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Open AccessArticle

Prevalence of Torque Teno Virus (TTV) in Cervical Precursor Lesions and Cancer in Chilean Women

by Matías Guzmán-Venegas, Carolina Moreno-León, Cristian Andrade-Madrigal, Alejandra Román, Rancés Blanco, Iván Gallegos and Francisco Aguayo

Int. J. Mol. Sci. 2025, 26(22), 11039; https://doi.org/10.3390/ijms262211039 - 14 Nov 2025

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Abstract

Torque teno virus (TTV) is a highly prevalent DNA virus in humans, but its role in carcinogenesis is not well understood. While human papillomavirus (HPV) is a well-established etiological agent in cervical cancer, co-infections with other viruses such as Epstein–Barr virus (EBV) or [...] Read more.

Torque teno virus (TTV) is a highly prevalent DNA virus in humans, but its role in carcinogenesis is not well understood. While human papillomavirus (HPV) is a well-established etiological agent in cervical cancer, co-infections with other viruses such as Epstein–Barr virus (EBV) or TTV may influence disease progression. We conducted a cross-sectional study using 94 formalin-fixed, paraffin-embedded (FFPE) cervical tissue samples. These specimens were collected from women with cervical intraepithelial lesions (CINI-III) or squamous cell carcinoma (SCC) at the Clinical Hospital of the University of Chile. After extracting DNA, we screened for TTV using real-time polymerase chain reaction (qPCR). Statistical analysis was performed using Fisher’s exact test. Of the 94 samples, 83 were positive for the human β-globin gene and included in the final analysis. TTV was detected in 12.0% (10/83) of these samples. Among the TTV-positive cases, the virus was most frequently detected in high-grade lesions (70.0%), followed by low-grade lesions (20.0%) and squamous cell carcinoma (10.0%). However, these differences were not statistically significant (p = 0.688). This is the first study to assess TTV prevalence in cervical lesions among Chilean women. Although we found no statistically significant associations, a higher frequency of TTV was detected in precursor lesions compared to SCC. Further studies are needed to understand the potential immunomodulatory role of TTV in cervical carcinogenesis. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

19 pages, 2936 KB

Open AccessArticle

Association of Gene Expression Profiles in HPV-Positive Head and Neck Squamous Cell Carcinoma with Patient Outcome: In Search of Prognostic Biomarkers

by J. Noé García-Chávez, Adriana Contreras-Paredes, Claudia González-Espinosa, Imelda Martínez-Ramírez, Elizabeth Langley, Marcela Lizano and J. Omar Muñoz-Bello

Int. J. Mol. Sci. 2025, 26(12), 5894; https://doi.org/10.3390/ijms26125894 - 19 Jun 2025

Cited by 2 | Viewed by 3458

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) ranks sixth in incidence and seventh in cancer mortality worldwide. Approximately 30% of HNSCC cases are related to human papillomavirus (HPV) infection, the oropharynx being the anatomical subsite most associated with HPV infection. Traditionally, HPV-positive HNSCC [...] Read more.

Head and Neck Squamous Cell Carcinoma (HNSCC) ranks sixth in incidence and seventh in cancer mortality worldwide. Approximately 30% of HNSCC cases are related to human papillomavirus (HPV) infection, the oropharynx being the anatomical subsite most associated with HPV infection. Traditionally, HPV-positive HNSCC has been considered to have better treatment response and clinical outcome. However, HPV-positive HNSCC is a heterogeneous group since 30% of the cases present early relapse, which implies that there are differences in molecular profiles within HPV-positive patients. In this study, we used bioinformatic data analysis from open-access repositories to compare molecular profiles differentially expressed between HPV-positive and -negative HNSCC patients. Using the TCGA HNSCC transcriptomic data, we identified a group of genes, whose expression is related to clinical outcome in patients. Our findings were validated in an independent cohort confirming that the expression levels of FABP4, HMGA2, S100A10, GDNF, SLC7A,2 and GPR18 genes were associated with overall survival (OS) exclusively in HPV-positive HNSCC patients, while ST6GALNAC1 expression was associated with OS in HPV-negative HNSCC. The expression of OS-related genes was independent of tumor stage and history of alcoholism. Our findings suggest that transcriptional profiles in HPV-positive HNSCC are an excellent source of information for the search for potential prognostic biomarkers. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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14 pages, 2088 KB

Open AccessArticle

Utility of an Archival Dried Blood Spot (DBS) Collection from HIV-Infected Individuals with and without Cancer in a Resource-Limited Setting

by Rongzhen Zhang, Paige M. Bracci, Alan Leong, Cassandra Rapp and Michael S. McGrath

Int. J. Mol. Sci. 2024, 25(19), 10235; https://doi.org/10.3390/ijms251910235 - 24 Sep 2024

Viewed by 2009

Abstract

The frequency of virus-associated cancers is growing worldwide, especially in resource-limited settings. One of the biggest challenges in cancer research among people living with HIV (PLWH) has been understanding how infection with both HIV and Kaposi sarcoma-associated herpesvirus (KSHV) promotes the pathogenesis of [...] Read more.

The frequency of virus-associated cancers is growing worldwide, especially in resource-limited settings. One of the biggest challenges in cancer research among people living with HIV (PLWH) has been understanding how infection with both HIV and Kaposi sarcoma-associated herpesvirus (KSHV) promotes the pathogenesis of Kaposi sarcoma (KS), the most common cancer among PLWH worldwide and a significant public health problem in regions with high prevalence of HIV such as Sub-Saharan Africa (SSA). The AIDS and Cancer Specimen Resource (ACSR) provides samples for research, including dried blood spots (DBS) that were collected from large clinical epidemiology studies of KSHV and KS in PLWH conducted more than a decade ago in SSA. Here, we validated the quality of DNA derived from DBS samples from SSA studies and provided evidence of quantitative recovery of inflammatory cytokines using these DBS samples through comparison with paired frozen plasma. Significant differences in DNA, protein yields, and inflammatory biomarker levels were also observed between PLWH with/without KS. Establishing the fitness of DBS samples for studies of KS pathogenesis extends the number of projects that can be supported by these ACSR special collections and provides evidence that DBS collection for future KS research is a practical option in resource-limited settings. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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14 pages, 6255 KB

Open AccessArticle

Oncolytic Activity of Sindbis Virus with the Help of GM-CSF in Hepatocellular Carcinoma

by Xiangwei Shi, Kangyixin Sun, Li Li, Jingwen Xian, Ping Wang, Fan Jia and Fuqiang Xu

Int. J. Mol. Sci. 2024, 25(13), 7195; https://doi.org/10.3390/ijms25137195 - 29 Jun 2024

Cited by 7 | Viewed by 2617

Abstract

Hepatocellular carcinoma is a refractory tumor with poor prognosis and high mortality. Many oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma. Based on previous studies, we constructed a recombinant GM-CSF-carrying Sindbis virus, named SINV-GM-CSF, which contains a mutation (G [...] Read more.

Hepatocellular carcinoma is a refractory tumor with poor prognosis and high mortality. Many oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma. Based on previous studies, we constructed a recombinant GM-CSF-carrying Sindbis virus, named SINV-GM-CSF, which contains a mutation (G to S) at amino acid 285 in the nsp1 protein of the viral vector. The potential of this mutated vector for liver cancer therapy was verified at the cellular level and in vivo, respectively, and the changes in the tumor microenvironment after treatment were also described. The results showed that the Sindbis virus could effectively infect hepatocellular carcinoma cell lines and induce cell death. Furthermore, the addition of GM-CSF enhanced the tumor-killing effect of the Sindbis virus and increased the number of immune cells in the intra-tumor microenvironment during the treatment. In particular, SINV-GM-CSF was able to efficiently kill tumors in a mouse tumor model of hepatocellular carcinoma by regulating the elevation of M1-type macrophages (which have a tumor-resistant ability) and the decrease in M2-type macrophages (which have a tumor-promoting capacity). Overall, SINV-GM-CSF is an attractive vector platform with clinical potential for use as a safe and effective oncolytic virus. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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15 pages, 3157 KB

Open AccessArticle

Epstein–Barr Virus Promotes Oral Squamous Cell Carcinoma Stemness through the Warburg Effect

by Chukkris Heawchaiyaphum, Hironori Yoshiyama, Hisashi Iizasa, Ati Burassakarn, Zolzaya Tumurgan, Tipaya Ekalaksananan and Chamsai Pientong

Int. J. Mol. Sci. 2023, 24(18), 14072; https://doi.org/10.3390/ijms241814072 - 14 Sep 2023

Cited by 18 | Viewed by 3264

Abstract

Epstein–Barr virus (EBV) is associated with various human malignancies. An association between EBV infection and oral squamous cell carcinoma (OSCC) has recently been reported. We established EBV-positive OSCC cells and demonstrated that EBV infection promoted OSCC progression. However, the mechanisms by which EBV [...] Read more.

Epstein–Barr virus (EBV) is associated with various human malignancies. An association between EBV infection and oral squamous cell carcinoma (OSCC) has recently been reported. We established EBV-positive OSCC cells and demonstrated that EBV infection promoted OSCC progression. However, the mechanisms by which EBV promotes OSCC progression remain poorly understood. Therefore, we performed metabolic analyses of EBV-positive OSCC cells and established a xenograft model to investigate the viral contribution to OSCC progression. Here, we demonstrated that EBV infection induced mitochondrial stress by reducing the number of mitochondrial DNA (mtDNA) copies. Microarray data from EBV-positive OSCC cells showed altered expression of glycolysis-related genes, particularly the upregulation of key genes involved in the Warburg effect, including LDHA, GLUT1, and PDK1. Furthermore, lactate production and LDH activity were elevated in EBV-positive OSCC cells. EBV infection significantly upregulated the expression levels of cancer stem cell (CSC) markers such as CD44 and CD133 in the xenograft model. In this model, tumor growth was significantly increased in EBV-positive SCC25 cells compared with that in uninfected cells. Furthermore, tumorigenicity increased after serial passages of EBV-positive SCC25 tumors. This study revealed the oncogenic role of EBV in OSCC progression by inducing the Warburg effect and cancer stemness. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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12 pages, 639 KB

Open AccessArticle

Preferential Tissue Sites of Different Cancer-Risk Groups of Human Papillomaviruses

by Mitsuaki Okodo, Kaori Okayama, Toshiyuki Sasagawa, Koji Teruya, Rei Settsu, Shuichi Mizuno, Yasuyoshi Ishii and Mizue Oda

Int. J. Mol. Sci. 2023, 24(17), 13151; https://doi.org/10.3390/ijms241713151 - 24 Aug 2023

Cited by 2 | Viewed by 2044

Abstract

The oncogenic potential of human papillomavirus (HPV) may be used to determine the tissue tropism of each HPV type. Cervical cancer develops in the squamo-columar junction of the cervices, and most lesions are induced by high-risk (HR) HPV types. This suggests that HR [...] Read more.

The oncogenic potential of human papillomavirus (HPV) may be used to determine the tissue tropism of each HPV type. Cervical cancer develops in the squamo-columar junction of the cervices, and most lesions are induced by high-risk (HR) HPV types. This suggests that HR types preferentially infect the cervix, whereas the preferential infection site for low-risk (LR) types is not well defined. The determination of HPV tropism when using cytology samples can be uncertain since it is difficult to avoid contamination of cell samples between the cervix and the vagina. Herein, cell samples were carefully collected by independently scraping the cervix and vagina, after which the HPV types were determined. HPV tissue tropism was determined by considering what HPV types were positive at only one of the sites (the cervix or the vagina) as the viruses that preferentially infected that site. This method revealed that all LR types were only identified in vaginal samples, whereas 87% of HR types were identified in cervical sites. Thus, LR types may preferentially infect the vagina, whereas HR types infect the cervix. These findings suggest that preferential tissue tropism of certain HPV types is a probable factor for malignant progression. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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Review

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25 pages, 2720 KB

Open AccessReview

Deciphering the Role of Mast Cells in HPV-Related Cancers

by Zyanya P. Espinosa-Riquer, J. Omar Muñoz-Bello, Claudia González-Espinosa, Alfredo Ibarra-Sánchez and Marcela Lizano

Int. J. Mol. Sci. 2025, 26(24), 12110; https://doi.org/10.3390/ijms262412110 - 16 Dec 2025

Viewed by 755

Abstract

Human Papillomavirus (HPV)-related cancers constitute a major global health problem, accounting for 4.5% of all human cancers. Studying the composition of the tumor microenvironment (TME) of HPV-related cancers may help develop therapeutic strategies or identify prognostic biomarkers with potential clinical significance. Among all [...] Read more.

Human Papillomavirus (HPV)-related cancers constitute a major global health problem, accounting for 4.5% of all human cancers. Studying the composition of the tumor microenvironment (TME) of HPV-related cancers may help develop therapeutic strategies or identify prognostic biomarkers with potential clinical significance. Among all the components of TME, mast cells (MCs) appear to be particularly relevant in HPV-related tumors. MCs are myeloid-derived immune cells that release a wide range of inflammatory mediators. It is now recognized that these immune cells are important players within the TME, where they can exert both anti- and pro-tumor activities depending on the type of MC-derived inflammatory mediators released. MCs may play an important role in the processes associated with cell transformation, development, and the progression of HPV-associated tumors; however, their specific functions in these neoplasms are not yet fully understood. This review addresses the current state of knowledge on MCs and their contribution to the molecular biology of HPV-related cancers. In addition, it highlights MCs’ roles in the pro- or anti-tumor paradigm and discusses their emerging potential as therapeutic targets or prognostic biomarkers. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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26 pages, 4517 KB

Open AccessReview

Recent Advances in the Histopathology, Molecular Biology, and Treatment of Kaposi Sarcoma: A Contemporary Review

by Tayarv Jayd Bagratee, Veron Ramsuran, Mpumelelo Msimang and Pratistadevi Kanaye Ramdial

Int. J. Mol. Sci. 2025, 26(20), 10058; https://doi.org/10.3390/ijms262010058 - 16 Oct 2025

Cited by 1 | Viewed by 2151

Abstract

Kaposi sarcoma (KS) is an intermediate-grade vascular tumour that has undergone major treatment and diagnostic breakthroughs following the discovery of Human herpesvirus 8 (HHV8). Whilst classically described in Eastern European populations, the endemic and epidemic forms of KS have facilitated its association with [...] Read more.

Kaposi sarcoma (KS) is an intermediate-grade vascular tumour that has undergone major treatment and diagnostic breakthroughs following the discovery of Human herpesvirus 8 (HHV8). Whilst classically described in Eastern European populations, the endemic and epidemic forms of KS have facilitated its association with AIDS. This was led by the detection of HHV8 by PCR, and thereafter, immunohistochemically. This not only enabled the recognition and diagnosis of complex histopathological KS subtypes but also facilitated distinction from its mimickers, including acroangiodermatitis and pyogenic granuloma. Recent advances in the viral genomics of HHV8 have expanded the diagnostic landscape of KS clinically and molecularly. The latent phase of replication in the HHV8 lifecycle reveals numerous angiogenic and inflammatory factors. Novel therapies targeting these viral–human molecular interactions may prove useful. However, this is highly dependent on the clonal nature of KS. Conflicting research outcomes demonstrate varying viewpoints on the clonal (monoclonal/oligoclonal/polyclonal) nature of KS, heightening the tumoural versus inflammatory pseudoneoplastic controversy. Understanding the clinical context of KS is fundamental to understanding its clonality, and a dearth of this clinical information in recent studies appears to be the critical factor in determining the true clonal nature of KS. The current molecular landscape, histopathology, treatment options, and opinions on clonality are critically reviewed. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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44 pages, 1364 KB

Open AccessReview

Oncoviruses in the Oral Cavity: Recent Advances in Understanding Viral Infections and Tumorigenesis

by Letícia Bomfim Campos, Ana Carolina Silva Guimarães, Jéssica Gonçalves Pereira, Carla Sousa da Silva, Nathália Alves Araújo de Almeida, Pedro do Nascimento Marinho, Rafaela Moraes Pereira de Sousa, Irena Duś-Ilnicka and Vanessa Salete de Paula

Int. J. Mol. Sci. 2025, 26(14), 6721; https://doi.org/10.3390/ijms26146721 - 13 Jul 2025

Cited by 2 | Viewed by 3253

Abstract

Oncoviruses, such as Epstein–Barr virus (EBV), human papillomavirus (HPV), and Kaposi sarcoma-associated herpesvirus (KSHV), have been widely discussed for their oncogenic risk. Initially, the oral cavity was disregarded. In recent years, orientation has shifted to the importance of the oral cavity and cancer-related [...] Read more.

Oncoviruses, such as Epstein–Barr virus (EBV), human papillomavirus (HPV), and Kaposi sarcoma-associated herpesvirus (KSHV), have been widely discussed for their oncogenic risk. Initially, the oral cavity was disregarded. In recent years, orientation has shifted to the importance of the oral cavity and cancer-related issues via Handbook 19 titled “Oral Cancer Prevention” by the International Agency for Research on Cancer, the WHO Global Oral Health Status Report 2022, and multiple other actions focused on reducing the oversight of this neglected area. Oncoviruses play a significant role in oral cavity malignancies by establishing persistent infections, evading host immune responses, and inducing cellular transformation through the disruption of normal regulatory pathways. Molecular biology and microbiome research have advanced our understanding of the complex interplay between oncoviruses and oral microbiota, demonstrating how coinfections and dysbiosis can enhance viral oncogenic potential. These findings improve the understanding of virus-induced oral cancers and support the development of novel diagnostic and therapeutic strategies. This narrative review focuses on the relationship between oncoviruses and the oral cavity by focusing on how a specific virus triggers tumorigenesis for each of the described viruses and how it affects oral cavity cancer development. Finally, we describe recent advances and future perspectives including vaccines and/or treatment. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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12 pages, 719 KB

Open AccessReview

Understanding HPV-Induced Cancers and Investigating the Barriers Faced by Low- and Middle-Income Countries in Prevention and Treatment

by Zahab N. Aleezada, Ishika Patel and Nabiha Yusuf

Int. J. Mol. Sci. 2025, 26(12), 5581; https://doi.org/10.3390/ijms26125581 - 11 Jun 2025

Cited by 7 | Viewed by 2589

Abstract

Human papillomavirus (HPV) is a leading cause of several cancers, most notably cervical cancer, but also anal, penile, vulvar, vaginal, and oropharyngeal malignancies. While vaccines and screening technologies offer highly effective prevention, the global burden of HPV-induced cancers remains disproportionately high in low- [...] Read more.

Human papillomavirus (HPV) is a leading cause of several cancers, most notably cervical cancer, but also anal, penile, vulvar, vaginal, and oropharyngeal malignancies. While vaccines and screening technologies offer highly effective prevention, the global burden of HPV-induced cancers remains disproportionately high in low- and middle-income countries (LMICs). This literature review provides a comprehensive synthesis of the types, mechanisms, treatments, and prevention strategies associated with HPV-related cancers, while also highlighting regional disparities in healthcare access and infrastructure. It critically examines the barriers LMICs face in adopting life-saving interventions, such as limited healthcare infrastructure, vaccine hesitancy, funding gaps, and cultural stigma. The review further explores recent scientific and policy advances—including single-dose vaccination, self-sampling HPV tests, and senolytic therapies—that have the potential to reduce global health inequities. By connecting molecular biology with public health systems, this paper underscores the need for interdisciplinary solutions and equity-centered approaches to combat HPV-induced cancers worldwide. The findings emphasize that eliminating cervical cancer and other HPV-related diseases is not only a scientific goal but also a moral imperative requiring global collaboration and local action. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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20 pages, 1530 KB

Open AccessReview

The Role of Xenobiotics and Anelloviruses in Colorectal Cancer: Mechanisms and Perspectives

by Francisco Aguayo, Julio C. Tapia, Gloria M. Calaf, Juan P. Muñoz, Julio C. Osorio, Matías Guzmán-Venegas, Carolina Moreno-León, Jorge Levican and Cristian Andrade-Madrigal

Int. J. Mol. Sci. 2025, 26(9), 4354; https://doi.org/10.3390/ijms26094354 - 3 May 2025

Cited by 1 | Viewed by 1357

Abstract

Xenobiotics are non-natural chemical compounds to which the human population is exposed. Chronic exposure to certain xenobiotics is associated with various diseases, including cancer development. Anelloviruses (AVs), including Torque Teno Virus (TTV), Torque Teno Mini Virus (TTMV), and Torque Teno Midi Virus (TTMDV), [...] Read more.

Xenobiotics are non-natural chemical compounds to which the human population is exposed. Chronic exposure to certain xenobiotics is associated with various diseases, including cancer development. Anelloviruses (AVs), including Torque Teno Virus (TTV), Torque Teno Mini Virus (TTMV), and Torque Teno Midi Virus (TTMDV), are ubiquitous viruses found in the general population. As no disease has been definitively associated with AVs, they are sometimes referred to as “viruses awaiting a disease”. This review explores the potential roles of xenobiotics and AVs in colorectal cancer (CRC) development and suggests a potential interplay between them. Evidence suggests an association between certain xenobiotics (like pesticides, cigarette smoke components, and dietary factors) and CRC, while such an association is less clear for AVs. The high prevalence of AVs suggests these infections alone may be insufficient to disrupt homeostasis; thus, additional factors might be required to promote disease, potentially including cancer. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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