses 14, no. 8: 1656. https://doi.org/10.3390/v14081656

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop