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Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis
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Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 24630

Special Issue Editor

Dr. Hava Gil-Henn

E-Mail Website
Guest Editor
Cytoskeletal Signaling Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
Interests: signal transduction; cytoskeletal signaling; cancer metastasis; cell migration and invasion
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in cancer patients. While research has identified treatment modalities that sometimes shrink or attenuate metastatic tumor growth, such as hormone-blocking drugs, radiation, or chemotherapy, these treatments do not prevent the initial invasive process and the dissemination of tumor cells from the primary tumor. At present, no treatment that permanently eradicates metastasis exists, and the prognostic analysis of metastasis is still very limited. Despite being the major cause of death in cancer patients, poor efforts are invested in clinical metastasis research, mainly because of the complex and long-term nature of the metastatic process. This Special Issue of Cells invites contributions that should improve our understanding of the molecular and cellular mechanisms of cancer invasion and metastasis, and suggest novel strategies for the inhibition of these mechanisms. A better understanding of the metastatic process and its regulation has the potential not only to identify new prognostic markers, but also to develop novel targeted therapeutic strategies.

Dr. Hava Gil-Henn
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer invasion and metastasis
  • signal transduction
  • therapeutics

Published Papers (7 papers)

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Research

Jump to: Review, Other

24 pages, 4216 KiB  
Article
Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
by Seung-Uon Shin, Hyun-Mi Cho, Rathin Das, Hava Gil-Henn, Sundaram Ramakrishnan, Ahmed Al Bayati, Stephen F. Carroll, Yu Zhang, Ankita P. Sankar, Christian Elledge, Augustin Pimentel, Marzenna Blonska and Joseph D. Rosenblatt
Cells 2021, 10(11), 2904; https://doi.org/10.3390/cells10112904 - 27 Oct 2021
Cited by 9 | Viewed by 3596
Abstract
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as [...] Read more.
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as ‘vasculogenic mimicry’ (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody–endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear β-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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24 pages, 4595 KiB  
Article
SUN-MKL1 Crosstalk Regulates Nuclear Deformation and Fast Motility of Breast Carcinoma Cells in Fibrillar ECM Microenvironment
by Ved P. Sharma, James Williams, Edison Leung, Joe Sanders, Robert Eddy, James Castracane, Maja H. Oktay, David Entenberg and John S. Condeelis
Cells 2021, 10(6), 1549; https://doi.org/10.3390/cells10061549 - 19 Jun 2021
Cited by 9 | Viewed by 3264
Abstract
Aligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in [...] Read more.
Aligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in the 2D context, but the mechanistic understanding of rapid single tumor cell motility in the in vivo context is still lacking. Here, we show that streaming tumor cells in vivo use collagen fibers with diameters below 3 µm. Employing 1D migration assays with matching in vivo fiber dimensions, we found a dependence of tumor cell motility on 1D substrate width, with cells moving the fastest and the most persistently on the narrowest 1D fibers (700 nm–2.5 µm). Interestingly, we also observed nuclear deformation in the absence of restricting extracellular matrix pores during high speed carcinoma cell migration in 1D, similar to the nuclear deformation observed in tumor cells in vivo. Further, we found that actomyosin machinery is aligned along the 1D axis and actomyosin contractility synchronously regulates cell motility and nuclear deformation. To further investigate the link between cell speed and nuclear deformation, we focused on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins and SRF-MKL1 signaling, key regulators of mechanotransduction, actomyosin contractility and actin-based cell motility. Analysis of The Cancer Genome Atlas dataset showed a dramatic decrease in the LINC complex proteins SUN1 and SUN2 in primary tumor compared to the normal tissue. Disruption of LINC complex by SUN1 + 2 KD led to multi-lobular elongated nuclei, increased tumor cell motility and concomitant increase in F-actin, without affecting Lamin proteins. Mechanistically, we found that MKL1, an effector of changes in cellular G-actin to F-actin ratio, is required for increased 1D motility seen in SUN1 + 2 KD cells. Thus, we demonstrate a previously unrecognized crosstalk between SUN proteins and MKL1 transcription factor in modulating nuclear shape and carcinoma cell motility in an in vivo relevant 1D microenvironment. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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19 pages, 3063 KiB  
Article
Xanthohumol Impairs the PMA-Driven Invasive Behaviour of Lung Cancer Cell Line A549 and Exerts Anti-EMT Action
by Adrianna Sławińska-Brych, Magdalena Mizerska-Kowalska, Sylwia Katarzyna Król, Andrzej Stepulak and Barbara Zdzisińska
Cells 2021, 10(6), 1484; https://doi.org/10.3390/cells10061484 - 12 Jun 2021
Cited by 17 | Viewed by 3270
Abstract
Xanthohumol (XN), the main prenylated flavonoid from hop cones, has been recently reported to exert significant proapoptotic, anti-proliferative, and growth inhibitory effects against lung cancer in both in vitro and in vivo studies. However, its anti-metastatic potential towards this malignancy is still unrevealed. [...] Read more.
Xanthohumol (XN), the main prenylated flavonoid from hop cones, has been recently reported to exert significant proapoptotic, anti-proliferative, and growth inhibitory effects against lung cancer in both in vitro and in vivo studies. However, its anti-metastatic potential towards this malignancy is still unrevealed. Previously, we indicated that the human lung adenocarcinoma A549 cell line was sensitive to XN treatment. Therefore, using the same tumour cell model, we have studied the influence of XN on the phorbol-12-myristate-13-acetate (PMA)-induced cell migration and invasion. The effects of XN on the expression/activity of pro-invasive MMP-9 and MMP-2 and the expression of MMP inhibitors, i.e., TIMP-1 and TIMP-2 (anti-angiogenic factors), were evaluated. Additionally, the influence of XN on the production of the key pro-angiogenic cytokine, i.e., VEGF, and the release of TGF-β, which is both a pro-angiogenic cytokine and an epithelial-mesenchymal transition (EMT) stimulator, was studied. Furthermore, the influence of XN on the expression of EMT-associated proteins such as E-cadherin and α-E-catenin (epithelial markers), vimentin and N-cadherin (mesenchymal markers), and Snail-1 (transcriptional repressor of E-cadherin) was studied. To elucidate the molecular mechanism underpinning the XN-mediated inhibition of metastatic progression in PMA-activated cells, the phosphorylation levels of AKT, FAK, and ERK1/2 kinases, which are signalling molecules involved in EMT program activation, were assayed. The results showed that XN in non-cytotoxic concentrations impaired the PMA-driven migratory and invasive capacity of A549 cells by decreasing the level of expression of MMP-9 and concomitantly increasing the expression of the TIMP-1 protein, i.e., a specific blocker of pro-MMP-9 activation. Moreover, XN decreased the PMA-induced production of VEGF and TGF-β. Furthermore, the XN-treatment counteracted the PMA-induced EMT of the A549 cells by the upregulation of E-cadherin and α-E-catenin and the downregulation of N-cadherin, vimentin, and Snail-1 expression. The proposed mechanism underlying the anti-invasive XN activity involved the inhibition of the ERK/MAPK pathway and suppression of FAK and PI3/AKT signalling. Our results suggesting migrastatic properties of XN against lung cancer cells require further verification in in vivo assays. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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11 pages, 1767 KiB  
Article
3D-Printed Collagen Scaffolds Promote Maintenance of Cryopreserved Patients-Derived Melanoma Explants
by Yun-Mi Jeong, ChulHwan Bang, MinJi Park, Sun Shin, Seokhwan Yun, Chul Min Kim, GaHee Jeong, Yeun-Jun Chung, Won-Soo Yun, Ji Hyun Lee and Songwan Jin
Cells 2021, 10(3), 589; https://doi.org/10.3390/cells10030589 - 7 Mar 2021
Cited by 16 | Viewed by 3253
Abstract
The development of an in vitro three-dimensional (3D) culture system with cryopreserved biospecimens could accelerate experimental research screening anticancer drugs, potentially reducing costs and time bench-to-beside. However, minimal research has explored the application of 3D bioprinting-based in vitro cancer models to cryopreserved biospecimens [...] Read more.
The development of an in vitro three-dimensional (3D) culture system with cryopreserved biospecimens could accelerate experimental research screening anticancer drugs, potentially reducing costs and time bench-to-beside. However, minimal research has explored the application of 3D bioprinting-based in vitro cancer models to cryopreserved biospecimens derived from patients with advanced melanoma. We investigated whether 3D-printed collagen scaffolds enable the propagation and maintenance of patient-derived melanoma explants (PDMEs). 3D-printed collagen scaffolds were fabricated with a 3DX bioprinter. After thawing, fragments from cryopreserved PDMEs (approximately 1–2 mm) were seeded onto the 3D-printed collagen scaffolds, and incubated for 7 to 21 days. The survival rate was determined with MTT and live and dead assays. Western blot analysis and immunohistochemistry staining was used to express the function of cryopreserved PDMEs. The results show that 3D-printed collagen scaffolds could improve the maintenance and survival rate of cryopreserved PDME more than 2D culture. MITF, Mel A, and S100 are well-known melanoma biomarkers. In agreement with these observations, 3D-printed collagen scaffolds retained the expression of melanoma biomarkers in cryopreserved PDME for 21 days. Our findings provide insight into the application of 3D-printed collagen scaffolds for closely mimicking the 3D architecture of melanoma and its microenvironment using cryopreserved biospecimens. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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27 pages, 4005 KiB  
Article
Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGFβ/CTGF Axis
by Nico Hinz, Anke Baranowsky, Michael Horn, Malte Kriegs, Freya Sibbertsen, Daniel J. Smit, Philippe Clezardin, Tobias Lange, Thorsten Schinke and Manfred Jücker
Cells 2021, 10(2), 430; https://doi.org/10.3390/cells10020430 - 18 Feb 2021
Cited by 16 | Viewed by 4263
Abstract
Bone metastases frequently occur in breast cancer patients and lack appropriate treatment options. Hence, understanding the molecular mechanisms involved in the multistep process of breast cancer bone metastasis and tumor-induced osteolysis is of paramount interest. The serine/threonine kinase AKT plays a crucial role [...] Read more.
Bone metastases frequently occur in breast cancer patients and lack appropriate treatment options. Hence, understanding the molecular mechanisms involved in the multistep process of breast cancer bone metastasis and tumor-induced osteolysis is of paramount interest. The serine/threonine kinase AKT plays a crucial role in breast cancer bone metastasis but the effect of individual AKT isoforms remains unclear. Therefore, AKT isoform-specific knockdowns were generated on the bone-seeking MDA-MB-231 BO subline and the effect on proliferation, migration, invasion, and chemotaxis was analyzed by live-cell imaging. Kinome profiling and Western blot analysis of the TGFβ/CTGF axis were conducted and metastasis was evaluated by intracardiac inoculation of tumor cells into NOD scid gamma (NSG) mice. MDA-MB-231 BO cells exhibited an elevated AKT3 kinase activity in vitro and responded to combined treatment with AKT- and mTOR-inhibitors. Knockdown of AKT3 significantly increased migration, invasion, and chemotaxis in vitro and metastasis to bone but did not significantly enhance osteolysis. Furthermore, knockdown of AKT3 increased the activity and phosphorylation of pro-metastatic HER2 and DDR1/2 but lowered protein levels of CTGF after TGFβ-stimulation, an axis involved in tumor-induced osteolysis. We demonstrated that AKT3 plays a crucial role in bone-seeking breast cancer cells by promoting metastatic potential without facilitating tumor-induced osteolysis. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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Review

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12 pages, 327 KiB  
Review
Invadopodia, a Kingdom of Non-Receptor Tyrosine Kinases
by Trishna Saha and Hava Gil-Henn
Cells 2021, 10(8), 2037; https://doi.org/10.3390/cells10082037 - 9 Aug 2021
Cited by 7 | Viewed by 3225
Abstract
Non-receptor tyrosine kinases (NRTKs) are crucial mediators of intracellular signaling and control a wide variety of processes such as cell division, morphogenesis, and motility. Aberrant NRTK-mediated tyrosine phosphorylation has been linked to various human disorders and diseases, among them cancer metastasis, to which [...] Read more.
Non-receptor tyrosine kinases (NRTKs) are crucial mediators of intracellular signaling and control a wide variety of processes such as cell division, morphogenesis, and motility. Aberrant NRTK-mediated tyrosine phosphorylation has been linked to various human disorders and diseases, among them cancer metastasis, to which no treatment presently exists. Invasive cancer cells leaving the primary tumor use invadopodia, feet-like structures which facilitate extracellular matrix (ECM) degradation and intravasation, to escape the primary tumor and disseminate into distant tissues and organs during metastasis. A major challenge in metastasis research is to elucidate the molecular mechanisms and signaling pathways underlying invadopodia regulation, as the general belief is that targeting these structures can potentially lead to the eradication of cancer metastasis. Non-receptor tyrosine kinases (NRTKs) play a central role in regulating invadopodia formation and function, but how they coordinate the signaling leading to these processes was not clear until recently. Here, we describe the major NRTKs that rule invadopodia and how they work in concert while keeping an accurate hierarchy to control tumor cell invasiveness and dissemination. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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Other

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8 pages, 246 KiB  
Perspective
Are We Ready for Migrastatics?
by Jonathan Solomon, Magdalena Raškova, Daniel Rösel, Jan Brábek and Hava Gil-Henn
Cells 2021, 10(8), 1845; https://doi.org/10.3390/cells10081845 - 21 Jul 2021
Cited by 12 | Viewed by 2391
Abstract
Metastasis accounts for the highest mortality rates in solid tumor cancer patients. However, research and development have neglected this most lethal characteristic and, instead, have concentrated on the hallmarks of cancer that make tumor cells highly proliferative and distinctive from nonmalignant cells. The [...] Read more.
Metastasis accounts for the highest mortality rates in solid tumor cancer patients. However, research and development have neglected this most lethal characteristic and, instead, have concentrated on the hallmarks of cancer that make tumor cells highly proliferative and distinctive from nonmalignant cells. The concentration on invasion and metastasis can be one of the most meaningful advancements in cancer investigation. Importantly, metastasis-free survival (MFS) was recently approved by the Food and Drug Administration (FDA) as a novel primary endpoint in clinical trials and has been used to evaluate the prognosis of patients with nonmetastatic castration-resistant prostate cancer and soft tissue sarcoma. This new definition enables to shift the focus of research and development in cancer therapeutics toward metastasis and to change the emphasis from using tumor shrinkage as a benchmark for indicating the efficacy of treatment to using MFS as a more representative endpoint for antimetastatic drugs. This perspective outlines the possibility to use this novel endpoint in other solid cancers, and examples of large clinical trials are given in which MFS is defined as an endpoint and/or in which antimetastatic strategies are being examined. These advances now open the door for the rapid development of antimetastatic therapies, which could be used in combination with standard cytotoxic cancer therapies. With pioneer research on metastasis prevention on the rise and the underlying biomechanisms of tumor cell motility and invasion explored further than ever before, we believe an intensified focus on antimetastatic properties will shape this era of cancer translational research. Full article
(This article belongs to the Special Issue Molecular, Cellular and Therapeutic Approaches to Cancer Metastasis)
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