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Human Papillomavirus and Cancers
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Human Papillomavirus and Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 91967

Special Issue Editors

Dr. Maria Lina Tornesello

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Guest Editor
Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy
Interests: viral oncology; human papillomavirus; genital cancer; oropharyngeal cancer; gene mutation; single nucleotide polymorphisms
Special Issues, Collections and Topics in MDPI journals
Dr. Franco M. Buonaguro

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Guest Editor
Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy
Interests: oncology; molecular biology; virology; biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The human papillomaviruses (HPV) are the major cause of nearly all cervical cancers and of a significant fraction of several other human malignancies arising from the mucosal squamous epithelia of anus, vagina, vulva, penis, and oropharynx. Despite the great long-term promise of HPV vaccination for the global prevention of cervical cancer, HPV-related cancers will remain a major health problem for decades to come.

The long-term persistent infection, the integration of the viral DNA in the human genome, and the constitutive expression of HPV oncoproteins cause the accumulation of various molecular changes in the infected cells leading to cancer development and progression. Many genetic and epigenetic alterations, as well as complex molecular networks, have been identified by “omics” technologies in HPV-related cancers.

We welcome submissions of research and review articles on the molecular mechanisms that contribute to HPV-induced carcinogenesis to bring together expert opinions and new advances from across the field in a Special Issue of Cancers. We welcome submissions that cover any relevant topic, including the role of oncoviral proteins in cell transformation, the gene mutational profile of viral and host genomes, expression levels of miRNAs, gene methylation, immune response, and new therapeutic opportunities including cancer vaccines for HPV-related cancers.

Dr. Maria Lina Tornesello
Dr. Franco M. Buonaguro
Guest Editors

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. Cancers 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 2900 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.

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Editorial

Jump to: Research, Review

5 pages, 190 KiB  
Editorial
Human Papillomavirus and Cancers
by Maria Lina Tornesello and Franco M. Buonaguro
Cancers 2020, 12(12), 3772; https://doi.org/10.3390/cancers12123772 - 15 Dec 2020
Cited by 7 | Viewed by 1997
Abstract
Persistent infection with oncogenic human papillomaviruses (HPVs) is the main cause of nearly all cervical cancers as well as of a significant proportion of other malignancies arising from the mucosal squamous epithelia of the anogenital tract as well as of the head and [...] Read more.
Persistent infection with oncogenic human papillomaviruses (HPVs) is the main cause of nearly all cervical cancers as well as of a significant proportion of other malignancies arising from the mucosal squamous epithelia of the anogenital tract as well as of the head and neck region [1]. [...] Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)

Research

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12 pages, 2004 KiB  
Article
Juvenile-Onset Recurrent Respiratory Papillomatosis Aggressiveness: In Situ Study of the Level of Transcription of HPV E6 and E7
by Charles Lépine, Thibault Voron, Dominique Berrebi, Marion Mandavit, Marine Nervo, Sophie Outh-Gauer, Hélène Péré, Louis Tournier, Natacha Teissier, Eric Tartour, Nicolas Leboulanger, Louise Galmiche and Cécile Badoual
Cancers 2020, 12(10), 2836; https://doi.org/10.3390/cancers12102836 - 01 Oct 2020
Cited by 10 | Viewed by 2782
Abstract
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a condition related to HPV 6 and 11 infection which is characterized by the repeated growth of benign exophytic papilloma in the respiratory tract. Disease progression is unpredictable: some children experience minor symptoms, while others require multiple [...] Read more.
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a condition related to HPV 6 and 11 infection which is characterized by the repeated growth of benign exophytic papilloma in the respiratory tract. Disease progression is unpredictable: some children experience minor symptoms, while others require multiple interventions due to florid growth. The aim of this study was to explore the biomarkers of JoRRP severity on a bicentric cohort of forty-eight children. We performed a CISH on the most recent sample of papilloma with a probe targeting the mRNA of the E6 and E7 genes of HPV 6 and 11 and an immunostaining with p16INK4a antibody. For each patient HPV RNA CISH staining was assessed semi-quantitatively to define two scores: 1+, defined as a low staining extent, and 2+, defined as a high staining extent. This series contained 19 patients with a score of 1+ and 29 with a score of 2+. Patients with a score of 2+ had a median of surgical excision (SE) per year that was twice that of patients with a score of 1+ (respectively 6.1 versus 2.8, p = 0.036). We found similar results with the median number of SE the first year. Regarding p16INK4a, all patients were negative. To conclude, HPV RNA CISH might be a biomarker which is predictive of disease aggressiveness in JoRRP, and might help in patient care management. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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34 pages, 12382 KiB  
Article
Anti-Retroviral Protease Inhibitors Regulate Human Papillomavirus 16 Infection of Primary Oral and Cervical Epithelium
by Samina Alam, Sreejata Chatterjee, Sa Do Kang, Janice Milici, Jennifer Biryukov, Han Chen and Craig Meyers
Cancers 2020, 12(9), 2664; https://doi.org/10.3390/cancers12092664 - 18 Sep 2020
Cited by 3 | Viewed by 3755
Abstract
Epidemiology studies suggest that Human Immunodeficiency Virus (HIV)-infected patients on highly active anti-retroviral therapy (HAART) may be at increased risk of acquiring opportunistic Human Papillomavirus (HPV) infections and developing oral and cervical cancers. Effective HAART usage has improved survival but increased the risk [...] Read more.
Epidemiology studies suggest that Human Immunodeficiency Virus (HIV)-infected patients on highly active anti-retroviral therapy (HAART) may be at increased risk of acquiring opportunistic Human Papillomavirus (HPV) infections and developing oral and cervical cancers. Effective HAART usage has improved survival but increased the risk for HPV-associated cancers. In this manuscript, we report that Protease Inhibitors (PI) treatment of three-dimensional tissues derived from primary human gingiva and cervical epithelial cells compromised cell-cell junctions within stratified epithelium and enhanced paracellular permeability of HPV16 to the basal layer for infection, culminating in de novo biosynthesis of progeny HPV16 as determined using 5-Bromo-2′-deoxyuridine (BrdU) labeling of newly synthesized genomes. We propose that HAART/PI represent a novel class of co-factors that modulate HPV infection of the target epithelium. Our in vitro tissue culture model is an important tool to study the mechanistic role of anti-retroviral drugs in promoting HPV infections in HAART-naïve primary epithelium. Changes in subsequent viral load could promote new infections, create HPV reservoirs that increase virus persistence, and increase the risk of oral and cervical cancer development in HIV-positive patients undergoing long-term HAART treatment. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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11 pages, 598 KiB  
Article
HPV-Induced Oropharyngeal Cancer and the Role of the E7 Oncoprotein Detection via Brush Test
by Wegene Borena, Volker H. Schartinger, Jozsef Dudas, Julia Ingruber, Maria C. Greier, Teresa B. Steinbichler, Johannes Laimer, Heribert Stoiber, Herbert Riechelmann and Barbara Kofler
Cancers 2020, 12(9), 2388; https://doi.org/10.3390/cancers12092388 - 23 Aug 2020
Cited by 4 | Viewed by 2033
Abstract
Background: High risk human papillomavirus (hr-HPV)-associated oropharyngeal cancers (OPCs) are characterized by significantly better therapy responses. In order to implement a de-escalated treatment strategy for this tumor entity, it is highly crucial to accurately distinguish HPV-associated OPCs from non-HPV-associated ones. Methods: In this [...] Read more.
Background: High risk human papillomavirus (hr-HPV)-associated oropharyngeal cancers (OPCs) are characterized by significantly better therapy responses. In order to implement a de-escalated treatment strategy for this tumor entity, it is highly crucial to accurately distinguish HPV-associated OPCs from non-HPV-associated ones. Methods: In this prospective study, 56 patients with histologically confirmed OPC were evaluated. A commercially available sandwich ELISA test system was used for the detection of hr-HPV E7 oncoprotein targeting the genotypes 16, 18 and 45. Results were presented as optical density. Positivity for HPV DNA and p16 immunohistochemistry (IHC) was taken as the reference method. Results: E7 positivity was significantly associated with the reference method (p = 0.048). The sensitivity, specificity, positive predictive value and negative predictive value for the E7 oncoptotein was 60.9% (95% CI 38.5 to 80.3%), 66.7% (95% CI 46% to 83.5%), 64.2% (95% CI 49.4 to 77.4%) and 63.01% (95% CI 48.9–75.2%), respectively, for the cutoff provided by the manufacturer. Conclusions: We found a significant association between E7 oncoprotein detection and the currently used combination. We believe that the use of the ELISA based E7 antigen test could be a valuable addition in cases of ambiguous findings and may be used in combination with other techniques to distinguish between HPV-driven and non-HPV-driven OPCs. However, the low sensitivity of the assay coupled with the small sample size in our study may represent a limitation. We recommend that future larger studies elucidate the diagnostic value of the E7 brush test. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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12 pages, 1143 KiB  
Article
Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients
by Thomas J. Carter, Jeyarooban Jeyaneethi, Juhi Kumar, Emmanouil Karteris, Rob Glynne-Jones and Marcia Hall
Cancers 2020, 12(8), 2229; https://doi.org/10.3390/cancers12082229 - 10 Aug 2020
Cited by 5 | Viewed by 2267
Abstract
Whilst anal cancer accounts for less than 1% of all new cancer cases, incidence rates have increased by up to 70% in the last 30 years with the majority of cases driven by human papilloma virus (HPV) infection. Standard treatment for localised anal [...] Read more.
Whilst anal cancer accounts for less than 1% of all new cancer cases, incidence rates have increased by up to 70% in the last 30 years with the majority of cases driven by human papilloma virus (HPV) infection. Standard treatment for localised anal cancer is chemoradiotherapy (CRT). Localised progression is the predominant pattern of relapse but well under 50% of cases are salvaged by surgery, predominantly because confirming recurrence within post-radiation change is very challenging. Identifying cancer-associated circulating cells (CCs) in peripheral blood could offer a corroborative method of monitoring treatment efficacy and identifying relapse early. To study this, nucleated cells were isolated from the blood of patients with anal cancer prior to, during, and after CRT and processed through the Amnis® ImageStream®X Mk II Imaging Flow Cytometer, without prior enrichment, using Pan-cytokeratin (PCK), CD45 antibodies and making use of the DNA dye DRAQ5. Analysis was undertaken using IDEAS software to identify those cells that were PCK-positive and DRAQ5-positive as well as CD45-negative; these were designated as CCs. CCs were identified in 7 of 8 patients; range 60–876 cells per mL of blood. This first report of the successful identification of CCs in anal cancer patients raises the possibility that liquid biopsies will find a future role as a prognostic/diagnostic tool in this patient group. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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18 pages, 1572 KiB  
Article
Adenoviral Vectors Armed with PAPILLOMAVIRUs Oncogene Specific CRISPR/Cas9 Kill Human-Papillomavirus-Induced Cervical Cancer Cells
by Eric Ehrke-Schulz, Sonja Heinemann, Lukas Schulte, Maren Schiwon and Anja Ehrhardt
Cancers 2020, 12(7), 1934; https://doi.org/10.3390/cancers12071934 - 17 Jul 2020
Cited by 22 | Viewed by 3612
Abstract
Human papillomaviruses (HPV) cause malignant epithelial cancers including cervical carcinoma, non-melanoma skin and head and neck cancer. They drive tumor development through the expression of their oncoproteins E6 and E7. Designer nucleases were shown to be efficient to specifically destroy HPV16 and HPV18 [...] Read more.
Human papillomaviruses (HPV) cause malignant epithelial cancers including cervical carcinoma, non-melanoma skin and head and neck cancer. They drive tumor development through the expression of their oncoproteins E6 and E7. Designer nucleases were shown to be efficient to specifically destroy HPV16 and HPV18 oncogenes to induce cell cycle arrest and apoptosis. Here, we used high-capacity adenoviral vectors (HCAdVs) expressing the complete CRISPR/Cas9 machinery specific for HPV18-E6 or HPV16-E6. Cervical cancer cell lines SiHa and CaSki containing HPV16 and HeLa cells containing HPV18 genomes integrated into the cellular genome, as well as HPV-negative cancer cells were transduced with HPV-type-specific CRISPR-HCAdV. Upon adenoviral delivery, the expression of HPV-type-specific CRISPR/Cas9 resulted in decreased cell viability of HPV-positive cervical cancer cell lines, whereas HPV-negative cells were unaffected. Transduced cervical cancer cells showed increased apoptosis induction and decreased proliferation compared to untreated or HPV negative control cells. This suggests that HCAdV can serve as HPV-specific cancer gene therapeutic agents when armed with HPV-type-specific CRISPR/Cas9. Based on the versatility of the CRISPR/Cas9 system, we anticipate that our approach can contribute to personalized treatment options specific for the respective HPV type present in each individual tumor. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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14 pages, 789 KiB  
Article
Epitope Mapping and Computational Analysis of Anti-HPV16 E6 and E7 Antibodies in Single-Chain Format for Clinical Development as Antitumor Drugs
by Carla Amici, Maria Gabriella Donà, Barbara Chirullo, Paola Di Bonito and Luisa Accardi
Cancers 2020, 12(7), 1803; https://doi.org/10.3390/cancers12071803 - 06 Jul 2020
Cited by 6 | Viewed by 2072
Abstract
Human Papillomavirus 16-associated cancer, affecting primarily the uterine cervix but, increasingly, other body districts, including the head–neck area, will long be a public health problem, despite there being a vaccine. Since the virus oncogenic activity is fully ascribed to the viral E6 and [...] Read more.
Human Papillomavirus 16-associated cancer, affecting primarily the uterine cervix but, increasingly, other body districts, including the head–neck area, will long be a public health problem, despite there being a vaccine. Since the virus oncogenic activity is fully ascribed to the viral E6 and E7 oncoproteins, one of the therapeutic approaches for HPV16 cancer is based on specific antibodies in single-chain format targeting the E6/E7 activity. We analyzed the Complementarity Determining Regions, repositories of antigen-binding activity, of four anti-HPV16 E6 and -HPV16 E7 scFvs, to highlight possible conformity to biophysical properties, recognized to be advantageous for therapeutic use. By epitope mapping, using E7 mutants with amino acid deletions or variations, we investigated differences among the anti-16E7 scFvs in terms of antigen-binding capacity. We also performed computational analyses to determine whether length, total net charge, surface hydrophobicity, polarity and charge distribution conformed well to those of the antibodies that had already reached clinical use, through the application of developability guidelines derived from recent literature on clinical-stage antibodies, and the Therapeutic Antibodies Profiler software. Overall, our findings show that the scFvs investigated may represent valid candidates to be developed as therapeutic molecules for clinical use, and highlight characteristics that could be improved by molecular engineering. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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11 pages, 244 KiB  
Article
The Role of HPV and Non-HPV Sexually Transmitted Infections in Patients with Oropharyngeal Carcinoma: A Case Control Study
by Barbara Kofler, Johannes Laimer, Emanuel Bruckmoser, Teresa B. Steinbichler, Annette Runge, Volker H. Schartinger, Dorothee von Laer and Wegene Borena
Cancers 2020, 12(5), 1192; https://doi.org/10.3390/cancers12051192 - 08 May 2020
Cited by 4 | Viewed by 2860
Abstract
Background: Certain high-risk (hr) types of human papillomavirus (HPV) can cause cervical cancer in women and penile cancer in men. Hr-HPV can also cause cancers of the oropharynx and anus in both sexes. In the anal and cervical region, a contribution of [...] Read more.
Background: Certain high-risk (hr) types of human papillomavirus (HPV) can cause cervical cancer in women and penile cancer in men. Hr-HPV can also cause cancers of the oropharynx and anus in both sexes. In the anal and cervical region, a contribution of co-infections with Ureaplasma spp. on the persistence of the hr-HPV infection by a profound inflammatory state is suggested. Here, we investigated if non-HPV sexually transmitted infections are associated with oropharyngeal carcinoma (OPC). Materials and Methods: In this case-control study, a brush test directly from the tumor surface of OPC patients (study group) and from the oropharynx of healthy volunteers (control group), both groups matching in age and sex, was performed. HPV subtypes were detected using a commercially available test kit. For non-HPV sexually transmitted infections (Ureaplasma spp., Chlamydia trachomatis, Mycoplasma hominis, and Mycoplasma genitalium), a multiplex nucleic acid amplification approach was performed. Results: In the study group, 96 patients (23 female/73 male), with histologically confirmed OPC and in the control group 112 patients (19 female/93 male), were included. Oropharyngeal hr-HPV-positivity was detected in 68% (65/96 patients) of the study group and 1.8% (2/112 patients) of the control group (p < 0.001). In three patients in the study group, Ureaplasma spp. was detected, whereas no patient was Ureaplasma spp. positive in the control group (p = 0.097). Chlamydia trachomatis, Mycoplasma hominis, and Mycoplasma genitalium were negative in both groups. Conclusion: Based on the current study, the prevalence of oropharyngeal Ureaplasma spp. among patients with OPC is low and does not support a role in oropharyngeal cancer. However, the detection of the pathogen only among OPC patients but not in the healthy individuals might indicate a potential role and needs further elucidation. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
12 pages, 793 KiB  
Article
Post-Treatment HPV Surface Brushings and Risk of Relapse in Oropharyngeal Carcinoma
by Barbara Kofler, Wegene Borena, Jozsef Dudas, Veronika Innerhofer, Daniel Dejaco, Teresa B Steinbichler, Gerlig Widmann, Dorothee von Laer and Herbert Riechelmann
Cancers 2020, 12(5), 1069; https://doi.org/10.3390/cancers12051069 - 25 Apr 2020
Cited by 8 | Viewed by 2374
Abstract
Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is a distinct subtype of head and neck cancer. Here, we investigated how frequently brushing remained high-risk (hr)-HPV positive after treatment and whether patients with positive post-treatment brushings have a higher recurrence rate. Following the [...] Read more.
Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is a distinct subtype of head and neck cancer. Here, we investigated how frequently brushing remained high-risk (hr)-HPV positive after treatment and whether patients with positive post-treatment brushings have a higher recurrence rate. Following the end of treatment of patients with initially hr-HPV positive OPSCC, surface brushings from the previous tumor site were performed and tested for hr-HPV DNA. Of 62 patients with initially hr-HPV DNA-positive OPSCC, seven patients remained hr-HPV-DNA positive at post-treatment follow-up. Of the seven hr-HPV-positive patients at follow-up, five had a tumor relapse or tumor progression, of whom three died. The majority of patients (55/62) was HPV-negative following treatment. All HPV-negative patients remained free of disease (p = 0.0007). In this study, all patients with recurrence were hr-HPV-positive with the same genotype as that before treatment. In patients who were hr-HPV negative after treatment, no recurrence was observed. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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19 pages, 3643 KiB  
Article
Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas and Paired Normal Mucosae Reveals Cyclin D1 Deregulation and Compensatory Effect of Cyclin D2
by Jiří Novotný, Veronika Bandúrová, Hynek Strnad, Martin Chovanec, Miluše Hradilová, Jana Šáchová, Martin Šteffl, Josipa Grušanović, Roman Kodet, Václav Pačes, Lukáš Lacina, Karel Smetana, Jr., Jan Plzák, Michal Kolář and Tomáš Vomastek
Cancers 2020, 12(4), 792; https://doi.org/10.3390/cancers12040792 - 26 Mar 2020
Cited by 10 | Viewed by 3876
Abstract
Aberrant regulation of the cell cycle is a typical feature of all forms of cancer. In head and neck squamous cell carcinoma (HNSCC), it is often associated with the overexpression of cyclin D1 (CCND1). However, it remains unclear how CCND1 expression [...] Read more.
Aberrant regulation of the cell cycle is a typical feature of all forms of cancer. In head and neck squamous cell carcinoma (HNSCC), it is often associated with the overexpression of cyclin D1 (CCND1). However, it remains unclear how CCND1 expression changes between tumor and normal tissues and whether human papillomavirus (HPV) affects differential CCND1 expression. Here, we evaluated the expression of D-type cyclins in a cohort of 94 HNSCC patients of which 82 were subjected to whole genome expression profiling of primary tumors and paired normal mucosa. Comparative analysis of paired samples showed that CCND1 was upregulated in 18% of HNSCC tumors. Counterintuitively, CCND1 was downregulated in 23% of carcinomas, more frequently in HPV-positive samples. There was no correlation between the change in D-type cyclin expression and patient survival. Intriguingly, among the tumors with downregulated CCND1, one-third showed an increase in cyclin D2 (CCND2) expression. On the other hand, one-third of tumors with upregulated CCND1 showed a decrease in CCND2. Collectively, we have shown that CCND1 was frequently downregulated in HNSCC tumors. Furthermore, regardless of the HPV status, our data suggested that a change in CCND1 expression was alleviated by a compensatory change in CCND2 expression. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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15 pages, 3163 KiB  
Article
Establishment and Molecular Phenotyping of Organoids from the Squamocolumnar Junction Region of the Uterine Cervix
by Yoshiaki Maru, Akira Kawata, Ayumi Taguchi, Yoshiyuki Ishii, Satoshi Baba, Mayuyo Mori, Takeshi Nagamatsu, Katsutoshi Oda, Iwao Kukimoto, Yutaka Osuga, Tomoyuki Fujii and Yoshitaka Hippo
Cancers 2020, 12(3), 694; https://doi.org/10.3390/cancers12030694 - 15 Mar 2020
Cited by 26 | Viewed by 4500
Abstract
The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, [...] Read more.
The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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18 pages, 2327 KiB  
Article
Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
by Karuna Mittal, Da Hoon Choi, Guanhao Wei, Jaspreet Kaur, Sergey Klimov, Komal Arora, Christopher C. Griffith, Mukesh Kumar, Precious Imhansi-Jacob, Brian D. Melton, Sonal Bhimji-Pattni, Remus M. Osan, Padmashree Rida, Paweł Golusinski and Ritu Aneja
Cancers 2020, 12(2), 517; https://doi.org/10.3390/cancers12020517 - 24 Feb 2020
Cited by 7 | Viewed by 3708
Abstract
Human papillomavirus-negative (HPV-neg) oropharyngeal squamous cell carcinomas (OPSCCs) are associated with poorer overall survival (OS) compared with HPV-positive (HPV-pos) OPSCCs. The major obstacle in improving outcomes of HPV-neg patients is the lack of robust biomarkers and therapeutic targets. Herein, we investigated the role [...] Read more.
Human papillomavirus-negative (HPV-neg) oropharyngeal squamous cell carcinomas (OPSCCs) are associated with poorer overall survival (OS) compared with HPV-positive (HPV-pos) OPSCCs. The major obstacle in improving outcomes of HPV-neg patients is the lack of robust biomarkers and therapeutic targets. Herein, we investigated the role of centrosome amplification (CA) as a prognostic biomarker in HPV-neg OPSCCs. A quantitative evaluation of CA in clinical specimens of OPSCC revealed that (a) HPV-neg OPSCCs exhibit higher CA compared with HPV-pos OPSCCs, and (b) CA was associated with poor OS, even after adjusting for potentially confounding clinicopathologic variables. Contrastingly, CA was higher in HPV-pos cultured cell lines compared to HPV-neg ones. This divergence in CA phenotypes between clinical specimens and cultured cells can therefore be attributed to an inaccurate recapitulation of the in vivo tumor microenvironment in the cultured cell lines, namely a hypoxic environment. The exposure of HPV-neg OPSCC cultured cells to hypoxia or stabilizing HIF-1α genetically increased CA. Both the 26-gene hypoxia signature as well as the overexpression of HIF-1α positively correlated with increased CA in HPV-neg OPSCCs. In addition, we showed that HIF-1α upregulation is associated with the downregulation of miR-34a, increase in CA and expression of cyclin- D1. Our findings demonstrate that the evaluation of CA may aid in therapeutic decision-making, and CA can serve as a promising therapeutic target for HPV-neg OPSCC patients. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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15 pages, 1316 KiB  
Article
Multistate Markov Model to Predict the Prognosis of High-Risk Human Papillomavirus-Related Cervical Lesions
by Ayumi Taguchi, Konan Hara, Jun Tomio, Kei Kawana, Tomoki Tanaka, Satoshi Baba, Akira Kawata, Satoko Eguchi, Tetsushi Tsuruga, Mayuyo Mori, Katsuyuki Adachi, Takeshi Nagamatsu, Katsutoshi Oda, Toshiharu Yasugi, Yutaka Osuga and Tomoyuki Fujii
Cancers 2020, 12(2), 270; https://doi.org/10.3390/cancers12020270 - 22 Jan 2020
Cited by 11 | Viewed by 3222
Abstract
Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability [...] Read more.
Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability of transitions between multiple states according to the genotypes of high-risk human papillomavirus (HPV). This retrospective cohort comprised 6022 observations in 737 patients (195 normal, 259 CIN1, and 283 CIN2 patients at the time of entry in the cohort). Patients were followed up or treated at the University of Tokyo Hospital between 2008 and 2015. Our model captured the prevalence trend satisfactory, particularly for up to two years. The estimated probabilities for 2-year transition to CIN3 or more were the highest in HPV 16-positive patients (13%, 30%, and 42% from normal, CIN1, and CIN2, respectively) compared with those in the other genotype-positive patients (3.1–9.6%, 7.6–16%, and 21–32% from normal, CIN1, and CIN2, respectively). Approximately 40% of HPV 52- or 58-related CINs remained at CIN1 and CIN2. The Markov model highlights the differences in transition and progression patterns between high-risk HPV-related CINs. HPV genotype-based management may be desirable for patients with cervical lesions. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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17 pages, 3476 KiB  
Article
Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers
by Martin A. Prusinkiewicz, Steven F. Gameiro, Farhad Ghasemi, Mackenzie J. Dodge, Peter Y. F. Zeng, Hanna Maekebay, John W. Barrett, Anthony C. Nichols and Joe S. Mymryk
Cancers 2020, 12(1), 253; https://doi.org/10.3390/cancers12010253 - 20 Jan 2020
Cited by 33 | Viewed by 5677
Abstract
Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive [...] Read more.
Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive HNSCC influences patient survival. The Cancer Genome Atlas RNA-seq data from primary HNSCC patient samples were categorized as 73 HPV-positive, 442 HPV-negative, and 43 normal-adjacent control tissues. We analyzed 229 metabolic genes and identified numerous differentially expressed genes between HPV-positive and negative HNSCC patients. HPV-positive carcinomas exhibited lower expression levels of genes involved in glycolysis and higher levels of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and β-oxidation than the HPV-negative carcinomas. Importantly, reduced expression of the metabolism-related genes SDHC, COX7A1, COX16, COX17, ELOVL6, GOT2, and SLC16A2 were correlated with improved patient survival only in the HPV-positive group. This work suggests that specific transcriptional alterations in metabolic genes may serve as predictive biomarkers of patient outcome and identifies potential targets for novel therapeutic intervention in HPV-positive head and neck cancers. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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15 pages, 2638 KiB  
Article
High Level Expression of MHC-II in HPV+ Head and Neck Cancers Suggests that Tumor Epithelial Cells Serve an Important Role as Accessory Antigen Presenting Cells
by Steven F. Gameiro, Farhad Ghasemi, John W. Barrett, Anthony C. Nichols and Joe S. Mymryk
Cancers 2019, 11(8), 1129; https://doi.org/10.3390/cancers11081129 - 07 Aug 2019
Cited by 22 | Viewed by 4318
Abstract
High-risk human papillomaviruses (HPVs) are responsible for a subset of head and neck squamous cell carcinomas (HNSCC). Expression of class II major histocompatibility complex (MHC-II) is associated with antigen presenting cells (APCs). During inflammation, epithelial cells can be induced to express MHC-II and [...] Read more.
High-risk human papillomaviruses (HPVs) are responsible for a subset of head and neck squamous cell carcinomas (HNSCC). Expression of class II major histocompatibility complex (MHC-II) is associated with antigen presenting cells (APCs). During inflammation, epithelial cells can be induced to express MHC-II and function as accessory APCs. Utilizing RNA-seq data from over 500 HNSCC patients from The Cancer Genome Atlas, we determined the impact of HPV-status on the expression of MHC-II genes and related genes involved in their regulation, antigen presentation, and T-cell co-stimulation. Expression of virtually all MHC-II genes was significantly upregulated in HPV+ carcinomas compared to HPV− or normal control tissue. Similarly, genes that encode products involved in antigen presentation were also significantly upregulated in the HPV+ cohort. In addition, the expression of CIITA and RFX5—regulators of MHC-II—were significantly upregulated in HPV+ tumors. This coordinated upregulation of MHC-II genes was correlated with higher intratumoral levels of interferon-gamma in HPV+ carcinomas. Furthermore, genes that encode various co-stimulatory molecules involved in T-cell activation and survival were also significantly upregulated in HPV+ tumors. Collectively, these results suggest a previously unappreciated role for epithelial cells in antigen presentation that functionally contributes to the highly immunogenic tumor microenvironment observed in HPV+ HNSCC. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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15 pages, 3841 KiB  
Article
The Antiviral Agent Cidofovir Induces DNA Damage and Mitotic Catastrophe in HPV-Positive and -Negative Head and Neck Squamous Cell Carcinomas In Vitro
by Femke Verhees, Dion Legemaate, Imke Demers, Robin Jacobs, Wisse Evert Haakma, Mat Rousch, Bernd Kremer and Ernst Jan Speel
Cancers 2019, 11(7), 919; https://doi.org/10.3390/cancers11070919 - 30 Jun 2019
Cited by 9 | Viewed by 3954
Abstract
Cidofovir (CDV) is an antiviral agent with antiproliferative properties. The aim of our study was to investigate the efficacy of CDV in HPV-positive and -negative head and neck squamous cell carcinoma (HNSCC) cell lines and whether it is caused by a difference in [...] Read more.
Cidofovir (CDV) is an antiviral agent with antiproliferative properties. The aim of our study was to investigate the efficacy of CDV in HPV-positive and -negative head and neck squamous cell carcinoma (HNSCC) cell lines and whether it is caused by a difference in response to DNA damage. Upon CDV treatment of HNSCC and normal oral keratinocyte cell lines, we carried out MTT analysis (cell viability), flow cytometry (cell cycle analysis), (immuno) fluorescence and western blotting (DNA double strand breaks, DNA damage response, apoptosis and mitotic catastrophe). The growth of the cell lines was inhibited by CDV treatment and resulted in γ-H2AX accumulation and upregulation of DNA repair proteins. CDV did not activate apoptosis but induced S- and G2/M phase arrest. Phospho-Aurora Kinase immunostaining showed a decrease in the amount of mitoses but an increase in aberrant mitoses suggesting mitotic catastrophe. In conclusion, CDV inhibits cell growth in HPV-positive and -negative HNSCC cell lines and was more profound in the HPV-positive cell lines. CDV treated cells show accumulation of DNA DSBs and DNA damage response activation, but apoptosis does not seem to occur. Rather our data indicate the occurrence of mitotic catastrophe. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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15 pages, 1848 KiB  
Article
Prevalence of Human Papillomavirus (HPV) Infection and the Association with Survival in Saudi Patients with Head and Neck Squamous Cell Carcinoma
by Ghazi Alsbeih, Najla Al-Harbi, Sara Bin Judia, Wejdan Al-Qahtani, Hatim Khoja, Medhat El-Sebaie and Asma Tulbah
Cancers 2019, 11(6), 820; https://doi.org/10.3390/cancers11060820 - 13 Jun 2019
Cited by 29 | Viewed by 4822
Abstract
Head and neck squamous cell carcinoma (HNSCC) shows wide disparities, association with human papillomavirus (HPV) infection, and prognosis. We aimed at determining HPV prevalence, and its prognostic association with overall survival (OS) in Saudi HNSCC patients. The study included 285 oropharyngeal and oral-cavity [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) shows wide disparities, association with human papillomavirus (HPV) infection, and prognosis. We aimed at determining HPV prevalence, and its prognostic association with overall survival (OS) in Saudi HNSCC patients. The study included 285 oropharyngeal and oral-cavity HNSCC patients. HPV was detected using HPV Linear-Array and RealLine HPV-HCR. In addition, p16INK4a (p16) protein overexpression was evaluated in 50 representative cases. Oropharyngeal cancers were infrequent (10%) compared to oral-cavity cancers (90%) with no gender differences. Overall, HPV-DNA was positive in 10 HNSCC cases (3.5%), mostly oropharyngeal (21%). However, p16 expression was positive in 21 cases of the 50 studied (42%) and showed significantly higher OS (p = 0.02). Kaplan–Meier univariate analysis showed significant associations between patients’ OS and age (p < 0.001), smoking (p = 0.02), and tumor stage (p < 0.001). A Cox proportional hazard multivariate analysis confirmed the significant associations with age, tumor stage, and also treatment (p < 0.01). In conclusion, HPV-DNA prevalence was significantly lower in our HNSCC patients than worldwide 32–36% estimates (p ≤ 0.001). Although infrequent, oropharyngeal cancer increased over years and showed 21% HPV-DNA positivity, which is close to the worldwide 36–46% estimates (p = 0.16). Besides age, smoking, tumor stage, and treatment, HPV/p16 status was an important determinant of patients’ survival. The HPV and/or p16 positivity patients had a better OS than HPV/p16 double-negative patients (p = 0.05). Thus, HPV/p16 status helps improve prognosis by distinguishing between the more favorable p16/HPV positive and the less favorable double-negative tumors. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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Review

Jump to: Editorial, Research

38 pages, 1257 KiB  
Review
Plant-Derived Natural Compounds in Genetic Vaccination and Therapy for HPV-Associated Cancers
by Rosella Franconi, Silvia Massa, Francesca Paolini, Patrizia Vici and Aldo Venuti
Cancers 2020, 12(11), 3101; https://doi.org/10.3390/cancers12113101 - 23 Oct 2020
Cited by 15 | Viewed by 3938
Abstract
Antigen-specific immunotherapy and, in particular, DNA vaccination provides an established approach for tackling human papillomavirus (HPV) cancers at different stages. DNA vaccines are stable and have a cost-effective production. Their intrinsic low immunogenicity has been improved by several strategies with some success, including [...] Read more.
Antigen-specific immunotherapy and, in particular, DNA vaccination provides an established approach for tackling human papillomavirus (HPV) cancers at different stages. DNA vaccines are stable and have a cost-effective production. Their intrinsic low immunogenicity has been improved by several strategies with some success, including fusion of HPV antigens with plant gene sequences. Another approach for the control of HPV cancers is the use of natural immunomodulatory agents like those derived from plants, that are able to interfere in carcinogenesis by modulating many different cellular pathways and, in some instances, to reduce chemo- and radiotherapy resistance of tumors. Indeed, plant-derived compounds represent, in many cases, an abundantly available, cost-effective source of molecules that can be either harvested directly in nature or obtained from plant cell cultures. In this review, an overview of the most relevant data reported in literature on the use of plant natural compounds and genetic vaccines that include plant-derived sequences against HPV tumors is provided. The purpose is also to highlight the still under-explored potential of multimodal treatments implying DNA vaccination along with plant-derived agents. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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Graphical abstract

28 pages, 2107 KiB  
Review
Beyond MicroRNAs: Emerging Role of Other Non-Coding RNAs in HPV-Driven Cancers
by Mariateresa Casarotto, Giuseppe Fanetti, Roberto Guerrieri, Elisa Palazzari, Valentina Lupato, Agostino Steffan, Jerry Polesel, Paolo Boscolo-Rizzo and Elisabetta Fratta
Cancers 2020, 12(5), 1246; https://doi.org/10.3390/cancers12051246 - 15 May 2020
Cited by 23 | Viewed by 4125
Abstract
Persistent infection with high-risk Human Papilloma Virus (HPV) leads to the development of several tumors, including cervical, oropharyngeal, and anogenital squamous cell carcinoma. In the last years, the use of high-throughput sequencing technologies has revealed a number of non-coding RNA (ncRNAs), distinct from [...] Read more.
Persistent infection with high-risk Human Papilloma Virus (HPV) leads to the development of several tumors, including cervical, oropharyngeal, and anogenital squamous cell carcinoma. In the last years, the use of high-throughput sequencing technologies has revealed a number of non-coding RNA (ncRNAs), distinct from micro RNAs (miRNAs), that are deregulated in HPV-driven cancers, thus suggesting that HPV infection may affect their expression. However, since the knowledge of ncRNAs is still limited, a better understanding of ncRNAs biology, biogenesis, and function may be challenging for improving the diagnosis of HPV infection or progression, and for monitoring the response to therapy of patients affected by HPV-driven tumors. In addition, to establish a ncRNAs expression profile may be instrumental for developing more effective therapeutic strategies for the treatment of HPV-associated lesions and cancers. Therefore, this review will address novel classes of ncRNAs that have recently started to draw increasing attention in HPV-driven tumors, with a particular focus on ncRNAs that have been identified as a direct target of HPV oncoproteins. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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20 pages, 2881 KiB  
Review
In Vitro Organotypic Systems to Model Tumor Microenvironment in Human Papillomavirus (HPV)-Related Cancers
by Vincenza De Gregorio, Francesco Urciuolo, Paolo Antonio Netti and Giorgia Imparato
Cancers 2020, 12(5), 1150; https://doi.org/10.3390/cancers12051150 - 03 May 2020
Cited by 15 | Viewed by 4702
Abstract
Despite the well-known role of chronic human papillomavirus (HPV) infections in causing tumors (i.e., all cervical cancers and other human malignancies from the mucosal squamous epithelia, including anogenital and oropharyngeal cavity), its persistence is not sufficient for cancer development. Other co-factors contribute to [...] Read more.
Despite the well-known role of chronic human papillomavirus (HPV) infections in causing tumors (i.e., all cervical cancers and other human malignancies from the mucosal squamous epithelia, including anogenital and oropharyngeal cavity), its persistence is not sufficient for cancer development. Other co-factors contribute to the carcinogenesis process. Recently, the critical role of the underlying stroma during the HPV life cycle and HPV-induced disease have been investigated. The tumor stroma is a key component of the tumor microenvironment (TME), which is a specialized entity. The TME is dynamic, interactive, and constantly changing—able to trigger, support, and drive tumor initiation, progression, and metastasis. In previous years, in vitro organotypic raft cultures and in vivo genetically engineered mouse models have provided researchers with important information on the interactions between HPVs and the epithelium. Further development for an in-depth understanding of the interaction between HPV-infected tissue and the surrounding microenvironment is strongly required. In this review, we critically describe the HPV-related cancers modeled in vitro from the simplified ‘raft culture’ to complex three-dimensional (3D) organotypic models, focusing on HPV-associated cervical cancer disease platforms. In addition, we review the latest knowledge in the field of in vitro culture systems of HPV-associated malignancies of other mucosal squamous epithelia (anogenital and oropharynx), as well as rare cutaneous non-melanoma associated cancer. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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Graphical abstract

14 pages, 301 KiB  
Review
Self-Collection for Cervical Screening Programs: From Research to Reality
by David Hawkes, Marco H. T. Keung, Yanping Huang, Tracey L. McDermott, Joanne Romano, Marion Saville and Julia M. L. Brotherton
Cancers 2020, 12(4), 1053; https://doi.org/10.3390/cancers12041053 - 24 Apr 2020
Cited by 45 | Viewed by 8021
Abstract
In 2018, there were an estimated 570,000 new cases of cervical cancer globally, with most of them occurring in women who either had no access to cervical screening, or had not participated in screening in regions where programs are available. Where programs are [...] Read more.
In 2018, there were an estimated 570,000 new cases of cervical cancer globally, with most of them occurring in women who either had no access to cervical screening, or had not participated in screening in regions where programs are available. Where programs are in place, a major barrier for women across many cultures has been the requirement to undergo a speculum examination. With the emergence of HPV-based primary screening, the option of self-collection (where the woman takes the sample from the vagina herself) may overcome this barrier, given that such samples when tested using a PCR-based HPV assay have similar sensitivity for the detection of cervical pre-cancers as practitioner-collected cervical specimens. Other advantages of HPV-based screening using self-collection, beyond the increase in acceptability to women, include scalability, efficiency, and high negative predictive value, allowing for long intervals between negative tests. Self-collection will be a key strategy for the successful scale up of cervical screening programs globally in response to the WHO call for all countries to work towards the elimination of cervical cancer as a public health problem. This review will examine self-collection for HPV-based cervical screening including the collection devices, assays and possible routine laboratory processes considering how they can be utilized in cervical screening programs. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
14 pages, 1507 KiB  
Review
Management of HPV-Related Squamous Cell Carcinoma of the Head and Neck: Pitfalls and Caveat
by Francesco Perri, Francesco Longo, Francesco Caponigro, Fabio Sandomenico, Agostino Guida, Giuseppina Della Vittoria Scarpati, Alessandro Ottaiano, Paolo Muto and Franco Ionna
Cancers 2020, 12(4), 975; https://doi.org/10.3390/cancers12040975 - 15 Apr 2020
Cited by 27 | Viewed by 5392
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are a very heterogeneous group of malignancies arising from the upper aerodigestive tract. They show different clinical behaviors depending on their origin site and genetics. Several data support the existence of at least two genetically different [...] Read more.
Head and neck squamous cell carcinomas (HNSCCs) are a very heterogeneous group of malignancies arising from the upper aerodigestive tract. They show different clinical behaviors depending on their origin site and genetics. Several data support the existence of at least two genetically different types of HNSCC, one virus-related and the other alcohol and/or tobacco and oral trauma-related, which show both clinical and biological opposite features. In fact, human papillomavirus (HPV)-related HNSCCs, which are mainly located in the oropharynx, are characterized by better prognosis and response to therapies when compared to HPV-negative HNSCCs. Interestingly, virus-related HNSCC has shown a better response to conservative (nonsurgical) treatments and immunotherapy, opening questions about the possibility to perform a pretherapy assessment which could totally guide the treatment strategy. In this review, we summarize molecular differences and similarities between HPV-positive and HPV-negative HNSCC, highlighting their impact on clinical behavior and on therapeutic strategies. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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18 pages, 3003 KiB  
Review
The Interplay between Antiviral Signalling and Carcinogenesis in Human Papillomavirus Infections
by Ana Rita Ferreira, Ana Catarina Ramalho, Mariana Marques and Daniela Ribeiro
Cancers 2020, 12(3), 646; https://doi.org/10.3390/cancers12030646 - 10 Mar 2020
Cited by 34 | Viewed by 5546
Abstract
Human papillomaviruses (HPV) are the causative agents of the most common sexually transmitted infection worldwide. While infection is generally asymptomatic and can be cleared by the host immune system, when persistence occurs, HPV can become a risk factor for malignant transformation. Progression to [...] Read more.
Human papillomaviruses (HPV) are the causative agents of the most common sexually transmitted infection worldwide. While infection is generally asymptomatic and can be cleared by the host immune system, when persistence occurs, HPV can become a risk factor for malignant transformation. Progression to cancer is actually an unintended consequence of the complex HPV life cycle. Different antiviral defence mechanisms recognize HPV early in infection, leading to the activation of the innate immune response. However, the virus has evolved several specific strategies to efficiently evade the antiviral immune signalling. Here, we review and discuss the interplay between HPV and the host cell innate immunity. We further highlight the evasion strategies developed by different HPV to escape this cellular response and focus on the correlation with HPV-induced persistence and tumorigenesis. Full article
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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