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Dervenis V. The Role of HPV in the Development of Cutaneous Squamous Cell Carcinoma-Friend or Foe? Cancers (Basel) 2025; 17:1195. [PMID: 40227794 PMCID: PMC11988061 DOI: 10.3390/cancers17071195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/19/2025] [Accepted: 03/30/2025] [Indexed: 04/15/2025] Open
Abstract
The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing, with UV radiation being the main cause. Other risk factors are age, sex, skin type and immunosuppression. Human papillomaviruses (HPVs) are associated with benign and malignant skin tumours. In contrast to anogenital and oropharyngeal carcinomas, which are caused by alpha papillomaviruses, the HPV types associated with cSCC belong to the beta-HPV genus. These viruses infect the skin epithelium and are widespread in skin samples from healthy people. It is assumed that HPV amplifies the DNA damage caused by UV radiation and disrupts the repair mechanisms of the cells, without remaining permanently detectable in the tumour tissue, the so-called hit-and-run theory. The HPV status of tumours appears to have a positive influence on prognosis and response to therapy due to increased immune infiltration, in particular by tissue-resident memory T cells and activation of immune effector cells. This favours responses to immunotherapies such as PD-1/PD-L1 inhibitors, whereas immunosuppression may promote a pro-carcinogenic effect. In conclusion, the role of beta HPV in the development of cSCC appears to be closely associated with the immune status of the host. Depending on the immune status, beta HPV can play either a protective or a tumour-promoting role, and in view of the increasing incidence of skin cancer worldwide, enhancing the immune response against virus-infected keratinocytes, e.g., through HPV vaccination, could represent a promising approach for the prevention and therapy of squamous cell carcinomas.
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Affiliation(s)
- Vasileios Dervenis
- Department of Dermatology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany
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Nam HJ, Ryu H, Lee DW, Byeon JY, Kim JH, Lee JH, Lim S, Choi HJ. Expression rates of p16, p53 in head and neck cutaneous squamous cell carcinoma based on human-papillomavirus positivity. World J Clin Cases 2025; 13:99463. [PMID: 40144480 PMCID: PMC11670024 DOI: 10.12998/wjcc.v13.i9.99463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/02/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND The high prevalence of human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (SCC) is well established, and p16 expression is a strong predictor. HPV-related tumors exhibit unique mechanisms that target p16 and p53 proteins. However, research on HPV prevalence and the combined predictive value of p16 and p53 expression in head and neck cutaneous SCC (HNCSCC), particularly in Asian populations, remains limited. This retrospective study surveyed 62 patients with HNSCC (2011-2020), excluding those with facial warts or other skin cancer. AIM To explore the prevalence of HPV and the predictive value of p16 and p53 expression in HNCSCC in Asian populations. METHODS All patients underwent wide excision and biopsy. Immunohistochemical staining for HPV, p16, and p53 yielded positive and negative results. The relevance of each marker was investigated by categorizing the tumor locations into high-risk and middle-risk zones based on recurrence frequency. RESULTS Of the 62 patients, 20 (32.26%) were male, with an average age of 82.27 years (range 26-103 years). High-risk included 19 cases (30.65%), with the eyelid and lip being the most common sites (five cases, 8.06%). Middle-risk included 43 cases (69.35%), with the cheek being the most common (29 cases, 46.77%). The p16 expression was detected in 24 patients (38.71%), p53 expression in 42 patients (72.58%), and HPV in five patients (8.06%). No significant association was found between p16 expression and the presence of HPV (P > 0.99), with a positive predictive value of 8.33%. CONCLUSION This study revealed that p16, a surrogate HPV marker in oropharyngeal SCC, is not reliable in HNCSCC, providing valuable insights for further research in Asian populations.
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Affiliation(s)
- Ha-Jong Nam
- Department of Plastic and Reconstructive Surgery, Soonchunhyang University Gumi Hospital, Gumi-si 39371, South Korea
| | - Heongrae Ryu
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan-si 31151, South Korea
| | - Da-Woon Lee
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan-si 31151, South Korea
| | - Je Yeon Byeon
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan-si 31151, South Korea
| | - Jun Hyuk Kim
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan-si 31151, South Korea
| | - Ji Hye Lee
- Department of Pathology, Soonchunhyang University Hospital, Cheonan-si 31151, South Korea
| | - Soomin Lim
- Bachelor of Medicine and Bachelor of Surgery, University College London, Medical School, London WC1E 6DE, United Kingdom
| | - Hwan Jun Choi
- Department of Plastic and Reconstructive Surgery, College of Medicine, Soonchunhyang University, Cheonan-si 31151, South Korea
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Wong M, Tu HF, Tseng SH, Mellinger-Pilgrim R, Best S, Tsai HL, Xing D, Hung CF, Lambert PF, Roden RBS. MmuPV1 infection of Tmc6/Ever1 or Tmc8/Ever2 deficient FVB mice as a model of βHPV in typical epidermodysplasia verruciformis. PLoS Pathog 2025; 21:e1012837. [PMID: 39813296 PMCID: PMC11734914 DOI: 10.1371/journal.ppat.1012837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/17/2024] [Indexed: 01/18/2025] Open
Abstract
Typical epidermodysplasia verruciformis (EV) is a rare, autosomal recessive disorder characterized by an unusual susceptibility to infection with specific skin-trophic types of human papillomavirus, principally betapapillomaviruses, and a propensity for developing malignant skin tumors in sun exposed regions. Its etiology reflects biallelic loss-of-function mutations in TMC6 (EVER1), TMC8 (EVER2) or CIB1. A TMC6-TMC8-CIB1 protein complex in the endoplasmic reticulum is hypothesized to be a restriction factor in keratinocytes for βHPV infection. However, the complex is also present in lymphocytes and its loss may compromise cellular immune control of βHPV infection. Indeed, certain primary immunodeficiencies, iatrogenic immunosuppression and AIDS are associated with the atypical form of EV. While well controlled in immunocompetent mice, murine papillomavirus MmuPV1 was first isolated from immunodeficient mice with florid skin warts, modeling atypical EV. To examine their potential as a model of typical EV, Tmc6-/-, Tmc8-/- or wildtype FVB mice were challenged with MmuPV1. At day 16 post vaginal challenge with MmuPV1, the levels of viral transcripts were similar in Tmc6-/- and Tmc8-/- mice and wildtype FVB mice, arguing against Tmc6/8 acting as intracellular restriction factors. Thereafter, greater clearance of MmuPV1 by the wildtype that the Tmc6-/- and Tmc8-/- FVB mice was evident, supporting the hypothesis that typical EV reflects a subtle cellular immune deficit. Indeed, Tmc6-/- or Tmc8-/- mice exhibit partial CD8 T cell deficits and elevated Treg. While interferon-γ production and surface CD25 were similarly elevated in CD8 T cells upon in vitro stimulation with anti-CD3/CD28, the fraction of Tmc6-/- or Tmc8-/- CD8 T cells that were dividing was lower compared to wildtype. Typical EV patients exhibit normal control of most viral infections; Tmc6-/-, Tmc8-/- and wildtype FVB mice similarly controlled vaccinia virus after skin challenge and induced neutralizing antibodies.
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Affiliation(s)
- Margaret Wong
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Hsin-Fang Tu
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Ssu-Hsieh Tseng
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Rebecca Mellinger-Pilgrim
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institution, Baltimore, Maryland, United States of America
| | - Simon Best
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institution, Baltimore, Maryland, United States of America
| | - Hua-Ling Tsai
- Oncology Biostatistics, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Deyin Xing
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Chien-fu Hung
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Richard B. S. Roden
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America
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Meyer T, Stockfleth E. Treatment and Prevention of HPV-Associated Skin Tumors by HPV Vaccination. Vaccines (Basel) 2024; 12:1439. [PMID: 39772099 PMCID: PMC11680430 DOI: 10.3390/vaccines12121439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/18/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
HPV-associated dermatological diseases include benign lesions like cutaneous warts and external genital warts. In addition, HPV infection is associated with the development of epithelial skin cancers, in particular cutaneous squamous cell carcinoma (cSCC). In contrast to anogenital and oropharyngeal cancers caused by mucosal HPV types of genus alpha papillomavirus, cSCC-associated HPV types belong to the genus beta papillomavirus. Currently available HPV vaccines that target mucosal HPV types associated with anogenital cancer and genital warts are type-specific and provide no cross-protection against beta HPV. When implementing vaccination to beta HPV to prevent skin tumors, it must be considered that acquisition of these HPV types occurs early in childhood and that the risk for cSCC increases with growing age and decreasing immune surveillance. Thus, individuals considered for beta HPV vaccination usually have pre-existing infection and are largely immunocompromised. On the other hand, worldwide increasing incidence rates of epithelial skin cancer reflect an urgent need for skin cancer prevention measures. Based on the pathogenic involvement of beta HPV, vaccination may represent a promising prevention strategy. Indeed, various procedures of prophylactic and therapeutic vaccination have been developed, and some of them have shown efficiency in animal models. Thus far, however, none of these vaccine candidates has been approved for application in humans.
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Affiliation(s)
- Thomas Meyer
- Department of Dermatology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany;
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Solanes-Vilanova F, Chiers K, Gil-Lianes J, Hellebuyck T. Clinical features, surgical management and outcome of squamous and basal cell carcinoma in squamates and chelonians. Vet Dermatol 2024; 35:626-640. [PMID: 39109495 DOI: 10.1111/vde.13282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 05/25/2024] [Accepted: 07/24/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Squamous cell carcinoma (SCC) is one of the most commonly diagnosed neoplastic disorders in reptiles. Recently, however, it has been demonstrated that basal cell carcinomas (BCCs) are frequently misclassified as SCCs. Several histological SCC and BCC variants have been characterised and their classification may allow the establishment of appropriate prognosis estimation and treatment approaches. HYPOTHESIS/OBJECTIVES To describe the clinical features and surgical outcomes of SCCs and BCCs diagnosed between 2010 and 2022 in reptiles. ANIMALS Thirty-three captive reptiles (21 squamates and 12 chelonians). MATERIALS AND METHODS Detailed clinical history, including staging and surgical outcomes, were performed. Statistical analysis assessed significant factors using Prism (v8.2.1). RESULTS While SCC was predominantly diagnosed in lizards, BCC was most commonly diagnosed in chelonians, and both neoplasms mainly occurred in adult to aged, male individuals. Although the gross pathological findings were highly comparable between SCC and BCC, considerable variation could be seen according to the primary location (oral, cutaneous or epidermis of the shell). Humane euthanasia or noncurative intent surgeries were performed in a minority of the cases. Curative intent surgeries were successful in 19 of 27 cases during a 1- to 7-year follow-up period, yet recurrence was seen in 8 cases. The results of this study allowed the identification of significant high-risk prognostic factors for SCC and BCC in reptiles. CONCLUSIONS AND CLINICAL RELEVANCE This study contributes to predicting the clinical behaviour and prognosis of distinct SCC and BCC histological variants, and selecting the most appropriate treatment protocol.
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Affiliation(s)
- Ferran Solanes-Vilanova
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Koen Chiers
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Javier Gil-Lianes
- Department of Dermatology, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
| | - Tom Hellebuyck
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
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Hasche D, Hufbauer M, Braspenning-Wesch I, Stephan S, Silling S, Schmidt G, Krieg S, Kreuter A, Akgül B. Cytokeratin 17 expression is commonly observed in keratinocytic skin tumours and controls tissue homeostasis impacting human papillomavirus protein expression. Br J Dermatol 2024; 191:949-963. [PMID: 38878280 DOI: 10.1093/bjd/ljae255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 06/06/2024] [Accepted: 06/09/2024] [Indexed: 07/26/2024]
Abstract
BACKGROUND The structured expression of several keratins in the skin is associated with differentiation status of the epidermal layers, whereas other keratins are upregulated only during wound healing, in skin disorders and in cancers. One of these stress keratins, K17, is correlated with poor prognosis in various cancer types and its loss has been shown to decelerate tumour growth. K17 expression can also be detected in cutaneous squamous cell carcinomas, where ultraviolet irradiation and infection with cutaneous human papillomaviruses are important cofactors. It was previously reported that K17 is upregulated in papillomavirus (PV)-induced benign skin lesions in mice and induces an immunological status that is beneficial for tumour growth. OBJECTIVES In order to investigate whether K17 upregulation is induced by PVs, we analysed K17 levels in skin tumour specimens of different animal models and humans. METHODS Various immunofluorescence stainings were performed to identify K17 expression as well as levels of E-cadherin, vimentin and CD271. Tissues were further analysed by polymerase chain reaction (PCR), quantitative (q)PCR and enzyme-linked immunosorbent assay to control for PV activity. K17 knockdown cells were generated and effects on viral life cycle were investigated by infection assays, qPCR and Western blotting. RESULTS We showed that K17 is commonly expressed in skin tumours and that its presence is not directly linked to viral oncoprotein expression. Rather, K17 expression seems to be a marker of epithelial differentiation and its absence in tumour tissue is associated with an epithelial-to-mesenchymal transition. We further demonstrated that the absence of K17 in skin tumours increases markers of cancer stem-like cells and negatively affects viral protein synthesis. CONCLUSIONS Collectively, our data indicate that K17 expression is a common feature in skin tumorigenesis. While K17 is not primarily targeted by PV oncoproteins, our in vivo and in vitro data suggest that it is an important regulator of epithelial differentiation and thus may play a role in controlling viral protein synthesis.
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Affiliation(s)
- Daniel Hasche
- Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Hufbauer
- National Reference Center for Papilloma- and Polyomaviruses and Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
| | - Ilona Braspenning-Wesch
- Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja Stephan
- Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Steffi Silling
- National Reference Center for Papilloma- and Polyomaviruses and Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
| | - Gabriele Schmidt
- Light Microscopy Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephan Krieg
- Helmholtz-University Group Cell Plasticity and Epigenetic Remodeling, German Cancer Research Center (DKFZ) & Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Alexander Kreuter
- Department of Dermatology, Venereology and Allergology, Helios St. Elisabeth Hospital Oberhausen, University of Witten/Herdecke, Oberhausen, Germany
| | - Baki Akgül
- National Reference Center for Papilloma- and Polyomaviruses and Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
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Gao S, Wei G, Ma Q, Wang X, Wang S, Niu Y. Causal relationship between anti-inflammatory drugs and cancer: a pan-cancer study with Mendelian randomization. Front Genet 2024; 15:1392745. [PMID: 38854429 PMCID: PMC11156997 DOI: 10.3389/fgene.2024.1392745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/08/2024] [Indexed: 06/11/2024] Open
Abstract
Background Numerous epidemiological studies have elucidated the intricate connection between inflammation and cancer, highlighting how sustained inflammatory responses can fuel carcinogenesis by fostering proliferation, angiogenesis, and metastasis, while dampening immune responses and sensitivity to chemotherapy. Previous clinical investigations have underscored the potential of anti-inflammatory medications in either preventing or mitigating tumor formation. Here, the causal relationship between anti-inflammatory drugs and cancer was further explored through Mendelian randomization studies. Methods Employing Mendelian randomization, we scrutinized the causal links between three anti-inflammatory drugs-NSAIDs, Aspirin, and Anilide-and 37 types of cancer. We primarily utilized inverse variance weighting (IVW) as the primary analytical approach to delineate the causal association between these drugs and cancer types. Concurrently, sensitivity analyses were conducted to ascertain the absence of horizontal pleiotropy and heterogeneity. Results Our investigation revealed a discernible causal relationship between certain anti-inflammatory drugs and a subset of cancers, albeit without a pervasive impact across all cancer types. Specifically, NSAIDs exhibited a risk-reducing effect on non-small cell lung cancer (OR: 0.76, 95% CI: 0.59-0.97, p-value: 0.03) and gastric cancer (OR: 0.57, 95% CI: 0.34-0.98, p-value: 0.04). Conversely, aspirin was associated with an increased risk of oral malignant tumors (OR: 2.18, 95% CI: 1.13-4.21, p-value: 0.02). Notably, no statistically significant findings were observed for anilide drugs (p < 0.05). Conclusion We identified several cancers with potential causal links to NSAIDs, including non-small cell lung cancer and gastric cancer. Despite our extensive analysis, we did not identify a substantial causal relationship between the use of anti-inflammatory drugs and the development of various cancers.
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Affiliation(s)
- Shen Gao
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Guojiang Wei
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Qianwang Ma
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xue Wang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Sen Wang
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuanjie Niu
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
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Polinas M, Cacciotto C, Zobba R, Antuofermo E, Burrai GP, Pirino S, Pittau M, Alberti A. Ovine papillomaviruses: Diversity, pathogenicity, and evolution. Vet Microbiol 2024; 289:109955. [PMID: 38160507 DOI: 10.1016/j.vetmic.2023.109955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/14/2023] [Accepted: 12/17/2023] [Indexed: 01/03/2024]
Abstract
The family Papillomaviridae includes a plethora of viral species infecting virtually all vertebrates excluding amphibians, with astonishing impact on human and animal health. Although more than 250 species have been described in humans, the total number of papillomaviruses (PVs) discovered in animals does not reach up to this number. In animals, PV infections are mostly asymptomatic or can cause variable clinical conditions ranging from self-limiting papillomas and other cutaneous and mucosal benign lesions to cancer. Most of animal PV types have been discovered in cattle, dogs, horses, and cats with other farm host species remaining overlooked. In particular, the number of PV types so far identified in sheep is limited. This paper comprehensively reviews ovine PVs features, including viral taxonomy and evolution; genome organization; viral tropism and pathogenesis; macroscopical features and histopathological patterns, as well as available diagnostics tools. Data are critically presented and discussed in terms of impact on veterinary and public health. The development of future dedicated research is also discussed.
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Affiliation(s)
- Marta Polinas
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy
| | - Carla Cacciotto
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy; Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy
| | - Rosanna Zobba
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy; Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy
| | - Elisabetta Antuofermo
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy; Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy
| | - Giovanni Pietro Burrai
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy; Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy
| | - Salvatore Pirino
- Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy
| | - Marco Pittau
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy; Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy
| | - Alberto Alberti
- Dipartimento di Medicina Veterinaria, Università degli studi di Sassari, Italy; Mediterranean Center for Disease Control, Università degli studi di Sassari, Italy.
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Lozar T, Keske A, Dube Mandishora RS, Yu Q, Bailey A, Xu J, Tommasino M, McGregor SM, Lambert PF, Gheit T, Fitzpatrick MB. Betapapillomaviruses in p16-Negative Vulvar Intraepithelial Lesions Associated with Squamous Cell Carcinoma. Viruses 2023; 15:1950. [PMID: 37766356 PMCID: PMC10537070 DOI: 10.3390/v15091950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/16/2023] [Accepted: 09/17/2023] [Indexed: 09/29/2023] Open
Abstract
Approximately 40% of vulvar squamous cell carcinoma (vSCC) cases are etiologically associated with high-risk human papillomaviruses (HPVs) of the alpha genera (α-HPV) that cause other anogenital cancers; however, the etiology of α-HPV-negative vSCC is poorly understood. HPVs of the beta genera (β-HPV) are risk factors for cutaneous squamous cell carcinoma (cSCC) and may be related to carcinomas originating in other cutaneous sites such as the vulva. In this study, we investigate the presence of β-HPVs, with an emphasis on p16-negative squamous lesions adjacent to vSCC. We subjected 28 vulvar squamous intraepithelial lesions adjacent to vSCC for comprehensive HPV genotyping, p16 and p53 immunohistochemistry, and consensus morphology review. Selected cases were subjected to qPCR and RNA in situ hybridization. Clinical data were obtained from medical records. β-HPV DNA was detected in eight of ten p16-negative lesions and three of fourteen p16-positive high-grade squamous intraepithelial lesions. The HPV DNA loads in vulvar squamous intraepithelial lesions ranged between less than 1 HPV DNA copy per cell to more than 100 HPV DNA copies per cell. This is, to the best of our knowledge, the first report of the association of p16-negative vulvar intraepithelial squamous lesions with detection of β-HPVs. These findings expand possible etiologic mechanisms that may contribute to p16-negative lesions of the vulva.
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Affiliation(s)
- Taja Lozar
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (T.L.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA
- University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Aysenur Keske
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | - Racheal S. Dube Mandishora
- Center for Immunization and Infection Research in Cancer (CIIRC), Moffit Cancer Center, Tampa, FL 33612, USA
- Medical Microbiology Unit, University of Zimbabwe Faculty of Health Sciences, Harare P.O. Box A178, Zimbabwe
| | - Qiqi Yu
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA;
| | - Adam Bailey
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | - Jin Xu
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | | | - Stephanie M. McGregor
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (T.L.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA
| | - Tarik Gheit
- International Agency for Research on Cancer, 69007 Lyon, France
| | - Megan B. Fitzpatrick
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
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Schäfer M, Schneider M, Müller T, Franz N, Braspenning-Wesch I, Stephan S, Schmidt G, Krijgsveld J, Helm D, Rösl F, Hasche D. Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus-induced keratinocyte carcinomas. J Med Virol 2023; 95:e28850. [PMID: 37322807 DOI: 10.1002/jmv.28850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/17/2023]
Abstract
Infection with certain cutaneous human papillomaviruses (HPV), in conjunction with chronic ultraviolet (UV) exposure, are the major cofactors of non-melanoma skin cancer (NMSC), the most frequent cancer type worldwide. Cutaneous squamous cell carcinomas (SCCs) as well as tumors in general represent three-dimensional entities determined by both temporal and spatial constraints. Whole tissue proteomics is a straightforward approach to understand tumorigenesis in better detail, but studies focusing on different progression states toward a dedifferentiated SCC phenotype on a spatial level are rare. Here, we applied an innovative proteomic workflow on formalin-fixed, paraffin-embedded (FFPE) epithelial tumors derived from the preclinical animal model Mastomys coucha. This rodent is naturally infected with its genuine cutaneous papillomavirus and closely mimics skin carcinogenesis in the context of cutaneous HPV infections in humans. We deciphered cellular networks by comparing diverse epithelial tissues with respect to their differentiation level and infection status. Our study reveals novel regulatory proteins and pathways associated with virus-induced tumor initiation and progression of SCCs. This approach provides the basis to better comprehend the multistep process of skin carcinogenesis.
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Affiliation(s)
- Miriam Schäfer
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Schneider
- Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Torsten Müller
- Division Proteomics of Stem Cells and Cancer, Research Program "Functional and Structural Genomics", German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg University, Medical Faculty, Heidelberg, Germany
| | - Natascha Franz
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ilona Braspenning-Wesch
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja Stephan
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Gabriele Schmidt
- Core Facility Unit Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen Krijgsveld
- Division Proteomics of Stem Cells and Cancer, Research Program "Functional and Structural Genomics", German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg University, Medical Faculty, Heidelberg, Germany
| | - Dominic Helm
- Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Rösl
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Hasche
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
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11
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Borgogna C, Martuscelli L, Olivero C, Lo Cigno I, De Andrea M, Caneparo V, Boldorini R, Patel G, Gariglio M. Enhanced Spontaneous Skin Tumorigenesis and Aberrant Inflammatory Response to UVB Exposure in Immunosuppressed Human Papillomavirus Type 8‒Transgenic Mice. J Invest Dermatol 2022; 143:740-750.e4. [PMID: 36481357 DOI: 10.1016/j.jid.2022.10.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 10/09/2022] [Accepted: 10/24/2022] [Indexed: 12/12/2022]
Abstract
Human papillomaviruses (HPVs) from the beta genus are commensal viruses of the skin usually associated with asymptomatic infection in the general population. However, in individuals with specific genetic backgrounds, such as patients with epidermodysplasia verruciformis, or those with immune defects, such as organ transplant recipients, they are functionally involved in sunlight-induced skin cancer development, mainly keratinocyte carcinoma. Despite their well-established protumorigenic role, the cooperation between β-HPV infection, impaired host immunosurveillance, and UVB exposure has never been formally shown in animal models. In this study, by crossing skin-specific HPV8-transgenic mice with Rag2-deficient mice, we have generated a preclinical mouse model, named Rag2‒/‒:K14-HPV8. These mice display an unhealthy skin phenotype and spontaneously develop papilloma-like lesions spreading to the entire skin much more rapidly compared with Rag2+/+:K14-HPV8 mice. Exposure to low doses of UVB radiation is sufficient to trigger severe skin inflammation in Rag2‒/‒:K14-HPV8 but not in Rag2+/+:K14-HPV8 mice. Their inflamed skin very much resembled that observed in cutaneous field cancerization in organ transplant recipients, showing high levels of UVB-damaged cells, enhanced production of proinflammatory cytokines, and mast cell recruitment to the dermis. Overall, this immunocompromised HPV8-transgenic mouse model shows that the coexistence of immune defects, β-HPV, and UVB exposure promotes skin cancer development.
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Affiliation(s)
- Cinzia Borgogna
- Virology Unit, Department of Translational Medicine, Novara Medical School, Novara, Italy
| | - Licia Martuscelli
- Virology Unit, Department of Translational Medicine, Novara Medical School, Novara, Italy
| | - Carlotta Olivero
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Irene Lo Cigno
- Virology Unit, Department of Translational Medicine, Novara Medical School, Novara, Italy
| | - Marco De Andrea
- Virology Unit, Department of Public Health and Pediatric Sciences, Turin Medical School, Turin, Italy; Center for Translational Research on Autoimmune and Allergic Disease (CAAD), Novara Medical School, Novara, Italy
| | - Valeria Caneparo
- Virology Unit, Department of Translational Medicine, Novara Medical School, Novara, Italy; Center for Translational Research on Autoimmune and Allergic Disease (CAAD), Novara Medical School, Novara, Italy
| | - Renzo Boldorini
- Pathology Unit, Department of Health Sciences, Novara Medical School, Novara, Italy
| | - Girish Patel
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Marisa Gariglio
- Virology Unit, Department of Translational Medicine, Novara Medical School, Novara, Italy; Center for Translational Research on Autoimmune and Allergic Disease (CAAD), Novara Medical School, Novara, Italy.
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12
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Yun CH, Kao WC, Hsu CY, Chang R, Cheng MF, Hung YM. Nontyphoidal Salmonella Infection Associated with Subsequent Risk of Hematological Malignancies: A Nationwide Population-Based Cohort Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:12943. [PMID: 36232242 PMCID: PMC9565030 DOI: 10.3390/ijerph191912943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 06/16/2023]
Abstract
This study aimed to investigate the relationship between nontyphoidal salmonellosis (NTS) and new-onset hematological malignancy. We conducted a 17-year nationwide, population-based, retrospective cohort study to examine the association between NTS and the risk of hematological malignancies by using the Longitudinal Health Insurance Database (LHID) of Taiwan. Participants were enrolled from 2000 to 2015 and were monitored until 2017. We traced the years 1998-2000 to ensure that the cases included were newly diagnosed with NTS. The NTS cohort included 13,790 patients with newly diagnosed NTS between 2000 and 2015. Each patient was propensity score matched at a 1:4 ratio with people without NTS. Cumulative incidence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated after adjusting for age, sex, income, urbanization, and medical comorbidities. The adjusted hazard ratio (aHR) of hematological malignancies for NTS patients relative to those without NTS was 1.42 (95% CI 0.91-2.20). In the age subgroup analysis, NTS had a significantly greater risk of hematological malignancies for patients older than 60 (aHR 3.04, 95% CI 1.46-6.34), with an incidence rate of 11.7 per 10,000 person-years. In patients over 60 years of age, a prominent risk of hematological malignancies was observed at a follow-up of more than 3 years after the index date (aHR 3.93, 95% CI 1.60-9.65). A history of NTS is associated with the risk of subsequent hematological malignancies in Taiwanese subjects older than 60.
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Affiliation(s)
- Chih-Hui Yun
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Wei-Chun Kao
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Chung Y. Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404328, Taiwan
| | - Renin Chang
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
- Department of Recreation Sports Management, Tajen University, Pingtung 907101, Taiwan
- Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung 84001, Taiwan
| | - Ming-Fang Cheng
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
- School of Nursing, Fooyin University, Kaohsiung 831301, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Yao-Min Hung
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal United Hospital, Kaohsiung 804051, Taiwan
- College of Health and Nursing, Meiho University, Pingtung 912009, Taiwan
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13
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Ahmels M, Mariz FC, Braspenning-Wesch I, Stephan S, Huber B, Schmidt G, Cao R, Müller M, Kirnbauer R, Rösl F, Hasche D. Next generation L2-based HPV vaccines cross-protect against cutaneous papillomavirus infection and tumor development. Front Immunol 2022; 13:1010790. [PMID: 36263027 PMCID: PMC9574214 DOI: 10.3389/fimmu.2022.1010790] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/16/2022] [Indexed: 11/25/2022] Open
Abstract
Licensed L1-VLP-based immunizations against high-risk mucosal human papillomavirus (HPV) types have been a great success in reducing anogenital cancers, although they are limited in their cross-protection against HPV types not covered by the vaccine. Further, their utility in protection against cutaneous HPV types, of which some contribute to non-melanoma skin cancer (NMSC) development, is rather low. Next generation vaccines achieve broadly cross-protective immunity against highly conserved sequences of L2. In this exploratory study, we tested two novel HPV vaccine candidates, HPV16 RG1-VLP and CUT-PANHPVAX, in the preclinical natural infection model Mastomys coucha. After immunization with either vaccines, a mock control or MnPV L1-VLPs, the animals were experimentally infected and monitored. Besides vaccine-specific seroconversion against HPV L2 peptides, the animals also developed cross-reactive antibodies against the cutaneous Mastomys natalensis papillomavirus (MnPV) L2, which were cross-neutralizing MnPV pseudovirions in vitro. Further, both L2-based vaccines also conferred in vivo protection as the viral loads in plucked hair after experimental infection were lower compared to mock-vaccinated control animals. Importantly, the formation of neutralizing antibodies, whether directed against L1-VLPs or L2, was able to prevent skin tumor formation and even microscopical signs of MnPV infection in the skin. For the first time, our study shows the proof-of-principle of next generation L2-based vaccines even across different PV genera in an infection animal model with its genuine PV. It provides fundamental insights into the humoral immunity elicited by L2-based vaccines against PV-induced skin tumors, with important implications to the design of next generation HPV vaccines.
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Affiliation(s)
- Melinda Ahmels
- Division of Viral Transformation Mechanisms, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Filipe C. Mariz
- Research Group Tumorvirus-specific Vaccination Strategies, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ilona Braspenning-Wesch
- Division of Viral Transformation Mechanisms, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja Stephan
- Division of Viral Transformation Mechanisms, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bettina Huber
- Laboratory of Viral Oncology, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Gabriele Schmidt
- Core Facility Unit Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rui Cao
- Division of Viral Transformation Mechanisms, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Müller
- Research Group Tumorvirus-specific Vaccination Strategies, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Reinhard Kirnbauer
- Laboratory of Viral Oncology, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Frank Rösl
- Division of Viral Transformation Mechanisms, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Hasche
- Division of Viral Transformation Mechanisms, Research Program “Infection, Inflammation and Cancer”, German Cancer Research Center (DKFZ), Heidelberg, Germany
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14
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Weng M, Zhao W, Yue Y, Guo M, Nan K, Liao Q, Sun M, Zhou D, Miao C. High preoperative white blood cell count determines poor prognosis and is associated with an immunosuppressive microenvironment in colorectal cancer. Front Oncol 2022; 12:943423. [PMID: 35965545 PMCID: PMC9373020 DOI: 10.3389/fonc.2022.943423] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/06/2022] [Indexed: 12/24/2022] Open
Abstract
Background The correlation between high white blood cell (WBC) count and poor prognosis has been identified in various types of cancer; however, the clinical significance and immune context of WBC count in colorectal cancer remains unclear. Methods Between February 2009 and November 2014, 7,433 patients at the Shanghai Cancer Center who had undergone elective surgery for colorectal cancer were enrolled in this retrospective cohort study. Patients were divided into two groups: low and high preoperative WBC groups. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan-Meier method and Cox regression analysis were used to identify independent prognostic factors in colorectal cancer patients. Tumor-infiltrating immune cells in the high and low preoperative WBC groups were compared using immunohistochemical staining. Results Of the 7,433 patients who underwent colorectal cancer surgery and were available for analysis, 5,750 were included in the low preoperative WBC group, and 1,683 were included in the high preoperative WBC group. After propensity score matching, 1,553 patients were included in each group. Kaplan-Meier survival curves showed that a high preoperative WBC count was associated with a decreased overall survival (P = 0.002) and disease-free survival (P = 0.003), and that preoperative WBC count was an independent risk factor for overall survival (hazard ratio, 1.234; 95% confidence interval, 1.068-1.426; P = 0.004) and disease-free survival (hazard ratio, 1.210; 95% confidence interval, 1.047-1.397, P = 0.01). Compared to the low preoperative WBC group, the high preoperative WBC group exhibited higher expression of regulatory T cells (P = 0.0034), CD68+ macrophages (P = 0.0071), and CD66b+ neutrophils (P = 0.0041); increased expression of programmed cell death protein 1 (P = 0.005) and programmed cell death ligand 1 (P = 0.0019); and lower expression of CD8+ T cells (P = 0.0057) in colorectal cancer patients. Conclusions Our research indicates that a high preoperative WBC count is a prognostic indicator in colorectal cancer patients and is associated with an immunosuppressive tumor microenvironment, which could aid in future risk stratification.
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Affiliation(s)
- Meilin Weng
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Wenling Zhao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Ying Yue
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Miaomiao Guo
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Ke Nan
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Qingwu Liao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Minli Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Di Zhou
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
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15
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Small DNA tumor viruses and human cancer: Preclinical models of virus infection and disease. Tumour Virus Res 2022; 14:200239. [PMID: 35636683 PMCID: PMC9194455 DOI: 10.1016/j.tvr.2022.200239] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 05/05/2022] [Accepted: 05/25/2022] [Indexed: 01/13/2023] Open
Abstract
Human tumor viruses cause various human cancers that account for at least 15% of the global cancer burden. Among the currently identified human tumor viruses, two are small DNA tumor viruses: human papillomaviruses (HPVs) and Merkel cell polyomavirus (MCPyV). The study of small DNA tumor viruses (adenoviruses, polyomaviruses, and papillomaviruses) has facilitated several significant biological discoveries and established some of the first animal models of virus-associated cancers. The development and use of preclinical in vivo models to study HPVs and MCPyV and their role in human cancer is the focus of this review. Important considerations in the design of animal models of small DNA tumor virus infection and disease, including host range, cell tropism, choice of virus isolates, and the ability to recapitulate human disease, are presented. The types of infection-based and transgenic model strategies that are used to study HPVs and MCPyV, including their strengths and limitations, are also discussed. An overview of the current models that exist to study HPV and MCPyV infection and neoplastic disease are highlighted. These comparative models provide valuable platforms to study various aspects of virus-associated human disease and will continue to expand knowledge of human tumor viruses and their relationship with their hosts.
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16
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Hu C, Wallace N. Beta HPV Deregulates Double-Strand Break Repair. Viruses 2022; 14:948. [PMID: 35632690 PMCID: PMC9146468 DOI: 10.3390/v14050948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
Beta human papillomavirus (beta HPV) infections are common in adults. Certain types of beta HPVs are associated with nonmelanoma skin cancer (NMSC) in immunocompromised individuals. However, whether beta HPV infections promote NMSC in the immunocompetent population is unclear. They have been hypothesized to increase genomic instability stemming from ultraviolet light exposure by disrupting DNA damage responses. Implicit in this hypothesis is that the virus encodes one or more proteins that impair DNA repair signaling. Fluorescence-based reporters, next-generation sequencing, and animal models have been used to test this primarily in cells expressing beta HPV E6/E7. Of the two, beta HPV E6 appears to have the greatest ability to increase UV mutagenesis, by attenuating two major double-strand break (DSB) repair pathways, homologous recombination, and non-homologous end-joining. Here, we review this dysregulation of DSB repair and emerging approaches that can be used to further these efforts.
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Affiliation(s)
| | - Nicholas Wallace
- Division of Biology, Kansas State University, Manhattan, KS 66506, USA;
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17
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Snell JA, Jandova J, Wondrak GT. Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer. Front Oncol 2022; 12:887220. [PMID: 35574306 PMCID: PMC9106365 DOI: 10.3389/fonc.2022.887220] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/31/2022] [Indexed: 12/15/2022] Open
Abstract
A multitude of extrinsic environmental factors (referred to in their entirety as the 'skin exposome') impact structure and function of skin and its corresponding cellular components. The complex (i.e. additive, antagonistic, or synergistic) interactions between multiple extrinsic (exposome) and intrinsic (biological) factors are important determinants of skin health outcomes. Here, we review the role of hypochlorous acid (HOCl) as an emerging component of the skin exposome serving molecular functions as an innate immune factor, environmental toxicant, and topical chemopreventive agent targeting solar UV-induced skin cancer. HOCl [and its corresponding anion (OCl-; hypochlorite)], a weak halogen-based acid and powerful oxidant, serves two seemingly unrelated molecular roles: (i) as an innate immune factor [acting as a myeloperoxidase (MPO)-derived microbicidal factor] and (ii) as a chemical disinfectant used in freshwater processing on a global scale, both in the context of drinking water safety and recreational freshwater use. Physicochemical properties (including redox potential and photon absorptivity) determine chemical reactivity of HOCl towards select biochemical targets [i.e. proteins (e.g. IKK, GRP78, HSA, Keap1/NRF2), lipids, and nucleic acids], essential to its role in innate immunity, antimicrobial disinfection, and therapeutic anti-inflammatory use. Recent studies have explored the interaction between solar UV and HOCl-related environmental co-exposures identifying a heretofore unrecognized photo-chemopreventive activity of topical HOCl and chlorination stress that blocks tumorigenic inflammatory progression in UV-induced high-risk SKH-1 mouse skin, a finding with potential implications for the prevention of human nonmelanoma skin photocarcinogenesis.
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Affiliation(s)
| | | | - Georg T. Wondrak
- Department of Pharmacology and Toxicology, R.K. Coit College of Pharmacy & UA Cancer Center, University of Arizona, Tucson, AZ, United States
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18
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Hasche D, Akgül B. [Role of human papillomavirus (HPV) in the development of skin cancer]. Hautarzt 2022; 73:417-425. [PMID: 35475906 DOI: 10.1007/s00105-022-04990-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2022] [Indexed: 11/28/2022]
Abstract
The incidence of nonmelanoma skin cancer, the most common cancer in humans, continues to rise. The development of precancerous actinic keratoses and cutaneous squamous cell carcinoma (cSCC) is associated with infection with human papillomavirus (HPV) of genus beta (betaHPV). Persistent betaHPV infections in immunocompetent individuals are generally very well controlled by the immune system and largely asymptomatic. However, immunosuppression results in high levels of betaHPV in the skin and consequently increased viral oncoprotein activity, which in turn leads to a significantly increased risk for skin cancer. However, even in immunocompetent individuals, the risk of cSCC increases with age as a result of accumulated UV-induced DNA damage in the skin. In these patients, the mechanism of betaHPV-dependent carcinogenesis seems to be different from that observed in immunocompromised patients. The underlying mechanism of oncogenesis in immunocompetent patients is currently less well understood. This review summarizes the current research data, which provide compelling evidence that cutaneous papillomaviruses, particularly in interaction with UV light, promote skin carcinogenesis via a "hit-and-run" mechanism by enhancing the genotoxic effects of UV light in the initial phases of this multistep process. Furthermore, an overview of novel vaccination strategies against papillomaviruses that are currently tested in clinical trials is provided, which could significantly improve the treatment options for high-risk patients in the future.
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Affiliation(s)
- Daniel Hasche
- Abteilung Virale Transformationsmechanismen; Forschungsschwerpunkt "Infektion, Entzündung und Krebs", Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Deutschland
| | - Baki Akgül
- Institut für Virologie der Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Fürst-Pückler-Str. 56, 50935, Köln, Deutschland.
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19
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Hasche D, Ahmels M, Braspenning-Wesch I, Stephan S, Cao R, Schmidt G, Müller M, Rösl F. Isoforms of the Papillomavirus Major Capsid Protein Differ in Their Ability to Block Viral Spread and Tumor Formation. Front Immunol 2022; 13:811094. [PMID: 35359995 PMCID: PMC8964102 DOI: 10.3389/fimmu.2022.811094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/15/2022] [Indexed: 11/29/2022] Open
Abstract
Notably, the majority of papillomaviruses associated with a high cancer risk have the potential to translate different isoforms of the L1 major capsid protein. In an infection model, the cutaneous Mastomys natalensis papillomavirus (MnPV) circumvents the humoral immune response of its natural host by first expressing a 30 amino acid extended L1 isoform (L1LONG). Although inducing a robust seroconversion, the raised antibodies are not neutralizing in vitro. In contrast, neutralizing antibodies induced by the capsid-forming isoform (L1SHORT) appear delayed by several months. We now provide evidence that, although L1LONG vaccination showed a strong seroconversion, these antibodies were not protective. As a consequence, virus-free animals subsequently infected with MnPV still accumulated high numbers of transcriptionally active viral genomes, ultimately leading to skin tumor formation. In contrast, vaccination with L1SHORT was completely protective. This shows that papillomavirus L1LONG expression is a unique strategy to escape from antiviral immune surveillance.
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Affiliation(s)
- Daniel Hasche
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Melinda Ahmels
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ilona Braspenning-Wesch
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja Stephan
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rui Cao
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Gabriele Schmidt
- Core Facility Unit Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Müller
- Research Group Tumorvirus-specific Vaccination Strategies, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Rösl
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center (DKFZ), Heidelberg, Germany
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20
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Restriction of viral gene expression and replication prevents immortalization of human keratinocytes by a beta-human papillomavirus. Proc Natl Acad Sci U S A 2022; 119:e2118930119. [PMID: 35254896 PMCID: PMC8931373 DOI: 10.1073/pnas.2118930119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
High-risk (HR) human papillomaviruses (HPV) from the genus alpha cause anogenital and oropharyngeal cancers, whereas the contribution of HPV from the genus beta to the development of cutaneous squamous cell cancer is still under debate. HR-HPV genomes display potent immortalizing activity in human keratinocytes, the natural target cell for HPV. This paper shows that immortalization of keratinocytes by the beta-HPV49 genome requires the inactivation of the viral E8^E2 repressor protein and the presence of the E6 and E7 oncoproteins but also of the E1 and E2 replication proteins. This reveals important differences in the carcinogenic properties of HR-HPV and beta-HPV but also warrants further investigations on the distribution and mutation frequencies of beta-HPV in human cancers. Beta-human papillomaviruses (HPV) have been implicated in the development of cutaneous squamous cell cancer (cSCC) in epidermodysplasia verruciformis (EV) patients and organ transplant recipients. In contrast to high-risk (HR) HPV, which cause anogenital and oropharyngeal cancers, immortalizing activity of complete beta-HPV genomes in normal human keratinocytes (NHK), the natural target cells for HPV, has not been reported. We now demonstrate that the beta-HPV49 wild-type genome is transcriptionally active in NHK but lacks immortalizing activity unless the E8 gene, which encodes the E8^E2 repressor, is inactivated. HPV49 E8− immortalized keratinocytes maintain high levels of viral gene expression and very high copy numbers of extrachromosomal viral genomes during long-term cultivation. Not only disruption of the viral E6 and E7 oncogenes but also of the E1 or E2 replication genes renders E8− genomes incapable of immortalization. E8−/E1− and E8−/E2− genomes display greatly reduced E6 and E7 RNA levels in short-term assays. This strongly suggests that high-level expression of E6 and E7 from extrachromosomal templates is necessary for immortalization. The requirement for an inactivation of E8 while maintaining E1 and E2 expression highlights important differences in the carcinogenic properties of HR-HPV and beta-HPV. These findings strengthen the notion that beta-HPV have carcinogenic potential that warrants further investigations into the distribution of beta-HPV in human cancers.
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Kricker A, Weber MF, Pawlita M, Sitas F, Hodgkinson VS, Rahman B, van Kemenade CH, Armstrong BK, Waterboer T. Cutaneous beta HPVs, sun exposure and risk of squamous and basal cell skin cancers in Australia. Cancer Epidemiol Biomarkers Prev 2021; 31:614-624. [PMID: 34933956 DOI: 10.1158/1055-9965.epi-21-1000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/24/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Sun exposure causes cutaneous squamous (SCC) and basal cell (BCC) carcinomas. Human papillomavirus (HPV) infection might cause SCC. METHODS We examined associations of beta and gamma HPV infection in skin-swab DNA and serum antibodies with skin cancer risk, and modification of the carcinogenic effects of sun exposure by them, in case-control studies of 385 SCC cases, 832 BCC cases and 1100 controls nested in an Australian prospective cohort study (enrolled 2006-2009). RESULTS Presence of beta-1 and beta-3 HPV DNA appeared to increase risks for SCC and BCC by 30%-40% (P adjusted <0.01). BCC was also associated with genus beta DNA, OR=1.48; 95%CI 1.10-2.00 (P adjusted <0.01). Associations were strengthened with each additional positive beta HPV DNA type: SCC (OR=1.07; 95%CI 1.02-1.12) and BCC (OR=1.06; 95%CI 1.03-1.10), P trend <0.01. Positivity to genus beta or gamma in serology, and genus gamma in DNA, was not associated with either cancer. There was little evidence that any beta HPV type was more strongly associated than others with either cancer. A weaker association of sun-exposure with SCC and BCC in the presence of beta-3 HPVs than in their absence suggests that beta-3 HPVs modify sun exposure's effect. CONCLUSIONS Our substantive findings are at the level of genus beta HPV. Like SCC, BCC risk may increase with increasing numbers of beta HPV types on skin. IMPACT The consistency in our findings that HPV infection may moderate the effects of sun exposure, the main environmental cause of SCC and BCC, merits further investigation.
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Affiliation(s)
- Anne Kricker
- The Daffodil Centre, a joint venture with Cancer Council NSW, Sydney School of Public Health, The University of Sydney
| | - Marianne F Weber
- The Daffodil Centre, a joint venture with Cancer Council NSW, Sydney School of Public Health, The University of Sydney
| | - Michael Pawlita
- Infections and Cancer Epidemiology, German Cancer Research Center
| | - Freddy Sitas
- Centre for Primary Health Care and Equity, University of New South Wales
| | | | | | | | - Bruce K Armstrong
- School of Population and Global Health, University of Western Australia
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center
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22
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Vandiver AR, Thomas BJ, Karimzada M, Knowles BC, Botten GA, Spreafico R, Rotman JN, Gharavi NM, Chesnut C, Wesel K, Mangul S, Soriano T, Scumpia PO. Detection of viral gene expression in risk-stratified biopsies reveals no active HPV in cutaneous squamous cell carcinoma. Exp Dermatol 2021; 30:1711-1716. [PMID: 34036652 PMCID: PMC9639216 DOI: 10.1111/exd.14385] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/05/2021] [Indexed: 01/23/2023]
Abstract
BACKGROUND Human papillomavirus (HPV) infection is known to promote the development of mucosal squamous cell carcinoma (mSCC), including pathologically high-grade lesions, but its role in cutaneous squamous cell carcinoma (cuSCC) remains unclear, particularly in lesions that are considered high risk. OBJECTIVE We aimed to determine whether enhanced HPV transcriptional activity can be detected in high-risk cuSCC samples compared with low-grade SCC samples or normal skin. METHODS We performed RNA sequencing of cuSCC across 23 risk-stratified skin lesions. A subset of samples was tested for the presence of HPV DNA. High-quality, non-human reads from each sample group were used for viral analysis using Microbiome Coverage Profiler. RESULTS None of the samples analysed had detectable expression of HPV RNA, while 64% of samples tested positive for HPV DNA. All samples were found to have expression of human endogenous retrovirus, and multiple samples showed expression of other viruses. CONCLUSIONS Viral and prophage gene expression can be monitored in cuSCC or normal skin biopsies, yet no sample in our study showed evidence of active HPV gene expression despite evidence of HPV genome presence. This suggests HPV transcription does not play a role in differentiating high-risk cuSCCs from low-risk cuSCCs or normal skin.
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Affiliation(s)
- Amy R. Vandiver
- Department of Medicine, Division of Dermatology, University of California, Los Angeles, CA, USA
| | - Brandon J. Thomas
- David Geffen School of Medicine, University of California at Los Angeles, CA, USA
| | - Mohammad Karimzada
- David Geffen School of Medicine, University of California at Los Angeles, CA, USA
| | - Byron C. Knowles
- Department of Dermatology, University of California at San Francisco, CA, USA
| | - Giovanni A. Botten
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA
| | - Roberto Spreafico
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA
| | - Jeremy N. Rotman
- Department of Computer Science, University of California, Los Angeles, CA, USA
| | - Nima M Gharavi
- Department of Dermatology and Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Cameron Chesnut
- University of Washington School of Medicine, Spokane, WAS, USA,Chestnut MD Cosmetic Surgery Fellowship at Clinic 5C, Spokane, WAS, USA
| | - Kevin Wesel
- Department of Computer Science, University of California, Los Angeles, CA, USA
| | - Serghei Mangul
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Teresa Soriano
- Department of Medicine, Division of Dermatology, University of California, Los Angeles, CA, USA
| | - Philip O. Scumpia
- Department of Medicine, Division of Dermatology, University of California, Los Angeles, CA, USA,Department of Dermatology, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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Kirschberg M, Syed AS, Dönmez HG, Heuser S, Wilbrand-Hennes A, Alonso A, Hufbauer M, Akgül B. Novel Insights Into Cellular Changes in HPV8-E7 Positive Keratinocytes: A Transcriptomic and Proteomic Analysis. Front Microbiol 2021; 12:672201. [PMID: 34552568 PMCID: PMC8450583 DOI: 10.3389/fmicb.2021.672201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/29/2021] [Indexed: 12/16/2022] Open
Abstract
Human papillomavirus type 8 (HPV8) is associated with the development of non-melanoma skin cancer. In the past we already delved into the mechanisms involved in keratinocyte invasion, showing that the viral E7 oncoprotein is a key player that drives invasion of basal keratinocytes controlled by the extracellular protein fibronectin. To unravel further downstream effects in E7 expressing keratinocytes we now aimed at characterizing gene and protein/phosphoprotein alterations to narrow down on key cellular targets of HPV8-E7. We now show that gene expression of GADD34 and GDF15 are strongly activated in the presence of E7 in primary human keratinocytes. Further analyses of fibronectin-associated factors led to the identification of the Src kinase family members Fyn and Lyn being aberrantly activated in the presence of HPV8-E7. Phospho-proteomics further revealed that E7 not only targets cell polarity and cytoskeletal organization, but also deregulates the phosphorylation status of nuclear proteins involved in DNA damage repair and replication. Many of these differentially phosphorylated proteins turned out to be targets of Fyn and Lyn. Taken together, by using unbiased experimental approaches we have now arrived at a deeper understanding on how fibronectin may affect the signaling cascades in HPV8 positive keratinocytes, which may be key for skin tumorigenesis and that may also aid in the development of novel therapeutic approaches for betaHPV-mediated cancers.
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Affiliation(s)
- Matthias Kirschberg
- Medical Faculty and University Hospital Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Adnan Shahzad Syed
- Medical Faculty and University Hospital Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Hanife Güler Dönmez
- Medical Faculty and University Hospital Cologne, Institute of Virology, University of Cologne, Cologne, Germany.,Department of Biology, Hacettepe University, Ankara, Turkey
| | - Sandra Heuser
- Medical Faculty and University Hospital Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Astrid Wilbrand-Hennes
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Angel Alonso
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Hufbauer
- Medical Faculty and University Hospital Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Baki Akgül
- Medical Faculty and University Hospital Cologne, Institute of Virology, University of Cologne, Cologne, Germany
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24
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Griesinger LM, Walline H, Wang GY, Lorenzatti Hiles G, Welch KC, Haefner HK, Lieberman RW, Skala SL. Expanding the Morphologic, Immunohistochemical, and HPV Genotypic Features of High-grade Squamous Intraepithelial Lesions of the Vulva With Morphology Mimicking Differentiated Vulvar Intraepithelial Neoplasia and/or Lichen Sclerosus. Int J Gynecol Pathol 2021; 40:205-213. [PMID: 32925443 PMCID: PMC7960553 DOI: 10.1097/pgp.0000000000000708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Squamous cell carcinoma of the vulva can arise through 2 pathways: human papillomavirus (HPV)-dependent high-grade squamous intraepithelial lesions (previously termed usual vulvar intraepithelial neoplasia) or HPV-independent (differentiated vulvar intraepithelial neoplasia, dVIN). Distinguishing between the 2 types can be clinically and histologically difficult. A subset of high-grade squamous intraepithelial lesions with superimposed chronic inflammation mimicking dVIN has recently been reported; p53 shows characteristic mid-epithelial staining (with basal sparing) in such cases. The pathology databases of 2 academic institutions were searched for vulva specimens with corresponding p53 and p16 immunohistochemical stains, yielding 38 specimens (from 27 patients). In situ hybridization and multiplex polymerase chain reaction-MassArray for high-risk HPV were performed on at least 1 block from each patient. All cases resembled dVIN or lichen sclerosus morphologically, but with a higher degree of atypia. All but 1 case demonstrated mid-epithelial p53 staining with basal sparing by immunohistochemistry. All cases showed block positivity for p16 and at least patchy positivity by HPV in situ hybridization. Of the 23 cases with valid HPV DNA polymerase chain reaction results, 15 were positive and 8 were negative. Of the positive cases, HPV16 was identified in 10 cases, with other high-risk types in the remaining 5. To our knowledge, this is the largest cohort of high-grade squamous intraepithelial lesions mimicking dVIN reported to date. Prior studies reported positivity for HPV16 in all cases tested, however, we found HPV16 in only 67% of HPV positive cases. This case series highlights the importance of immunohistochemistry, and occasionally HPV in situ hybridization, for accurate diagnosis, and expands the spectrum of associated HPV types.
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25
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Dorfer S, Strasser K, Schröckenfuchs G, Bonelli M, Bauer W, Kittler H, Cataisson C, Fischer MB, Lichtenberger BM, Handisurya A. Mus musculus papillomavirus 1 is a key driver of skin cancer development upon immunosuppression. Am J Transplant 2021; 21:525-539. [PMID: 33063442 PMCID: PMC7894140 DOI: 10.1111/ajt.16358] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/16/2020] [Accepted: 10/06/2020] [Indexed: 01/25/2023]
Abstract
Epidemiological and experimental data implicate cutaneous human papillomavirus infection as co-factor in the development of cutaneous squamous cell carcinomas (cSCCs), particularly in immunocompromised organ transplant recipients (OTRs). Herein, we established and characterized a skin cancer model, in which Mus musculus papillomavirus 1 (MmuPV1) infection caused cSCCs in cyclosporine A (CsA)-treated mice, even in the absence of UV light. Development of cSCCs and their precursors were observed in 70% of MmuPV1-infected, CsA-treated mice on back as well as on tail skin. Immunosuppression by systemic CsA, but not UV-B irradiation, was a prerequisite, as immunocompetent or UV-B-irradiated mice did not develop skin malignancies after infection. In the virus-driven cSCCs the MmuPV1-E6/E7 oncogenes were abundantly expressed, and transcriptional activity and productive infection demonstrated. MmuPV1 infection induced the expression of phosphorylated H2AX, but not degradation of proapoptotic BAK in the cSCCs. Transfer of primary cells, established from a MmuPV1-induced cSCC from back skin, into athymic nude mice gave rise to secondary cSCCs, which lacked viral DNA, demonstrating that maintenance of the malignant phenotype was virus independent. This papillomavirus-induced skin cancer model opens future investigations into viral involvement, pathogenesis, and cancer surveillance, aiming at understanding and controlling the high incidence of skin cancer in OTRs.
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Affiliation(s)
- Sonja Dorfer
- Department of DermatologyMedical University of ViennaViennaAustria
| | | | | | - Michael Bonelli
- Department of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Wolfgang Bauer
- Department of DermatologyMedical University of ViennaViennaAustria
| | - Harald Kittler
- Department of DermatologyMedical University of ViennaViennaAustria
| | - Christophe Cataisson
- Laboratory of Cancer Biology and GeneticsNational Institutes of HealthNational Cancer InstituteBethesdaMDUSA
| | - Michael B. Fischer
- Department of Transfusion MedicineMedical University of ViennaViennaAustria
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27
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Lambert PF, Münger K, Rösl F, Hasche D, Tommasino M. Beta human papillomaviruses and skin cancer. Nature 2020; 588:E20-E21. [PMID: 33328661 DOI: 10.1038/s41586-020-3023-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 10/20/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Paul F Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, USA
| | - Karl Münger
- Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Frank Rösl
- Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Hasche
- Division of Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Massimo Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, Lyon, France.
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28
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Chen ML, Wang SH, Wei JCC, Yip HT, Hung YM, Chang R. The Impact of Human Papillomavirus Infection on Skin Cancer: A Population-Based Cohort Study. Oncologist 2020; 26:e473-e483. [PMID: 33191546 DOI: 10.1002/onco.13593] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/22/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This study investigated the correlation between a history of human papillomavirus (HPV) infection and skin cancer risk. MATERIALS AND METHODS The study cohort comprised 26,919 patients with newly diagnosed HPV infection between 2000 and 2012; with the use of computer-generated numbers, patients without previous HPV infection were randomly selected as the comparison cohort. The patients in the HPV infection cohort were matched to comparison individuals at a 1:4 ratio by demographic characteristics and comorbidities. All study individuals were followed up until they developed skin cancer, withdrew from the National Health Insurance program, were lost to follow-up, or until the end of 2013. The primary outcome was subsequent skin cancer development. Cox proportional hazards regression analysis was used to analyze the risk of skin cancer with hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. RESULTS The adjusted HR of skin cancer for patients with HPV relative to controls was 2.45 after adjusting sex, age and comorbidities. (95% CI, 1.44-4.18, p < .01). The subgroup analysis indicated that a patient with HPV infection had a significantly greater risk of skin cancer if they were aged >40 years. Notably, a risk of skin cancer was found in the group diagnosed with HPV within the first 5 years after the index date (adjusted HR, 3.12; with 95% CI, 1.58-5.54). Sensitivity analysis by propensity score, matching with balanced sex, age, and comorbidities, showed consistent results. CONCLUSION A history of HPV infection is associated with the development of subsequent skin cancer in Taiwanese subjects, and the risk wanes 5 years later. IMPLICATIONS FOR PRACTICE In this Taiwan nationwide cohort study, there was a 2.45-fold increased risk of developing new-onset skin cancers for patients with incident human papillomavirus (HPV) infection, compared with the matched controls. Furthermore, the risk was noticeably significant among patients aged >40 years. A prominent risk of skin cancers was found in the group diagnosed with HPV within the first 5 years after the index date in this study. The results of this analysis may raise consensus on the effect of HPV infection on the risk of skin cancers. Clinicians are encouraged to implement prudently on the differential diagnosis of skin cancers and HPV prevention and treatment, especially in older patients.
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Affiliation(s)
- Ming-Li Chen
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shuo-Hsuan Wang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - James Cheng-Chung Wei
- Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University, Taichung, Taiwan.,Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Hei-Tung Yip
- Management office for Health Data, China Medical University, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan.,Institute of Public Health (Biostatistics), National Yangming University, Taiwan
| | - Yao-Min Hung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan.,Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan.,Tajen University, Pingtung, Taiwan
| | - Renin Chang
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Department of Recreation Sports Management, Tajen University, Pingtung, Taiwan
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29
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Ferreira DA, Tayyar Y, Idris A, McMillan NAJ. A "hit-and-run" affair - A possible link for cancer progression in virally driven cancers. Biochim Biophys Acta Rev Cancer 2020; 1875:188476. [PMID: 33186643 DOI: 10.1016/j.bbcan.2020.188476] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/03/2020] [Accepted: 11/08/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND It is well-known that certain cancers are caused by viruses. However, viral oncogenesis is complex and only a small fraction of the infected people develop cancer. Indeed, a number of environmental factors can contribute to virally infected cells developing cancer hallmarks, promoting tumorigenesis. SCOPE OF REVIEW The hit-and-run theory proposes that viruses facilitate the accumulation of mutations and promote genomic instability until the virus becomes dispensable for tumour maintenance. Indeed, several studies have reported viral genome, episome and/or oncogene loss in tumour cells without losing malignant phenotype. MAJOR CONCLUSIONS The current evidence supports the clear contribution of certain viruses to develop cancers. Importantly, the evidence supporting the sustained maintenance of malignancy after the loss of viral "presence" is sufficient to support the hit-and-run hypothesis of viral cancer development. Long-term tracking of vaccination outcome over the decades will test this theory. GENERAL SIGNIFICANCE If the hit-and-run theory is true, viruses might cause more cancers than previously thought and will have implications in the prevention of many cancers through implementing vaccination programs.
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Affiliation(s)
- Danyelle A Ferreira
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - Yaman Tayyar
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - Adi Idris
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia.
| | - Nigel A J McMillan
- Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia
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Fu Y, Cao R, Schäfer M, Stephan S, Braspenning-Wesch I, Schmitt L, Bischoff R, Müller M, Schäfer K, Vinzón SE, Rösl F, Hasche D. Expression of different L1 isoforms of Mastomys natalensis papillomavirus as mechanism to circumvent adaptive immunity. eLife 2020; 9:e57626. [PMID: 32746966 PMCID: PMC7402679 DOI: 10.7554/elife.57626] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022] Open
Abstract
Although many high-risk mucosal and cutaneous human papillomaviruses (HPVs) theoretically have the potential to synthesize L1 isoforms differing in length, previous seroepidemiological studies only focused on the short L1 variants, co-assembling with L2 to infectious virions. Using the multimammate mouse Mastomys coucha as preclinical model, this is the first study demonstrating seroconversion against different L1 isoforms during the natural course of papillomavirus infection. Intriguingly, positivity with the cutaneous MnPV was accompanied by a strong seroresponse against a longer L1 isoform, but to our surprise, the raised antibodies were non-neutralizing. Only after a delay of around 4 months, protecting antibodies against the short L1 appeared, enabling the virus to successfully establish an infection. This argues for a novel humoral immune escape mechanism that may also have important implications on the interpretation of epidemiological data in terms of seropositivity and protection of PV infections in general.
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Affiliation(s)
- Yingying Fu
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Rui Cao
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Miriam Schäfer
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Sonja Stephan
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Ilona Braspenning-Wesch
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Laura Schmitt
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Ralf Bischoff
- Division of Functional Genome Analysis, Research Program 'Functional and Structural Genomics', German Cancer Research CenterHeidelbergGermany
| | - Martin Müller
- Research Group Tumorvirus-specific Vaccination Strategies, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Kai Schäfer
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Sabrina E Vinzón
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Frank Rösl
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
| | - Daniel Hasche
- Division of Viral Transformation Mechanisms, Research Program 'Infection, Inflammation and Cancer', German Cancer Research CenterHeidelbergGermany
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Li SC, Xu Z, Deng YL, Wang YN, Jia YM. Higher neutrophil-lymphocyte ratio is associated with better prognosis of hepatocellular carcinoma. Medicine (Baltimore) 2020; 99:e20919. [PMID: 32629689 PMCID: PMC7337484 DOI: 10.1097/md.0000000000020919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide; its morbidity and mortality have both recently increased. Lately, the role played by the neutrophil-lymphocyte ratio (NLR) in the development of HCC has attracted attention. However, the exact relationship is not fully understood.A total of 538 participants diagnosed with HCC were recruited between 2010 and 2018. Their relevant routine blood parameters were measured, including NLR. Pearson Chi-Squared test, Spearman Rho test, and logistic regression analysis were performed to explore any correlations between NLR and HCC. A receiver operating characteristic (ROC) curve analysis was performed to determine the usefulness of NLR for predicting HCC. Univariate and multivariate Cox regression analysis for relevant routine blood parameters and any relationships with overall survival (OS) were performed. The Kaplan-Meier method was used to explore any further relationships with OS.NLR was significantly correlated with HCC tumor size by Pearson Chi-Squared test (P = .008). Furthermore, Spearman correlation coefficient showed that HCC tumor size was significantly correlated with NLR (P = .115, P = .008). NLR could sensitively and specifically predict HCC tumor size (area under the curve [AUC], 0.605; 95% confidence interval [CI], 0.429-0.743; P = .000). Higher NLR in patients with HCC was correlated with better OS (hazard ratio [HR] = 0.584; P = .000).A close correlation existed between increased NLR and HCC; NLR could sensitively and specifically predict HCC. High NLR might be an independent protective factor in the prognosis of patients with HCC.
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Affiliation(s)
| | - Zhuo Xu
- Department of Hepatobiliary Surgery
| | - Yan-li Deng
- Clinical Laboratory, Fourth Hospital of Hebei Medical University
| | - Ya-ni Wang
- School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, Hebei , PR China
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Bandolin L, Borsetto D, Fussey J, Da Mosto MC, Nicolai P, Menegaldo A, Calabrese L, Tommasino M, Boscolo-Rizzo P. Beta human papillomaviruses infection and skin carcinogenesis. Rev Med Virol 2020; 30:e2104. [PMID: 32232924 DOI: 10.1002/rmv.2104] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 03/12/2020] [Accepted: 03/15/2020] [Indexed: 12/17/2022]
Abstract
During the last decade, the worldwide incidence of keratinocyte carcinomas (KC) has increased significantly. They are now the most common malignancy, representing approximately 30% of all cancers. The role of ultraviolet (UV) radiation as a major environmental risk factor for skin cancers is well recognized. The aim of this review is to analyse the current understanding of the nature of beta-human papillomavirus (HPV) and its association with KC and explore the implications for the management and prevention of these cancers. A comprehensive review of the literature on beta-HPV and its association with KC was undertaken, the results reported in the form of a narrative review. A subgroup of HPV that infects the mucosal epithelia of the genital tract has been firmly associated with carcinogenesis. In addition, some HPV types with cutaneous tropism have been proposed to cooperate with UV in the development of KC. The first evidence for this association was reported in 1922 in patients with epidermodysplasia verruciformis (EV). Since then, epidemiological studies have highlighted the higher risk of skin cancer in patients with EV and certain cutaneous HPV types, and in vitro studies have elucidated molecular mechanisms and transforming properties of beta-HPV. Furthermore, in vivo research conducted on transgenic mice models has shown the possible role of beta-HPV in cutaneous carcinogenesis as a co-factor with UV radiation and immunosuppression. There is good evidence supporting the role of beta-HPV in the oncogenesis of KC. The high prevalence of beta-HPV in human skin and the worldwide burden of KC makes the search for an effective vaccine relevant and worthwhile.
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Affiliation(s)
- Luigia Bandolin
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Padova, Italy
| | | | - Jonathan Fussey
- Department of Otolaryngology, Royal Devon and Exeter Hospital, Exeter, UK
| | | | - Piero Nicolai
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Padova, Italy
| | - Anna Menegaldo
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Padova, Italy
| | - Luca Calabrese
- Head and Neck Department, Ospedale di Bolzano, Bolzano, Italy
| | - Massimo Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France
| | - Paolo Boscolo-Rizzo
- Department of Neurosciences, Section of Otolaryngology, University of Padova, Padova, Italy
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Spurgeon ME, Lambert PF. Mus musculus Papillomavirus 1: a New Frontier in Animal Models of Papillomavirus Pathogenesis. J Virol 2020; 94:e00002-20. [PMID: 32051276 PMCID: PMC7163119 DOI: 10.1128/jvi.00002-20] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 02/04/2020] [Indexed: 01/06/2023] Open
Abstract
Animal models of viral pathogenesis are essential tools in human disease research. Human papillomaviruses (HPVs) are a significant public health issue due to their widespread sexual transmission and oncogenic potential. Infection-based models of papillomavirus pathogenesis have been complicated by their strict species and tissue specificity. In this Gem, we discuss the discovery of a murine papillomavirus, Mus musculus papillomavirus 1 (MmuPV1), and how its experimental use represents a major advancement in models of papillomavirus-induced pathogenesis/carcinogenesis, and their transmission.
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Affiliation(s)
- Megan E Spurgeon
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Paul F Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Zhang K, Ren J, Ren JX, Liu C, Sun L. Successful treatment of verruca plana with NB-UVB: A case report. Dermatol Ther 2020; 33:e13207. [PMID: 31885155 DOI: 10.1111/dth.13207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/08/2019] [Accepted: 12/24/2019] [Indexed: 01/10/2023]
Abstract
Verruca plana is a kind of benign proliferative skin disease that generally occurs in exposed parts, but the treatment of warts poses a therapeutic challenge for physicians, as there is no method, among numerous approaches, that has been proven effective for completely curing this disease. We report a case of verruca plana cured by narrow-band ultraviolet B (NB-UVB), which provides a new treatment of verruca plana.
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Affiliation(s)
- Kun Zhang
- Department of Dermatology, Weinan Central Hospital, Affiliated to Shaanxi University of Chinese Medicine, Weinan City, Shaanxi, P.R. China
| | - Jianwen Ren
- Department of Dermatology, The Second Affiliated Hospital Of Xi'an Jiaotong University, Xi'an City, Shaanxi, P.R. China
| | - Jian X Ren
- Department of Dermatology, Weinan Central Hospital, Affiliated to Shaanxi University of Chinese Medicine, Weinan City, Shaanxi, P.R. China
| | - Chunling Liu
- Department of Dermatology, Weinan Central Hospital, Affiliated to Shaanxi University of Chinese Medicine, Weinan City, Shaanxi, P.R. China
| | - Lu Sun
- Department of Dermatology, Weinan Central Hospital, Affiliated to Shaanxi University of Chinese Medicine, Weinan City, Shaanxi, P.R. China
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35
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Abstract
Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood.From patients with the rare genetic disorder epidermodysplasia verruciformis (EV) and animal models, evidence is accumulating that cutaneous PV of genus β synergize with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma (cSCC). In 2009, the International Agency for Research on Cancer (IARC) classified the genus β-HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. Epidemiological and biological studies indicate that genus β-PV infection may also play a role in UV-mediated skin carcinogenesis in non-EV patients. However, they rather act at early stages of carcinogenesis and become dispensable for the maintenance of the malignant phenotype, compatible with a "hit-and-run" mechanism.This chapter will give an overview on genus β-PV infections and discuss similarities and differences of cutaneous and genus α mucosal high-risk HPV in epithelial carcinogenesis.
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36
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Song XD, Wang YN, Zhang AL, Liu B. Advances in research on the interaction between inflammation and cancer. J Int Med Res 2019; 48:300060519895347. [PMID: 31885347 PMCID: PMC7686609 DOI: 10.1177/0300060519895347] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Inflammation is the body's response to cell damage. Cancer is a general
term that describes all malignant tumours. There are no confirmed data
on cancer-related inflammation, but some research suggests that up to
50% of cancers may be linked to inflammation, which has led to the
concept of ‘cancer-associated inflammation’. Although some cancer
patients do not appear to have a chronic inflammatory background,
there might be inflammatory cell infiltration in their cancer tissues.
The continuation of the inflammatory response plays an important role
in the initiation, promotion, malignant transformation, invasion and
metastasis of cancer. Anti-inflammatory therapy has been shown to have
some effects on the prevention and treatment of cancer, which supports
a pathogenic relationship between inflammation and cancer. This review
describes the interaction between inflammation and tumour development
and the main mechanism of regulation of the inflammatory response
during tumour development.
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Affiliation(s)
- Xin-Da Song
- Department of Urinary Surgery, Graduate School of Peking Union Medical College, Beijing Hospital, National Centre of Gerontology, Beijing, China
| | - Ya-Ni Wang
- School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Ai-Li Zhang
- Department of Urinary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Bin Liu
- Department of Urinary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
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37
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Starrett GJ, Buck CB. The case for BK polyomavirus as a cause of bladder cancer. Curr Opin Virol 2019; 39:8-15. [PMID: 31336246 PMCID: PMC6901737 DOI: 10.1016/j.coviro.2019.06.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/20/2019] [Accepted: 06/21/2019] [Indexed: 12/17/2022]
Abstract
In 2014, the International Agency for Research on Cancer judged Merkel cell polyomavirus (MCPyV) to be a probable human carcinogen. BK polyomavirus (BKPyV, a distant cousin of MCPyV) was ruled a possible carcinogen. In this review, we argue that it has recently become reasonable to view both of these viruses as known human carcinogens. In particular, several complementary lines of evidence support a causal role for BKPyV in the development of bladder carcinomas affecting organ transplant patients. The expansion of inexpensive deep sequencing has opened new approaches to investigating the important question of whether BKPyV causes urinary tract cancers in the general population.
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Affiliation(s)
- Gabriel J Starrett
- National Cancer Institute, Building 37 Room 4118, 9000 Rockville Pike, Bethesda, MD 20892-4263, United States.
| | - Christopher B Buck
- National Cancer Institute, Building 37 Room 4118, 9000 Rockville Pike, Bethesda, MD 20892-4263, United States
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Kricker A, Weber MF, Brenner N, Banks E, Pawlita M, Sitas F, Hodgkinson VS, Rahman B, van Kemenade CH, Armstrong BK, Waterboer T. High Ambient Solar UV Correlates with Greater Beta HPV Seropositivity in New South Wales, Australia. Cancer Epidemiol Biomarkers Prev 2019; 29:49-56. [PMID: 31597664 DOI: 10.1158/1055-9965.epi-19-0400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 07/28/2019] [Accepted: 10/01/2019] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Human papillomavirus (HPV) infection is highly prevalent worldwide and may have a role, with sun exposure, in causing cutaneous squamous cell carcinoma. Little is known about the relationship of UV exposure and seroprevalence of cutaneous HPVs in the general population. METHODS Using multiplex serology, we estimated the seroprevalence of 23 beta and 7 gamma HPVs and 7 other antigens (mu HPV1, HPV63, nu HPV41, alpha HPV16; polyomaviruses HPyV7 and MCV; p53) in a population-based sample of 1,161 Australian 45 and Up Study participants with valid data from blood specimens collected from 2010 to 2012. We calculated prevalence ratios (PR) for the association of each antigen with residential ambient solar UV and other UV-related variables. RESULTS Seropositivity for at least one beta or gamma HPV was high at 88% (beta HPVs 74%, gamma HPVs 70%), and less in women than men [e.g., PR beta-2 HPV38 = 0.70; 95% confidence interval (CI), 0.56-0.87; any gamma = 0.90; 95% CI, 0.84-0.97]. A high ambient UV level in the 10 years before study enrollment was associated with elevated seroprevalence for genus beta (PRtertile3vs1 any beta = 1.17; 95% CI, 1.07-1.28), and beta-1 to beta-3 species, but not for gamma HPVs. Other UV-related measures had less or no evidence of an association. CONCLUSIONS Seroprevalence of cutaneous beta HPVs is higher with higher ambient UV exposure in the past 10 years. IMPACT The observed association between ambient UV in the past 10 years and cutaneous HPVs supports further study of the possible joint role of solar UV and HPV in causing skin cancer.
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Affiliation(s)
- Anne Kricker
- Sydney School of Public Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
| | - Marianne F Weber
- Cancer Research Division, Cancer Council New South Wales, Sydney, New South Wales, Australia
| | - Nicole Brenner
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Emily Banks
- National Centre for Epidemiology and Population Health, Research School of Population Health, Australian National University, Canberra, Australia.,Sax Institute, Sydney, New South Wales, Australia
| | - Michael Pawlita
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Freddy Sitas
- Sydney School of Public Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.,School of Public Health and Community Medicine, University of New South Wales, New South Wales, Australia
| | | | - Bayzid Rahman
- School of Public Health and Community Medicine, University of New South Wales, New South Wales, Australia
| | - Cathelijne H van Kemenade
- Sydney School of Public Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Bruce K Armstrong
- Sydney School of Public Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.,School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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39
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Oswald E, Kirschberg M, Aubin F, Alonso A, Hufbauer M, Akgül B, Auvinen E. BetaHPV E6 and E7 colocalize with NuMa in dividing keratinocytes. Virus Genes 2019; 55:600-609. [PMID: 31290065 DOI: 10.1007/s11262-019-01685-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/02/2019] [Indexed: 01/01/2023]
Abstract
Human papillomaviruses (HPVs) of genus betapapillomavirus (betaHPV) are implicated in skin carcinogenesis, but their exact role in keratinocyte transformation is poorly understood. We show an interaction of HPV5 and HPV8 oncoproteins E6 and E7 with the nuclear mitotic apparatus protein 1 (NuMA). Binding of E6 or E7 to NuMA induces little aneuploidy, cell cycle alterations, or aberrant centrosomes. Intracellular localization of NuMA is not altered by E6 and E7 expression in 2D cultures. However, the localization profile is predominantly cytoplasmic in 3D organotypic skin models. Both viral proteins colocalize with NuMA in interphase cells, while only E7 colocalizes with NuMA in mitotic cells. Intriguingly, a small subset of cells shows E7 at only one spindle pole, whereas NuMA is present at both poles. This dissimilar distribution of E7 at the spindle poles may alter cell differentiation, which may in turn be relevant for betaHPV-induced skin carcinogenesis.
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Affiliation(s)
| | - Matthias Kirschberg
- Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Fürst-Pückler-Str.56, 50935, Cologne, Germany
| | - François Aubin
- Department of Dermatology, Université de Franche-Comté, Besançon, France
| | - Angel Alonso
- German Cancer Research Center, Heidelberg, Germany
| | - Martin Hufbauer
- Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Fürst-Pückler-Str.56, 50935, Cologne, Germany
| | - Baki Akgül
- Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Fürst-Pückler-Str.56, 50935, Cologne, Germany.
| | - Eeva Auvinen
- University of Helsinki and Helsinki University Hospital Laboratory, Helsinki, Finland
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40
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Tommasino M. HPV and skin carcinogenesis. PAPILLOMAVIRUS RESEARCH (AMSTERDAM, NETHERLANDS) 2019; 7:129-131. [PMID: 30953864 PMCID: PMC6460321 DOI: 10.1016/j.pvr.2019.04.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 04/01/2019] [Accepted: 04/02/2019] [Indexed: 12/22/2022]
Abstract
Epidemiological and biological studies provide several lines of evidence for the involvement of cutaneous beta human papillomaviruses (HPVs), together with ultraviolet (UV) radiation, in the development of cutaneous squamous cell carcinoma. These viruses appear to act with a hit-and-run mechanism, being necessary at an early stage of carcinogenesis and being dispensable for the maintenance of the malignant phenotype. Studies in experimental models show that beta HPVs, mainly via the E6 and E7 oncoproteins, are able to promote proliferation and to circumvent cellular stresses induced by UV radiation. These findings support a model of skin carcinogenesis in which beta HPV-infected keratinocytes remain alive despite the accumulation of UV-induced DNA mutations. In this manner, these cells become highly susceptible to progression towards malignancy. Thus, UV radiation is the main driver of skin cancer development, while beta HPVs act as facilitators of the accumulation of UV-induced DNA mutations.
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Affiliation(s)
- Massimo Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France.
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41
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Venuti A, Lohse S, Tommasino M, Smola S. Cross-talk of cutaneous beta human papillomaviruses and the immune system: determinants of disease penetrance. Philos Trans R Soc Lond B Biol Sci 2019; 374:20180287. [PMID: 30955489 PMCID: PMC6501898 DOI: 10.1098/rstb.2018.0287] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2019] [Indexed: 12/19/2022] Open
Abstract
Human papillomaviruses (HPVs) infect the epithelia of skin or mucosa, where they can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. Mucosal high-risk HPVs are causative for cancers of the anogenital region and oropharynx. Clinical data from patients with the rare genetic disorder epidermodysplasia verruciformis (EV) indicate that genus beta-HPVs cooperate with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma. In addition, epidemiological and biological findings indicate that beta-HPV types play a role in UV-mediated skin carcinogenesis also in non-EV individuals. However, the mechanisms used by these cutaneous viruses to promote epithelial carcinogenesis differ significantly from those of mucosal HPVs. Recent studies point to a delicate cross-talk of beta-HPVs with the cell-autonomous immunity of the host keratinocytes and the local immune microenvironment that eventually determines the fate of cutaneous HPV infection and the penetrance of disease. This review gives an overview of the critical interactions of genus beta-HPVs with the local immune system that allow the virus to complete its life cycle, to escape from extrinsic immunity, and eventually to cause chronic inflammation contributing to skin carcinogenesis. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
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Affiliation(s)
- Assunta Venuti
- 1 Infections and Cancer Biology Group, International Agency for Research on Cancer , 150 Cours Albert Thomas, Lyon 69008 , France
| | - Stefan Lohse
- 2 Institute of Virology, Saarland University Medical Center , Kirrbergerstr. Building 47, 66421 Homburg/Saar , Germany
| | - Massimo Tommasino
- 1 Infections and Cancer Biology Group, International Agency for Research on Cancer , 150 Cours Albert Thomas, Lyon 69008 , France
| | - Sigrun Smola
- 2 Institute of Virology, Saarland University Medical Center , Kirrbergerstr. Building 47, 66421 Homburg/Saar , Germany
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42
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Gheit T. Mucosal and Cutaneous Human Papillomavirus Infections and Cancer Biology. Front Oncol 2019; 9:355. [PMID: 31134154 PMCID: PMC6517478 DOI: 10.3389/fonc.2019.00355] [Citation(s) in RCA: 199] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022] Open
Abstract
Papillomaviridae is a family of small non-enveloped icosahedral viruses with double-stranded circular DNA. More than 200 different human papillomaviruses (HPVs) have been listed so far. Based on epidemiological data, a subgroup of alphapapillomaviruses (alpha HPVs) was referred to as high-risk (HR) HPV types. HR HPVs are the etiological agents of anogenital cancer and a subset of head and neck cancers. The cutaneous HPV types, mainly from beta and gamma genera, are widely present on the surface of the skin in the general population. However, there is growing evidence of an etiological role of betapapillomaviruses (beta HPVs) in non-melanoma skin cancer (NMSC), together with ultraviolet (UV) radiation. Studies performed on mucosal HR HPV types, such as 16 and 18, showed that both oncoproteins E6 and E7 play a key role in cervical cancer by altering pathways involved in the host immune response to establish a persistent infection and by promoting cellular transformation. Continuous expression of E6 and E7 of mucosal HR HPV types is essential to initiate and to maintain the cellular transformation process, whereas expression of E6 and E7 of cutaneous HPV types is not required for the maintenance of the skin cancer phenotype. Beta HPV types appear to play a role in the initiation of skin carcinogenesis, by exacerbating the accumulation of UV radiation-induced DNA breaks and somatic mutations (the hit-and-run mechanism), and they would therefore act as facilitators rather than direct actors in NMSC. In this review, the natural history of HPV infection and the transforming properties of various HPV genera will be described, with a particular focus on describing the state of knowledge about the role of cutaneous HPV types in NMSC.
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Affiliation(s)
- Tarik Gheit
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France
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43
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Rollison DE, Viarisio D, Amorrortu RP, Gheit T, Tommasino M. An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma. J Virol 2019; 93:e01003-18. [PMID: 30700603 PMCID: PMC6430537 DOI: 10.1128/jvi.01003-18] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Evidence suggests that beta human papillomaviruses (HPVs), together with ultraviolet radiation, contribute to the development of cutaneous squamous cell carcinoma. Beta HPVs appear to be not the main drivers of carcinogenesis but rather facilitators of the accumulation of ultraviolet-induced DNA mutations. Beta HPVs are promoters of skin carcinogenesis, although they are dispensable for the maintenance of the malignant phenotype. Therefore, beta HPV represents a target for skin cancer prevention, especially in high-risk populations.
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Affiliation(s)
- Dana E Rollison
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Daniele Viarisio
- Infection and Cancer Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | | | - Tarik Gheit
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Massimo Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France
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44
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Lucas RM, Yazar S, Young AR, Norval M, de Gruijl FR, Takizawa Y, Rhodes LE, Sinclair CA, Neale RE. Human health in relation to exposure to solar ultraviolet radiation under changing stratospheric ozone and climate. Photochem Photobiol Sci 2019; 18:641-680. [PMID: 30810559 DOI: 10.1039/c8pp90060d] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The Montreal Protocol has limited increases in the UV-B (280-315 nm) radiation reaching the Earth's surface as a result of depletion of stratospheric ozone. Nevertheless, the incidence of skin cancers continues to increase in most light-skinned populations, probably due mainly to risky sun exposure behaviour. In locations with strong sun protection programs of long duration, incidence is now reducing in younger age groups. Changes in the epidemiology of UV-induced eye diseases are less clear, due to a lack of data. Exposure to UV radiation plays a role in the development of cataracts, pterygium and possibly age-related macular degeneration; these are major causes of visual impairment world-wide. Photodermatoses and phototoxic reactions to drugs are not uncommon; management of the latter includes recognition of the risks by the prescribing physician. Exposure to UV radiation has benefits for health through the production of vitamin D in the skin and modulation of immune function. The latter has benefits for skin diseases such as psoriasis and possibly for systemic autoimmune diseases such as multiple sclerosis. The health risks of sun exposure can be mitigated through appropriate sun protection, such as clothing with both good UV-blocking characteristics and adequate skin coverage, sunglasses, shade, and sunscreen. New sunscreen preparations provide protection against a broader spectrum of solar radiation, but it is not clear that this has benefits for health. Gaps in knowledge make it difficult to derive evidence-based sun protection advice that balances the risks and benefits of sun exposure.
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Affiliation(s)
- R M Lucas
- National Centre for Epidemiology and Population Health, Research School of Population Health, Australian National University, Canberra, Australia. and Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - S Yazar
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia and MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | | | - M Norval
- Biomedical Sciences, University of Edinburgh Medical School, Edinburgh, Scotland, UK
| | - F R de Gruijl
- Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Y Takizawa
- Akita University School of Medicine, National Institute for Minamata Disease, Nakadai, Itabashiku, Tokyo, Japan
| | - L E Rhodes
- Centre for Dermatology Research, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | | | - R E Neale
- QIMR Berghofer Institute of Medical Research, Herston, Brisbane, Australia and School of Public Health, University of Queensland, Australia
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45
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Mastomys Species as Model Systems for Infectious Diseases. Viruses 2019; 11:v11020182. [PMID: 30795569 PMCID: PMC6409723 DOI: 10.3390/v11020182] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/13/2019] [Accepted: 02/20/2019] [Indexed: 12/17/2022] Open
Abstract
Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo situations as found in humans. Despite proven limitations of both approaches, only a combined experimental arrangement guarantees generalizability of results and their transfer to the clinics. Although the laboratory mouse still stands as a paradigm for many scientific discoveries and breakthroughs, it is mandatory to broaden our view by also using nontraditional animal models. The present review will first reflect the value of experimental systems in life science and subsequently describes the preclinical rodent model Mastomys coucha that-although still not well known in the scientific community-has a long history in research of parasites, bacteria, papillomaviruses and cancer. Using Mastomys, we could recently show for the first time that cutaneous papillomaviruses-in conjunction with UV as an environmental risk factor-induce squamous cell carcinomas of the skin via a "hit-and-run" mechanism. Moreover, Mastomys coucha was also used as a proof-of-principle model for the successful vaccination against non-melanoma skin cancer even under immunosuppressive conditions.
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46
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Abstract
Although some members of the viral family Papillomaviridae cause benign skin warts (papillomas), many human papillomavirus (HPV) infections are not associated with visible symptoms. For example, most healthy adults chronically shed Gammapapillomavirus (Gamma) virions from apparently healthy skin surfaces. To further explore the diversity of papillomaviruses, we performed viromic surveys on immunodeficient individuals suffering from florid skin warts. Our results nearly double the number of known Gamma HPV types and suggest that WHIM syndrome patients are uniquely susceptible to Gamma HPV-associated skin warts. Preliminary results suggest that treatment with the drug plerixafor may promote resolution of the unusual Gamma HPV skin warts observed in WHIM patients. Several immunodeficiencies are associated with high susceptibility to persistent and progressive human papillomavirus (HPV) infection leading to a wide range of cutaneous and mucosal lesions. However, the HPV types most commonly associated with such clinical manifestations in these patients have not been systematically defined. Here, we used virion enrichment, rolling circle amplification, and deep sequencing to identify circular DNA viruses present in skin swabs and/or wart biopsy samples from 48 patients with rare genetic immunodeficiencies, including patients with warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, or epidermodysplasia verruciformis (EV). Their profiles were compared with the profiles of swabs from 14 healthy adults and warts from 6 immunologically normal children. Individual patients were typically infected with multiple HPV types; up to 26 different types were isolated from a single patient (multiple anatomical sites, one time point). Among these, we identified the complete genomes of 83 previously unknown HPV types and 35 incomplete genomes representing possible additional new types. HPV types in the genus Gammapapillomavirus were common in WHIM patients, whereas EV patients mainly shed HPVs from the genus Betapapillomavirus. Preliminary evidence based on three WHIM patients treated with plerixafor, a leukocyte mobilizing agent, suggest that longer-term therapy may correlate with decreased HPV diversity and increased predominance of HPV types associated with childhood skin warts. IMPORTANCE Although some members of the viral family Papillomaviridae cause benign skin warts (papillomas), many human papillomavirus (HPV) infections are not associated with visible symptoms. For example, most healthy adults chronically shed Gammapapillomavirus (Gamma) virions from apparently healthy skin surfaces. To further explore the diversity of papillomaviruses, we performed viromic surveys on immunodeficient individuals suffering from florid skin warts. Our results nearly double the number of known Gamma HPV types and suggest that WHIM syndrome patients are uniquely susceptible to Gamma HPV-associated skin warts. Preliminary results suggest that treatment with the drug plerixafor may promote resolution of the unusual Gamma HPV skin warts observed in WHIM patients.
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47
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Bolatti EM, Hošnjak L, Chouhy D, Re-Louhau MF, Casal PE, Bottai H, Kocjan BJ, Stella EJ, Gorosito MD, Sanchez A, Bussy RF, Poljak M, Giri AA. High prevalence of Gammapapillomaviruses (Gamma-PVs) in pre-malignant cutaneous lesions of immunocompetent individuals using a new broad-spectrum primer system, and identification of HPV210, a novel Gamma-PV type. Virology 2018; 525:182-191. [PMID: 30292127 DOI: 10.1016/j.virol.2018.09.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 12/13/2022]
Abstract
Genus Gammapapillomavirus (Gamma-PV) is the most diverse and largest clade within the Papillomaviridae family. A novel set of degenerate primers targeting the E1 gene was designed and further used in combination with the well-known CUT PCR assay to assess HPV prevalence and genus distribution in a variety of cutaneous samples from 448 immunocompetent individuals. General HPV, Gamma-PV and mixed infections prevalence were significantly higher in actinic keratosis with respect to benign and malignant neoplasms, respectively (p = 0.0047, p = 0.0172, p = 0.00001). Gamma-PVs were significantly more common in actinic keratosis biopsies than Beta- and Alpha-PVs (p = 0.002). The full-length genome sequence of a novel putative Gamma-PV type was amplified by 'hanging droplet' long-range PCR and cloned. The novel virus, designated HPV210, clustered within species Gamma-12. This study provides an additional tool enabling detection of HPV infections in skin and adds new insights about possible early roles of Gamma-PVs in the development of cutaneous malignant lesions.
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Affiliation(s)
- Elisa M Bolatti
- Grupo Virología Humana, Instituto de Biología Molecular y Celular de Rosario (CONICET), Suipacha 590, 2000 Rosario, Argentina; Área Virología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Lea Hošnjak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
| | - Diego Chouhy
- Grupo Virología Humana, Instituto de Biología Molecular y Celular de Rosario (CONICET), Suipacha 590, 2000 Rosario, Argentina; Área Virología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Maria F Re-Louhau
- Grupo Virología Humana, Instituto de Biología Molecular y Celular de Rosario (CONICET), Suipacha 590, 2000 Rosario, Argentina
| | - Pablo E Casal
- Área Virología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Hebe Bottai
- Área Estadística y Procesamiento de Datos, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Boštjan J Kocjan
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
| | - Emma J Stella
- Grupo Virología Humana, Instituto de Biología Molecular y Celular de Rosario (CONICET), Suipacha 590, 2000 Rosario, Argentina
| | - Mario D Gorosito
- División de Anatomía Patológica, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100, 2000 Rosario, Argentina
| | - Adriana Sanchez
- División de Dermatología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100, 2000 Rosario, Argentina
| | - Ramón Fernandez Bussy
- División de Dermatología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100, 2000 Rosario, Argentina
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia.
| | - Adriana A Giri
- Grupo Virología Humana, Instituto de Biología Molecular y Celular de Rosario (CONICET), Suipacha 590, 2000 Rosario, Argentina; Área Virología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
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48
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Marx B, Hufbauer M, Zigrino P, Majewski S, Markiefka B, Sachsenheimer T, Brügger B, Akgül B. Phospholipidation of nuclear proteins by the human papillomavirus E6 oncoprotein: implication in carcinogenesis. Oncotarget 2018; 9:34142-34158. [PMID: 30344928 PMCID: PMC6183346 DOI: 10.18632/oncotarget.26140] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 09/06/2018] [Indexed: 12/16/2022] Open
Abstract
Phospholipids regulate numerous cellular functions and their deregulation is known to be associated with cancer development. Here, we show for the first time that expression of the E6 oncoprotein of human papillomavirus type 8 (HPV8) leads to a profound increase in nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) lipid levels in monolayer cultures, that led to an aberrant phospholipidation of cellular proteins. Elevated PI(4,5)P2 levels in organotypic skin cultures, skin tumors of K14-HPV8-E6 transgenic mice as well as HPV8 positive skin carcinomas highly suggest a decisive role of PI(4,5)P2 in HPV associated squamous-cell-carcinoma development. Furthermore, mass-spectrometric analysis confirmed an increase of PI(4,5)P2, which was characterized by a shift in the distribution of lipid species. PI(4,5)P2 upregulation was independent of E6 interference with MAML1. However, E6 does interfere with the PI(4,5)P2 metabolic pathway by upregulation of phosphatidylinositol-4-phosphate-5-kinase type I and phosphatidylinositol-5-phosphate 4-kinase type II as well as the binding to 5'-phosphatase OCRL and phosphatidylinositol. All of these mechanisms combined may contribute to PI(4,5)P2 elevation in E6 positive cells. The identification of CAND1 and SND1 - two proteins known to be involved in carcinogenic processes - were significantly stronger phospholipidized in the presence of E6. In conclusion we provide evidence that the modulation of the PI(4,5)P2 metabolism is a novel oncogenic mechanism relevant for HPV-induced carcinogenesis.
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Affiliation(s)
- Benjamin Marx
- Institute of Virology, University of Cologne, Cologne, Germany
| | - Martin Hufbauer
- Institute of Virology, University of Cologne, Cologne, Germany
| | - Paola Zigrino
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
| | - Slawomir Majewski
- Department of Dermatology and Venereology, Medical University of Warsaw, Warsaw, Poland
| | - Birgid Markiefka
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | | | - Britta Brügger
- Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany
| | - Baki Akgül
- Institute of Virology, University of Cologne, Cologne, Germany
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49
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de Gruijl FR, Tensen CP. Pathogenesis of Skin Carcinomas and a Stem Cell as Focal Origin. Front Med (Lausanne) 2018; 5:165. [PMID: 29896477 PMCID: PMC5986939 DOI: 10.3389/fmed.2018.00165] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 05/09/2018] [Indexed: 01/04/2023] Open
Abstract
UV radiation in sunlight has long been recognized as the main exogenous cause of skin carcinomas. We present a brief historical perspective on the progress in understanding the pathogenesis of skin carcinomas, and recent advances. Sun-exposed skin carries numerous UV-related mutations, and skin carcinomas rank among the tumors with the highest mutational loads. In this multitude of mutations only a few are crucial in driving the tumor. Some are known from hereditary (skin) cancer syndromes and other recurrent ones have been validated in transgenic mice. Considering the continuous renewal of the epidermis, the question arises whether the lifelong residing stem cells are the main targets in skin carcinogenesis, a multistep process that would require ample time to evolve. Therefore, classic quiescent stem cells have been studied as potential tumor-initiating cells, as well as more recently discovered actively dividing stem cells (either Lgr5+ or Lgr6+). Interesting differences have emerged between experimental UV and two-stage chemical carcinogenesis, e.g., the latter appears to originate from follicular stem cells, in contrast to the former.
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Affiliation(s)
- Frank R de Gruijl
- Department of Dermatology, Leiden University Medical Center Leiden, Netherlands
| | - Cornelis P Tensen
- Department of Dermatology, Leiden University Medical Center Leiden, Netherlands
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50
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Hasche D, Vinzón SE, Rösl F. Cutaneous Papillomaviruses and Non-melanoma Skin Cancer: Causal Agents or Innocent Bystanders? Front Microbiol 2018; 9:874. [PMID: 29770129 PMCID: PMC5942179 DOI: 10.3389/fmicb.2018.00874] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/16/2018] [Indexed: 12/12/2022] Open
Abstract
There is still controversy in the scientific field about whether certain types of cutaneous human papillomaviruses (HPVs) are causally involved in the development of non-melanoma skin cancer (NMSC). Deciphering the etiological role of cutaneous HPVs requires - besides tissue culture systems - appropriate preclinical models to match the obtained results with clinical data from affected patients. Clear scientific evidence about the etiology and underlying mechanisms involved in NMSC development is fundamental to provide reasonable arguments for public health institutions to classify at least certain cutaneous HPVs as group 1 carcinogens. This in turn would have implications on fundraising institutions and health care decision makers to force - similarly as for anogenital cancer - the implementation of a broad vaccination program against "high-risk" cutaneous HPVs to prevent NMSC as the most frequent cancer worldwide. Precise knowledge of the multi-step progression from normal cells to cancer is a prerequisite to understand the functional and clinical impact of cofactors that affect the individual outcome and the personalized treatment of a disease. This overview summarizes not only recent arguments that favor the acceptance of a viral etiology in NMSC development but also reflects aspects of causality in medicine, the use of empirically meaningful model systems and strategies for prevention.
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Affiliation(s)
- Daniel Hasche
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center, Heidelberg, Germany
| | - Sabrina E Vinzón
- Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Buenos Aires, Argentina
| | - Frank Rösl
- Division of Viral Transformation Mechanisms, Research Program "Infection, Inflammation and Cancer", German Cancer Research Center, Heidelberg, Germany
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