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Simion L, Rotaru V, Cirimbei C, Gales L, Stefan DC, Ionescu SO, Luca D, Doran H, Chitoran E. Inequities in Screening and HPV Vaccination Programs and Their Impact on Cervical Cancer Statistics in Romania. Diagnostics (Basel) 2023; 13:2776. [PMID: 37685314 PMCID: PMC10486539 DOI: 10.3390/diagnostics13172776] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
(1) Introduction: A Romanian woman is diagnosed with cervical cancer every two hours; the country ranks second in Europe in terms of the mortality and incidence rate of this disease. This paper aims to identify the main reasons that have led to this situation, focusing on the measures taken by the Romanian Ministry of Health for the prevention of this type of cancer-national programs for cervical cancer screening and HPV vaccination. (2) Materials and methods: We performed a study based on the available secondary data from the National Statistics Institute, World Health Organization and Bucharest Institute of Oncology in order to assess the burden associated with cervical cancer and place it in the context of known global and European incidence and mortality rates, thus evaluating the importance of this health issue in Romania. The second component of our study was a cross-sectional study. Here, we used a 14-question questionnaire applied to the women participating in the National Screening Program for Cervical Cancer and aimed to evaluate the women's level of knowledge about screening and HPV vaccination and their access cervical-cancer-specific healthcare services. (3) Results: The results of this research show that a high percentage of women postpone routine checks due to a lack of time and financial resources and indicate that a low level of knowledge about the disease and the specific preventive methods determines the low participation in screening and HPV vaccination programs implemented in Romania, contributing to the country's cervical cancer situation. (4) Conclusions: The national programs have complicated procedures, are underfunded and do not motivate healthcare workers enough. This, combined with the lack of information for the eligible population, adds up to an extremely low number of women screened and vaccinated. Our conclusion is that the Romanian Ministry of Health must take immediate action by conducting major awareness campaigns, implementing measures to make the programs functional and ensuring coherent funding.
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Affiliation(s)
- Laurentiu Simion
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Vlad Rotaru
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Ciprian Cirimbei
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Laurentia Gales
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- Medical Oncology Department, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Daniela-Cristina Stefan
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
| | - Sinziana-Octavia Ionescu
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Dan Luca
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Horia Doran
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- Surgical Clinic I, Clinical Hospital Dr. I. Cantacuzino Bucharest, 030167 Bucharest, Romania
| | - Elena Chitoran
- “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (L.S.); (L.G.); (D.-C.S.); (D.L.); (H.D.); (E.C.)
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
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Miotto IZ, Neto CF, de Oliveira WRP. Cutaneous infections from viral sources in solid organ transplant recipients. Transpl Immunol 2023; 78:101838. [PMID: 37085124 DOI: 10.1016/j.trim.2023.101838] [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: 12/22/2022] [Revised: 04/16/2023] [Accepted: 04/16/2023] [Indexed: 04/23/2023]
Abstract
INTRODUCTION Solid organ transplant recipients (SOTRs) are susceptible to various dermatological complications caused by long-term immunosuppressive therapy. Of these complications, viral infections are noteworthy because of their high prevalence and the potential morbidity associated with viral carcinogenesis. OBJECTIVES To evaluate the occurrence of cutaneous viral infections in SOTRs and their correlation with clinical features, transplant type, and the length and intensity of immunosuppressive therapy. METHODS This retrospective cohort study included SOTRs followed up at the Department of Dermatology in a tertiary hospital. The outcomes analyzed were the occurrence of cutaneous viral infections, including human papillomavirus (HPV) infection, herpes simplex, herpes zoster, molluscum contagiosum, Merkel cell carcinoma, Kaposi's sarcoma, and cytomegalovirus, and the occurrence of HPV-related neoplasms. Clinical variables, such as length and intensity of immunosuppression, type of transplanted organ, and comorbidities, were analyzed as possible risk factors for cutaneous viral infections in SOTRs. RESULTS A total of 528 SOTRs were included in this study, among which 53.8% had one or more viral infections. Of these, 10% developed a virus-associated malignancy (HPV-associated carcinoma, Merkel cell carcinoma, or Kaposi's sarcoma). The higher risk of viral infections among SOTRs was associated with cyclosporine intake (1.40-fold higher risk) and younger age at transplantation. The use of an immunosuppressive regimen, including additional drugs, was associated with a higher risk of genital HPV infection (1.50-fold higher risk for each incremental drug). CONCLUSIONS The occurrence of cutaneous viral infections in SOTRs is directly associated with the duration and intensity of immunosuppressive therapy. Patients at higher risk were those taking drugs with a stronger impact on cellular immunity and/or those on an immunosuppressive regimen comprising various drugs.
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Affiliation(s)
- Isadora Zago Miotto
- Department of Dermatology, University of São Paulo Medical School, Av Dr Enéas de Carvalho Aguiar, 255, Zip Code, 05403-900, São Paulo, Brazil.
| | - Cyro Festa Neto
- Department of Dermatology, University of São Paulo Medical School, Av Dr Enéas de Carvalho Aguiar, 255, Zip Code, 05403-900, São Paulo, Brazil
| | - Walmar Roncalli Pereira de Oliveira
- Department of Dermatology, University of São Paulo Medical School, Av Dr Enéas de Carvalho Aguiar, 255, Zip Code, 05403-900, São Paulo, Brazil.
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3
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Papastamelos C, Linder M. Human papillomavirus anogenital screening in solid organ transplant recipients: a narrative review. Arch Gynecol Obstet 2023; 307:1277-1283. [PMID: 35476141 DOI: 10.1007/s00404-022-06577-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 04/12/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE To provide a narrative review of anogenital screening for human papillomavirus in solid organ transplant recipients. METHODS Keyword searches of PubMed and Ovid MEDLINE databases were performed. Keywords included human papillomavirus, malignancy, cervical cancer, Pap smear, solid organ transplant, and immunosuppression. Manual searches were also conducted of other relevant journals and reference lists of primary articles. RESULTS Forty-one studies, articles, or clinical practice guidelines across 25 years of literature were included. Eligible literature was written in English or offered an English translation. CONCLUSION Human papillomavirus-related anogenital malignancies disproportionately affect transplant recipients compared to the general population. Evidence-based guidelines for cervical cancer screening and prevention in transplant patients are lacking. Current practice guidelines generally agree on increased Pap screening for transplant recipients compared to the general population. However, recommended screening frequency differs between organizations and amongst medical specialties. Vaccination against HPV remains the most effective strategy to prevent HPV-driven pre-malignant and malignant lesions.
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Affiliation(s)
| | - Mitchell Linder
- University of Rochester Medical Center, Obstetrics and Gynecology, Rochester, NY, USA
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Gale A, Merzel Šabović EK, Kaiser DJ, Starbek Zorko M. Acquired epidermodysplasia verruciformis in a renal transplant patient: a case report. ACTA DERMATOVENEROLOGICA ALPINA PANNONICA ET ADRIATICA 2022. [DOI: 10.15570/actaapa.2022.s6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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5
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Urso B, Kelsey A, Bordelon J, Sheiner P, Finch J, Cohen JL. Risk factors and prevention strategies for cutaneous squamous cell carcinoma in transplant recipients. Int J Dermatol 2022; 61:1218-1224. [PMID: 35080249 DOI: 10.1111/ijd.16070] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/31/2021] [Accepted: 12/31/2021] [Indexed: 11/30/2022]
Abstract
It has been well established that organ transplant recipients (OTRs) are at an increased risk of skin cancer. Studies vary on the exact degree of this risk, but it is likely somewhere between 60 and 100 times more likely that an OTR patient will develop skin cancer. The management of skin cancer burden in OTRs requires a multidisciplinary approach with the transplant team, dermatologists, and oncology. In many major hospital systems, there are dedicated transplant dermatology clinics that allow for specialized and more frequent screenings of this high-risk population. Here we discuss the pathogenesis, presentation, and treatment options used by dermatologists to prevent and treat commonly found skin cancers in this vulnerable population.
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Affiliation(s)
- Brittany Urso
- Department of Dermatology, University of California Irvine, Irvine, California, USA
| | - Andrew Kelsey
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Jenna Bordelon
- Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Patricia Sheiner
- Department of Surgery, Hartford Hospital, Hartford, Connecticut, USA
| | - Justin Finch
- Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut, USA.,Central Connecticut Dermatology, Cromwell, Connecticut, USA
| | - Joel L Cohen
- Department of Dermatology, University of California Irvine, Irvine, California, USA.,AboutSkin Dermatology and DermSurgery, Greenwood Village and Lone Tree, Colorado, USA
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Zauner R, Wimmer M, Dorfer S, Ablinger M, Koller U, Piñón Hofbauer J, Guttmann-Gruber C, Bauer JW, Wally V. Transcriptome-Guided Drug Repurposing for Aggressive SCCs. Int J Mol Sci 2022; 23:ijms23021007. [PMID: 35055192 PMCID: PMC8780441 DOI: 10.3390/ijms23021007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/03/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023] Open
Abstract
Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa (RDEB), SCCs arise more frequently and follow a particularly aggressive course. Notably, such SCC types display molecular similarities, despite their differing etiologies. We leveraged the similarities in transcriptomes between tumors from organ transplant recipients and RDEB-patients, augmented with data from more common head and neck (HN)-SCCs, to identify drugs that can be repurposed to treat these SCCs. The in silico approach used is based on the assumption that SCC-derived transcriptome profiles reflect critical tumor pathways that, if reversed towards healthy tissue, will attenuate the malignant phenotype. We determined tumor-specific signatures based on differentially expressed genes, which were then used to mine drug-perturbation data. By leveraging recent efforts in the systematic profiling and cataloguing of thousands of small molecule compounds, we identified drugs including selumetinib that specifically target key molecules within the MEK signaling cascade, representing candidates with the potential to be effective in the treatment of these rare and aggressive SCCs.
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Affiliation(s)
- Roland Zauner
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
- Correspondence:
| | - Monika Wimmer
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
| | - Sonja Dorfer
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
| | - Michael Ablinger
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
| | - Ulrich Koller
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
| | - Josefina Piñón Hofbauer
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
| | - Christina Guttmann-Gruber
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
| | - Johann W. Bauer
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
- Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
| | - Verena Wally
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (M.W.); (S.D.); (M.A.); (U.K.); (J.P.H.); (C.G.-G.); (J.W.B.); (V.W.)
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Moore S, Rady P, Tyring S. Acquired epidermodysplasia verruciformis: clinical presentation and treatment update. Int J Dermatol 2021; 61:1325-1335. [PMID: 34403500 DOI: 10.1111/ijd.15857] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/08/2021] [Accepted: 07/28/2021] [Indexed: 12/01/2022]
Abstract
Acquired epidermodysplasia verruciformis (AEV) is a form of epidermodysplasia verruciformis (EV) that is most commonly found in immunocompromised or immunosuppressed patients. EV is commonly associated with human papillomavirus (HPV), which is often found in EV and AEV lesions. Clinical presentation of AEV in patients with organ transplantation, HIV+, congenital HIV+, hematological diseases, and other iatrogenic immunosuppression are reviewed. Treatment options include topical cidofovir, topical retinoids, topical imiquimod, topical glycolic acid, HPV 9-valent vaccine, acitretin, improving cellular immunity, and changing transplant medication to mycophenolate mofetil.
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Affiliation(s)
- Stephen Moore
- Department of Dermatology, McGovern Medical School at UTHealth, Houston, Texas, USA.,Rice University, Houston, Texas, USA
| | - Peter Rady
- Department of Dermatology, McGovern Medical School at UTHealth, Houston, Texas, USA
| | - Stephen Tyring
- Department of Dermatology, McGovern Medical School at UTHealth, Houston, Texas, USA
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Quinlan S, May S, Weeks R, Yuan H, Luff J. Canine Papillomavirus 2 E6 Does Not Interfere With UVB-Induced Upregulation of p53 and p53-Regulated Genes. Front Vet Sci 2021; 8:570982. [PMID: 33748203 PMCID: PMC7965962 DOI: 10.3389/fvets.2021.570982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 02/01/2021] [Indexed: 11/13/2022] Open
Abstract
Cutaneous papillomaviruses are oncogenic viruses that cause severe, persistent infections that can develop into skin cancers within ultraviolet (UV)-exposed skin of immunodeficient individuals, such as those with X-linked severe combined immunodeficiency (XSCID). A canine research model of XSCID exhibits a similar phenotype; these dogs develop severe canine papillomavirus 2 (CPV2) infections that often progress to cancer. Thus, the dog is a natural, spontaneous model to investigate cutaneous papillomavirus infections in immunodeficient patients. The human papillomavirus oncogene E6 contributes to cancer development, in part, by initiating degradation of the tumor suppressor protein p53, or by inhibiting upregulation of p53-dependent genes required within the cell growth arrest and apoptotic pathways, thereby leading to an accumulation of DNA damage required for oncogenesis. Currently, little is known about CPV2, and how it promotes cancer development. The aim of this study was to determine if CPV2 oncogene E6 similarly affects p53 upon activation by UV radiation, as well as the downstream p53-regulated genes necessary to control growth arrest and apoptosis. We determined that cutaneous CPV2 E6 does not degrade p53, or interfere with the upregulation of p53-regulated genes p21, Bax, Bak, or lncRNA-p21, suggesting that CPV2 may use a p53-independent mechanism to contribute to oncogenesis.
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Affiliation(s)
- Sarah Quinlan
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Susan May
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Ryan Weeks
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Hang Yuan
- Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
| | - Jennifer Luff
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
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Cutaneous Head and Neck Cancers in the High-Risk Immunosuppressed Population. Otolaryngol Clin North Am 2021; 54:397-413. [PMID: 33602516 DOI: 10.1016/j.otc.2020.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The immunosuppressed (IS) population encompasses a diverse cohort of patients to include iatrogenically immunocompromised organ transplant recipients as well as patients with chronic lymphoid malignancies, human immunodeficiency virus/acquired immunodeficiency syndrome, and autoimmune disorders. Cutaneous cancers in this high-risk patient group are clinically distinct from the general immunocompetent population, showing aggressive behavior with associated poor outcomes. This article reviews the pathogenesis, epidemiology, incidence, prognosis, and special considerations required in managing cutaneous cancers in the IS patient population.
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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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Ritter A, Badir S, Mansour M, Segal Z, Ad-El D, Bachar G, Shpitzer T, Popovtzer A, Mizrachi A. Solid organ transplantation worsens the prognosis of patients with cutaneous squamous cell carcinoma of the head and neck region-Comparison between solid organ transplant recipients and immunocompetent patients. Head Neck 2020; 43:884-894. [PMID: 33247523 DOI: 10.1002/hed.26546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 10/25/2020] [Accepted: 11/09/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinoma of the head and neck (CSCC-HN) appears to behave more aggressively in immunosuppressed patients. We aimed to investigate this hypothesis by comparing solid organ transplant recipients (SOTR) with CSCC-HN to immunocompetent patients. METHODS A retrospective comparative study was conducted for SOTR and immunocompetent patients who were treated for CSCC-HN. RESULTS A total of 177 SOTR and 157 immunocompetent patients with CSCC-HN were included. Lymph node metastases were more common in the SOTR group (9% vs 3%), and distant metastases occurred only in SOTR (3% of patients). SOTR had a higher rate of recurrences (19% vs 10%), which were mostly regional (7%) and distant (3%). The 2-year disease-specific survival of SOTR was lower (93% vs 100%). CONCLUSIONS SOTR with CSCC-HN has significantly worse outcomes compared to immunocompetent patients. Solid-organ transplantation should be regarded as a negative prognostic factor in patients with CSCC-HN.
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Affiliation(s)
- Amit Ritter
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Samih Badir
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Muhammad Mansour
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Zvi Segal
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Dean Ad-El
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Gideon Bachar
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Thomas Shpitzer
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aron Popovtzer
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
| | - Aviram Mizrachi
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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12
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Tampa M, Mitran CI, Mitran MI, Nicolae I, Dumitru A, Matei C, Manolescu L, Popa GL, Caruntu C, Georgescu SR. The Role of Beta HPV Types and HPV-Associated Inflammatory Processes in Cutaneous Squamous Cell Carcinoma. J Immunol Res 2020; 2020:5701639. [PMID: 32322596 PMCID: PMC7165336 DOI: 10.1155/2020/5701639] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 03/25/2020] [Indexed: 11/21/2022] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with a complex but not fully understood pathogenesis. Recent research suggests the role of beta human papillomavirus (HPV) types and HPV-associated inflammatory processes in cSCC development. Beta HPV types are components of the normal flora; however, under the influence of certain cofactors, the virus may trigger a malignant process. Dysregulation of the immune system (chronic inflammation and immunosuppression), environmental factors (ultraviolet radiation), and genetic factors are the most important cofactors involved in beta HPV-related carcinogenesis. In addition, the oncoproteins E6 and E7 of beta HPV types differ biochemically from their counterparts in the structure of alpha HPV types, resulting in different mechanisms of action in carcinogenesis. The aim of our manuscript is to present an updated point of view on the involvement of beta HPV types in cSCC pathogenesis.
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Affiliation(s)
- Mircea Tampa
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
- “Victor Babes” Clinical Hospital for Infectious Diseases, 281 Mihai Bravu, 030303 Bucharest, Romania
| | - Cristina Iulia Mitran
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
| | - Madalina Irina Mitran
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
| | - Ilinca Nicolae
- “Victor Babes” Clinical Hospital for Infectious Diseases, 281 Mihai Bravu, 030303 Bucharest, Romania
| | - Adrian Dumitru
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
- Emergency University Hospital Bucharest, 169 Splaiul Independenței, 050098 Bucharest, Romania
| | - Clara Matei
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
| | - Loredana Manolescu
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
| | - Gabriela Loredana Popa
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
- Colentina Clinical Hospital, 19-21 Ștefan cel Mare, 020125 Bucharest, Romania
| | - Constantin Caruntu
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
- “Prof. N. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 22-24 Gr. Manolescu, Bucharest 011233, Romania
| | - Simona Roxana Georgescu
- “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021 Bucharest, Romania
- “Victor Babes” Clinical Hospital for Infectious Diseases, 281 Mihai Bravu, 030303 Bucharest, Romania
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Ewald PW, Swain Ewald HA. The scope of viral causation of human cancers: interpreting virus density from an evolutionary perspective. Philos Trans R Soc Lond B Biol Sci 2020; 374:20180304. [PMID: 30955500 DOI: 10.1098/rstb.2018.0304] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Most known oncogenic viruses of humans use DNA as their genomic material. Research over the past quarter century has revealed that their oncogenicity results largely from direct interference with barriers to oncogenesis. In contrast to viruses that have been accepted causes of particular cancers, candidate viral causes tend to have fewer viral than cellular genomes in the tumours. These low viral loads have caused researchers to conclude that the associated viruses are not primary causes of the associated cancers. Consideration of differential survival, reproduction and infiltration of cells in a tumour suggest, however, that viral loads could be low even when viruses are primary causes of cancer. Resolution of this issue has important implications for human health because medical research tends to be effective at preventing and controlling infectious diseases. Mathematical models may clarify the problem and help guide future research by assessing whether low viral loads are likely outcomes of the differential survival, reproduction, and infiltration of cells in a tumour and, more generally, the extent to which viruses contribute to cancer. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
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Affiliation(s)
- Paul W Ewald
- Department of Biology, University of Louisville , Louisville, KY 40292 , USA
| | - Holly A Swain Ewald
- Department of Biology, University of Louisville , Louisville, KY 40292 , USA
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14
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Oh Y, Kim J, Zheng Z, Kim SK, Chung KY, Roh MR. Risk factors for recurrence in cutaneous squamous cell carcinoma after Mohs micrographic surgery: A retrospective review of 237 Asian patients. J Dermatol 2019; 47:72-77. [PMID: 31674043 DOI: 10.1111/1346-8138.15129] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 09/29/2019] [Indexed: 02/03/2023]
Abstract
Even after complete removal with Mohs micrographic surgery (MMS), cutaneous squamous cell carcinoma (cSCC) may recur; however, information about risk factors for recurrence in Asian patients is limited. This retrospective study reviewed cSCC patients treated with MMS at a single tertiary referral center from 2000 to 2017. Two hundred and thirty-seven patients were included and 36 showed recurrence (20 with local recurrence, 16 with distant metastasis). History of organ transplantation, diabetes, other malignancies and poorly differentiated histology correlated with cSCC recurrence. History of organ transplantation and cryotherapy at the cSCC site were related to higher local recurrence rates, and poor differentiation related to higher distant metastasis in Asian cSCC patients treated with MMS.
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Affiliation(s)
- Yeongjoo Oh
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jemin Kim
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Zhenlong Zheng
- Department of Dermatology, Yanbian University Hospital, Yanji, China
| | - Sang Kyem Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Kee Yang Chung
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Mi Ryung Roh
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
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15
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Lang CMR, Chan CK, Veltri A, Lien WH. Wnt Signaling Pathways in Keratinocyte Carcinomas. Cancers (Basel) 2019; 11:cancers11091216. [PMID: 31438551 PMCID: PMC6769728 DOI: 10.3390/cancers11091216] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 08/17/2019] [Accepted: 08/19/2019] [Indexed: 12/12/2022] Open
Abstract
The skin functions as a barrier between the organism and the surrounding environment. Direct exposure to external stimuli and the accumulation of genetic mutations may lead to abnormal cell growth, irreversible tissue damage and potentially favor skin malignancy. Skin homeostasis is coordinated by an intricate signaling network, and its dysregulation has been implicated in the development of skin cancers. Wnt signaling is one such regulatory pathway orchestrating skin development, homeostasis, and stem cell activation. Aberrant regulation of Wnt signaling cascades not only gives rise to tumor initiation, progression and invasion, but also maintains cancer stem cells which contribute to tumor recurrence. In this review, we summarize recent studies highlighting functional evidence of Wnt-related oncology in keratinocyte carcinomas, as well as discussing preclinical and clinical approaches that target oncogenic Wnt signaling to treat cancers. Our review provides valuable insight into the significance of Wnt signaling for future interventions against keratinocyte carcinomas.
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Affiliation(s)
| | - Chim Kei Chan
- de Duve Institute, Université catholique de Louvain, Brussels 1200, Belgium
| | - Anthony Veltri
- de Duve Institute, Université catholique de Louvain, Brussels 1200, Belgium
| | - Wen-Hui Lien
- de Duve Institute, Université catholique de Louvain, Brussels 1200, Belgium.
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16
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Chin-Hong PV, Reid GE. Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13590. [PMID: 31077438 DOI: 10.1111/ctr.13590] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023]
Abstract
These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially, so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer-causing strains. Organ transplant recipients should be screened for HPV-associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.
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Affiliation(s)
- Peter V Chin-Hong
- Division of Infectious Diseases, University of California at San Francisco, San Francisco, California
| | - Gail E Reid
- Division of Infectious Diseases, Loyola University Medical Center, Maywood, Illinois
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17
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Nadhan KS, Larijani M, Abbott J, Doyle AM, Linfante AW, Chung CL. Prevalence and Types of Genital Lesions in Organ Transplant Recipients. JAMA Dermatol 2019; 154:323-329. [PMID: 29387873 DOI: 10.1001/jamadermatol.2017.5801] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Importance Squamous cell carcinoma (SCC) is the most common skin cancer diagnosed in solid organ transplant recipients (OTRs) and confers significant mortality. The development of SCC in the genital region is elevated in nonwhite OTRs. Viral induction, specifically human papillomavirus (HPV), is hypothesized to play a role in the pathophysiology of these lesions. Objective To assess the prevalence and types of genital lesions observed in OTRs. Design, Setting, and Participants This retrospective review included 496 OTRs who underwent full skin examination from November 1, 2011, to April 28, 2017, at an academic referral center. The review was divided into 2 distinct periods before a change in clinical management that took effect on February 1, 2016 (era 1) and after that change (era 2). Patient awareness of genital lesions was assessed. All lesions clinically suggestive of malignant tumors were biopsied and underwent HPV polymerase chain reaction typing. Main Outcomes and Measures Number and types of genital lesions, proportion of malignant tumors positive for HPV, and patients cognizant of genital lesions. Results Of the total 496 OTRs, 376 OTRs were evaluated during era 1 (mean [SD] age, 60 years; age range, 32-94 years; 45 [65.2%] male; 164 [43.6%] white) and 120 OTRs were evaluated during era 2 of the study (mean age, 56 years; age range, 22-79 years; 76 [63.3%] male; 30 [25.0%] white). Overall, 111 of the 120 OTRs (92.5%) denied the presence of genital lesions during the history-taking portion of the medical examination. Genital lesions were found in 53 OTRs (44.2%), cutaneous malignant tumors (basal cell carcinoma and SCC in situ) in 6 (5.0%), genital SCC in situ in 3 (4.2%), and condyloma in 29 (24.2%). Eight of the 12 SCC in situ lesions (66.7%) were positive for high-risk HPV. Seven tested positive for HPV-16 and HPV-18, and 1 tested positive for high-risk HPV DNA but could not be further specified. Conclusions and Relevance Genital lesions in OTRs are common, but awareness is low. All OTRs should undergo thorough inspection of genital skin as a part of routine posttransplant skin examinations. Patients with darker skin types are disproportionately affected by cutaneous genital malignant tumors and should undergo a targeted program of early detection, prevention, and awareness focused on the risk of genital skin cancer after transplant. High-risk HPV subtypes are associated with genital SCC in OTRs. Additional studies are warranted to identify significant risk factors for HPV infection and to assess the utility of pretransplant HPV vaccination in the prevention of cutaneous genital malignant tumors.
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Affiliation(s)
- Kumar S Nadhan
- Department of Dermatology, Drexel University, Philadelphia, Pennsylvania
| | - Mary Larijani
- Department of Dermatology, Drexel University, Philadelphia, Pennsylvania
| | - James Abbott
- Department of Dermatology, Drexel University, Philadelphia, Pennsylvania
| | - Alden M Doyle
- Department of Internal Medicine, University of Virginia, Charlottesville
| | - Anthony W Linfante
- Department of Dermatology, Drexel University, Philadelphia, Pennsylvania
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18
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Luff J, Mader M, Rowland P, Britton M, Fass J, Yuan H. Viral genome integration of canine papillomavirus 16. PAPILLOMAVIRUS RESEARCH 2019; 7:88-96. [PMID: 30771493 PMCID: PMC6402295 DOI: 10.1016/j.pvr.2019.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/30/2019] [Accepted: 02/12/2019] [Indexed: 01/03/2023]
Abstract
Papillomaviruses infect humans and animals, most often causing benign proliferations on skin or mucosal surfaces. Rarely, these infections persist and progress to cancer. In humans, this transformation most often occurs with high-risk papillomaviruses, where viral integration is a critical event in carcinogenesis. The first aim of this study was to sequence the viral genome of canine papillomavirus (CPV) 16 from a pigmented viral plaque that progressed to metastatic squamous cell carcinoma in a dog. The second aim was to characterize multiple viral genomic deletions and translocations as well as host integration sites. The full viral genome was identified using a combination of PCR and high throughput sequencing. CPV16 is most closely related to chipapillomaviruses CPV4, CPV9, and CPV12 and we propose CPV16 be classified as a chipapillomavirus. Assembly of the full viral genome enabled identification of deletion of portions of the E1 and E2/E4 genes and two viral translocations within the squamous cell carcinoma. Genome walking was performed which identified four sites of viral integration into the host genome. This is the first description of integration of a canine papillomavirus into the host genome, raising the possibility that CPV16 may be a potential canine high-risk papillomavirus type.
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Affiliation(s)
- Jennifer Luff
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, North Carolina, USA.
| | - Michelle Mader
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, North Carolina, USA
| | | | - Monica Britton
- UC Davis Genome Center-Bioinformatics Core, University of California, Davis, CA, USA
| | - Joseph Fass
- UC Davis Genome Center-Bioinformatics Core, University of California, Davis, CA, USA
| | - Hang Yuan
- Department of Pathology, Georgetown University Medical Center, Washington, DC, USA
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19
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Haley CT, Mui UN, Vangipuram R, Rady PL, Tyring SK. Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention: Papillomaviruses and Merkel cell polyomavirus. J Am Acad Dermatol 2018; 81:1-21. [PMID: 30502418 DOI: 10.1016/j.jaad.2018.09.062] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 12/18/2022]
Abstract
In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.
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Affiliation(s)
| | | | - Ramya Vangipuram
- Center for Clinical Studies, Webster, Texas; Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas
| | - Peter L Rady
- Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas
| | - Stephen K Tyring
- Center for Clinical Studies, Webster, Texas; Department of Dermatology, University of Texas Health Science Center at Houston, Houston, Texas
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20
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Gao D, Chen HQ. Specific knockdown of HOXB7 inhibits cutaneous squamous cell carcinoma cell migration and invasion while inducing apoptosis via the Wnt/β-catenin signaling pathway. Am J Physiol Cell Physiol 2018; 315:C675-C686. [PMID: 30067384 DOI: 10.1152/ajpcell.00291.2017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metastatic cutaneous squamous cell carcinoma (CSCC) is a major cause of death associated with nonmelanoma skin cancer. The involvement of homeobox B7 ( HOXB7) in cancers has been reported. Thus, the current study intends to explore the effect of HOXB7 on CSCC and its relationship with the Wnt/β-catenin signaling pathway. Initially, microarray-based gene expression profiling of CSCC was performed, and HOXB7 was identified as an upregulated gene based on the microarray data of GSE66359 . Following this, the experimental results indicated that HOXB7 and β-catenin formed a composite, demonstrating that endogenous HOXB7 binds to β-catenin. Subsequently, CSCC cells were treated with siRNA against HOXB7 or an inhibitor of the Wnt/β-catenin signaling pathway to analyze any underlying regulatory mechanism of HOXB7 on the CSCC cells. Tumor growth involving xenografts in nude mice was also observed so as to explore whether or not HOXB7 could regulate subcutaneous tumor growth through in vivo culturing. To investigate the potential effects of HOXB7 on the Wnt/β-catenin signaling pathway, we determined the expression of HOXB7 and downstream genes of the Wnt/β-catenin signaling pathway. Notably, siRNA-mediated knockdown of HOXB7 inhibited the activation of the Wnt/β-catenin signaling pathway, thereby impeding the progression of cell viability, migration, and invasion as well as of the tumor growth, although contrarily facilitating cell apoptosis. Taken together, silencing of the HOXB7 has the mechanism of inactivating the Wnt/β-catenin signaling pathway, thereby accelerating cell apoptosis and suppressing cell migration and invasion in CSCC, which could provide a candidate target for the CSCC treatment.
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Affiliation(s)
- Dong Gao
- Department of Dermatology, Yantai Yu Huang Ding Hospital, Yantai, People’s Republic of China
| | - Hong-Quan Chen
- Department of Dermatology, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
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21
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Purdie KJ, Proby CM, Rizvi H, Griffin H, Doorbar J, Sommerlad M, Feltkamp MC, der Meijden EV, Inman GJ, South AP, Leigh IM, Harwood CA. The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions. Front Microbiol 2018; 9:1806. [PMID: 30154763 PMCID: PMC6102365 DOI: 10.3389/fmicb.2018.01806] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/18/2018] [Indexed: 12/19/2022] Open
Abstract
Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC. Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays. Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012–2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden. Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies.
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Affiliation(s)
- Karin J Purdie
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Charlotte M Proby
- Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Hasan Rizvi
- Department of Pathology, Barts Health NHS Trust, London, United Kingdom
| | - Heather Griffin
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - John Doorbar
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Mary Sommerlad
- Department of Dermatology, Barts Health NHS Trust, London, United Kingdom
| | - Mariet C Feltkamp
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands
| | - Els Van der Meijden
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands
| | - Gareth J Inman
- Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Andrew P South
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, United States
| | - Irene M Leigh
- Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Department of Dermatology, Barts Health NHS Trust, London, United Kingdom
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22
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Stiebing BN, Rosado FG, Vos JA. Human Papillomavirus-Related Malignancies in the Setting of Posttransplantation Immunosuppression. Arch Pathol Lab Med 2018; 142:711-714. [PMID: 29848025 DOI: 10.5858/arpa.2017-0586-ra] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - The use of immunosuppression to avoid allograft rejection within the host creates the opportunity for unchecked development of malignancy in the posttransplantation setting. These malignancies frequently show association with human papillomavirus. Within this specific patient population, understanding the oncogenic role of this virus is vital for prompt recognition and treatment of malignancy and precursor lesions as well as the institution of appropriate preventive measures. OBJECTIVE - To review the role of human papillomavirus in the development of malignancies and their precursor lesions in the posttransplantation setting. DATA SOURCES - The study comprised a review of the literature. CONCLUSIONS - The development of human papillomavirus-related malignancies in transplantation patients is dependent on several factors, such as virus subtype, length of immunosuppression, and type of immunosuppressive therapy. Malignancies within these patients differ from those in the general population in terms of pathogenesis, frequency, and recurrence rate, and therefore require further understanding to allow for optimal surveillance and clinical management.
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Affiliation(s)
| | | | - Jeffrey A Vos
- From the West Virginia University School of Medicine, Morgantown (Ms Stiebing); the Department of Pathology, University of Texas Southwestern BioCenter, Dallas (Dr Rosado); and the Department of Pathology, West Virginia University School of Medicine, Morgantown (Dr Vos)
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23
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Cavalieri S, Perrone F, Miceli R, Ascierto PA, Locati LD, Bergamini C, Granata R, Alfieri S, Resteghini C, Galbiati D, Busico A, Paielli N, Patuzzo R, Maurichi A, Gallino G, Ruggeri R, Mariani L, Palla M, Licitra L, Bossi P. Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer. Eur J Cancer 2018; 97:7-15. [PMID: 29734047 DOI: 10.1016/j.ejca.2018.04.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/07/2017] [Accepted: 04/05/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
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Affiliation(s)
- S Cavalieri
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - F Perrone
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Department of Pathology, Unit of Experimental Molecular Pathology, Milan, Italy
| | - R Miceli
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Clinical Epidemiology and Trial Organization, Milan, Italy
| | - P A Ascierto
- Istituto Nazionale Tumori Fondazione "G. Pascale", Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Naples, Italy
| | - L D Locati
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - C Bergamini
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - R Granata
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - S Alfieri
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - C Resteghini
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - D Galbiati
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy
| | - A Busico
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Department of Pathology, Unit of Experimental Molecular Pathology, Milan, Italy
| | - N Paielli
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Department of Pathology, Unit of Experimental Molecular Pathology, Milan, Italy
| | - R Patuzzo
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Melanoma and Sarcoma Surgery Unit, Milan, Italy
| | - A Maurichi
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Melanoma and Sarcoma Surgery Unit, Milan, Italy
| | - G Gallino
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Melanoma and Sarcoma Surgery Unit, Milan, Italy
| | - R Ruggeri
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Melanoma and Sarcoma Surgery Unit, Milan, Italy
| | - L Mariani
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Clinical Epidemiology and Trial Organization, Milan, Italy
| | - M Palla
- Istituto Nazionale Tumori Fondazione "G. Pascale", Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Naples, Italy
| | - L Licitra
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy; Università Degli Studi di Milano, Medical Oncology Department, Milan, Italy
| | - P Bossi
- Fondazione IRCCS Istituto Nazionale Dei Tumori, Medical Oncology/Head and Neck Unit, Milan, Italy.
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Bouwes Bavinck JN, Feltkamp MCW, Green AC, Fiocco M, Euvrard S, Harwood CA, Nasir S, Thomson J, Proby CM, Naldi L, Diphoorn JCD, Venturuzzo A, Tessari G, Nindl I, Sampogna F, Abeni D, Neale RE, Goeman JJ, Quint KD, Halk AB, Sneek C, Genders RE, de Koning MNC, Quint WGV, Wieland U, Weissenborn S, Waterboer T, Pawlita M, Pfister H, the EPI‐HPV‐UV‐CA group van der Zwan‐KraltP.de GraafY. G. L.VosL. E.Uphoff‐MeijerinkE. J.WillemzeR.StruijkL.WanningenP.van der MeijdenE.PlasmeijerE. I.WolterbeekR.OcampoA. C. M. A.KanitakisJ.StockflethE.ForschnerT.PizzagalliA.SassiF.GottiE.FiocchiR.BreuerJ.MitchellL.PurdieK.LambertS. R.RanH.SehrP.MichaelK. M.ter ScheggetJ.KleterB.van DoornL. J.SimoniS.Petasecca DonatiG. P.MasiniC.OlsenC.O’RourkeP.HarrisonS.ButtnerP.. Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study. Am J Transplant 2018; 18:1220-1230. [PMID: 29024374 PMCID: PMC5947129 DOI: 10.1111/ajt.14537] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/20/2017] [Accepted: 10/03/2017] [Indexed: 01/25/2023]
Abstract
Organ transplant recipients (OTRs) have a 100-fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between β genus human papillomaviruses (βPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003-2006 (n = 274) and cohort 2 was transplanted in 1986-2002 (n = 352). Participants were followed until death or cessation of follow-up in 2016. βPV infection was assessed in eyebrow hair by using polymerase chain reaction-based methods. βPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of βPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different βPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1-2.6). A similar risk was seen with high βPV loads (HR 1.8, 95% confidence interval 1.2-2.8). No significant associations were seen between serum antibodies and cSCC or between βPV and basal cell carcinoma. The diversity and load of βPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that βPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies.
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Affiliation(s)
| | - Mariet C. W. Feltkamp
- Department of Medical MicrobiologyLeiden University Medical CenterLeidenThe Netherlands
| | - Adele C. Green
- QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Marta Fiocco
- Department of Medical Statistics and BioinformaticsLeiden University Medical CenterLeidenThe Netherlands,Institute of MathematicsLeiden UniversityLeidenThe Netherlands
| | - Sylvie Euvrard
- Department of DermatologyEdouard Herriot HospitalHospices Civils de LyonLyonFrance
| | - Catherine A. Harwood
- Centre for Cell Biology and Cutaneous ResearchBlizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonUK
| | - Shaaira Nasir
- Centre for Cell Biology and Cutaneous ResearchBlizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonUK
| | - Jason Thomson
- Centre for Cell Biology and Cutaneous ResearchBlizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonUK
| | - Charlotte M. Proby
- Division of Cancer ResearchUniversity of DundeeNinewells Hospital and Medical SchoolDundeeUK
| | - Luigi Naldi
- Department of DermatologyAzienda Ospedaliera papa Giovanni XXIII, and GISED Study CenterBergamoItaly
| | - Janouk C. D. Diphoorn
- Department of DermatologyAzienda Ospedaliera papa Giovanni XXIII, and GISED Study CenterBergamoItaly
| | - Anna Venturuzzo
- Department of DermatologyAzienda Ospedaliera papa Giovanni XXIII, and GISED Study CenterBergamoItaly
| | - Gianpaolo Tessari
- Department of MedicineSection of DermatologyUniversity of Veronac/o Ospedale Civile MaggioreVeronaItaly
| | - Ingo Nindl
- Department of DermatologyUniversity Hospital CharitéSkin Cancer Center CharitéBerlinGermany
| | | | | | | | - Jelle J. Goeman
- Department of Medical Statistics and BioinformaticsLeiden University Medical CenterLeidenThe Netherlands
| | - Koen D. Quint
- Department of DermatologyLeiden University Medical CenterLeidenThe Netherlands
| | - Anne B. Halk
- Department of DermatologyLeiden University Medical CenterLeidenThe Netherlands
| | - Carmen Sneek
- Department of DermatologyLeiden University Medical CenterLeidenThe Netherlands
| | - Roel E. Genders
- Department of DermatologyLeiden University Medical CenterLeidenThe Netherlands
| | | | | | - Ulrike Wieland
- Institute of VirologyUniversity of CologneCologneGermany
| | | | - Tim Waterboer
- German Cancer Research Center (DKFZ)HeidelbergGermany
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25
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WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma. Oncogene 2018; 37:3753-3762. [PMID: 29662191 PMCID: PMC6033839 DOI: 10.1038/s41388-018-0244-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 03/01/2018] [Accepted: 03/06/2018] [Indexed: 12/14/2022]
Abstract
Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/β-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.
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26
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Luff JA, Burns RE, Mader M, Priest KD, Tuttle AD. Cutaneous squamous cell carcinoma associated with Zalophus californianus papillomavirus 1 in a California sea lion. J Vet Diagn Invest 2018; 30:572-575. [PMID: 29629648 DOI: 10.1177/1040638718769702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Papillomaviruses (PVs) are found in many species and infect epithelial cells at both mucosal and cutaneous sites. PVs are generally species-specific and cause benign epithelial proliferations, often forming papillomas or plaques. Rarely, these infections can persist, allowing progression to in situ and invasive cancers. We describe herein a case of multiple cutaneous pigmented plaques from a California sea lion ( Zalophus californianus) that progressed to in situ and invasive squamous cell carcinoma (SCC). The lesions were characterized by epithelial hyperplasia, hyperkeratosis, and hypergranulosis that bordered more dysplastic areas, and, at one site, bordered an invasive SCC. Immunohistochemistry for papillomavirus antigen revealed strong nuclear immunoreactivity within keratinocytes in the hyperplastic epidermis. PCR was performed using degenerate and specific primers to detect papillomavirus DNA. Specific primers were used to amplify Zalophus californianus papillomavirus 1 (ZcPV-1), the only sea lion papillomavirus known to date. We detected ZcPV-1 DNA within the pigmented plaque, and in both in situ and invasive SCC samples.
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Affiliation(s)
- Jennifer A Luff
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Luff, Mader).,Department of Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT (Burns, Priest).,Mystic Aquarium, Department of Animal Care, Mystic, CT (Tuttle)
| | - Rachel E Burns
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Luff, Mader).,Department of Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT (Burns, Priest).,Mystic Aquarium, Department of Animal Care, Mystic, CT (Tuttle)
| | - Michelle Mader
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Luff, Mader).,Department of Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT (Burns, Priest).,Mystic Aquarium, Department of Animal Care, Mystic, CT (Tuttle)
| | - Kara D Priest
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Luff, Mader).,Department of Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT (Burns, Priest).,Mystic Aquarium, Department of Animal Care, Mystic, CT (Tuttle)
| | - Allison D Tuttle
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (Luff, Mader).,Department of Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT (Burns, Priest).,Mystic Aquarium, Department of Animal Care, Mystic, CT (Tuttle)
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27
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Mrad M, Ayoub N, Mehi R. Topical ingenol mebutate is effective against plantar warts in immunocompromised patients. JAAD Case Rep 2018; 4:53-54. [PMID: 29387748 PMCID: PMC5771734 DOI: 10.1016/j.jdcr.2017.09.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Marc Mrad
- Department of Dermatology, Holy Spirit University of Kaslik, Kaslik, Lebanon
| | - Nakhle Ayoub
- Department of Dermatology, Holy Spirit University of Kaslik, Kaslik, Lebanon
| | - Ribal Mehi
- Department of Dermatology, Holy Spirit University of Kaslik, Kaslik, Lebanon
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28
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Hoggard N, Munday JS, Luff J. Localization of Felis catus Papillomavirus Type 2 E6 and E7 RNA in Feline Cutaneous Squamous Cell Carcinoma. Vet Pathol 2018; 55:409-416. [PMID: 29343198 DOI: 10.1177/0300985817750456] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Findings from polymerase chain reaction-based methods have suggested a role of Felis catus papillomavirus 2 (FcaPV-2) in the development of feline cutaneous squamous cell carcinoma (SCC). However, because polymerase chain reaction cannot localize deoxyribonucleic acid or ribonucleic acid within the lesion, it is difficult to differentiate a coincidental FcaPV-2 infection and a causative association. Given that a key event in the pathogenesis of human papillomavirus-induced cancer is the expression of viral E6 and E7 oncogenes, localization of FcaPV-2 E6 and E7 transcription within neoplastic cells in feline SCCs would support a causative role for this papillomavirus. Therefore, RNAscope in situ hybridization was used to localize FcaPV-2 E6 and E7 transcripts in 18 formalin-fixed paraffin-embedded samples of cutaneous SCC. Positive signals were present within 5 of 9 samples (56%) from ultraviolet-protected sites and 0 of 9 samples from ultraviolet-exposed sites. In the 4 in situ hybridization-positive samples that contained adjacent hyperplastic skin, hybridization patterns in these regions were characterized by intense nuclear signals within the superficial epidermis and punctate signals within the basal epithelial layers. However, within the 5 SCCs, punctate signals were present within all layers of the epidermis, with progressive loss of intense nuclear signals within the superficial epidermis. This hybridization pattern is consistent with unregulated E6 and E7 transcription and decreased viral replication and is similar to the pattern observed in human papillomavirus-induced cancers as they progress from hyperplastic lesions containing productive infections to nonproductive neoplasms. These findings support a causative role for FcaPV-2 in the pathogenesis of feline SCC.
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Affiliation(s)
- Nathan Hoggard
- 1 College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - John S Munday
- 2 Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand
| | - Jennifer Luff
- 1 College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
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29
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Uberoi A, Yoshida S, Lambert PF. Development of an in vivo infection model to study Mouse papillomavirus-1 (MmuPV1). J Virol Methods 2017; 253:11-17. [PMID: 29253496 DOI: 10.1016/j.jviromet.2017.12.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 12/11/2017] [Indexed: 12/20/2022]
Abstract
Preclinical model systems to study multiple features of the papillomavirus life cycle are extremely valuable tools to aid our understanding of Human Papillomavirus (HPV) biology, disease progression and treatments. Mouse papillomavirus (MmuPV1) is the first ever rodent papillomavirus that can infect the laboratory strain of mice and was discovered recently in 2011. This model is an attractive model to study papillomavirus pathogenesis due to the ubiquitous availability of lab mice and the fact that this mouse species is easily genetically modifiable. Several other groups, including ours, have reported that MmuPV1-induced papillomas are restricted to T-cell deficient immunosuppressed mice. In our lab we showed for the first time that MmuPV1 causes skin cancers in UVB-irradiated immunocompetent animals. In this report we describe in detail the MmuPV1-UV infection model that can be adapted to study MmuPV1 biology in immunocompetent animals.
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Affiliation(s)
- Aayushi Uberoi
- McArdle Laboratory of Cancer Research, 1111 Highland Avenue, University of Wisconsin, Madison 53705, United States
| | - Satoshi Yoshida
- McArdle Laboratory of Cancer Research, 1111 Highland Avenue, University of Wisconsin, Madison 53705, United States
| | - Paul F Lambert
- McArdle Laboratory of Cancer Research, 1111 Highland Avenue, University of Wisconsin, Madison 53705, United States.
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30
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Abstract
Preclinical infection model systems are extremely valuable tools to aid in our understanding of Human Papillomavirus (HPV) biology, disease progression, prevention, and treatments. In this context, rodent papillomaviruses and their respective infection models are useful tools but remain underutilized resources in the field of papillomavirus biology. Two rodent papillomaviruses, MnPV1, which infects the Mastomys species of multimammate rats, and MmuPV1, which infects laboratory mice, are currently the most studied rodent PVs. Both of these viruses cause malignancy in the skin and can provide attractive infection models to study the lesser understood cutaneous papillomaviruses that have been frequently associated with HPV-related skin cancers. Of these, MmuPV1 is the first reported rodent papillomavirus that can naturally infect the laboratory strain of mice. MmuPV1 is an attractive model virus to study papillomavirus pathogenesis because of the ubiquitous availability of lab mice and the fact that this mouse species is genetically modifiable. In this review, we have summarized the knowledge we have gained about PV biology from the study of rodent papillomaviruses and point out the remaining gaps that can provide new research opportunities.
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31
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Harwood CA, Toland AE, Proby CM, Euvrard S, Hofbauer GFL, Tommasino M, Bouwes Bavinck JN. The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients. Br J Dermatol 2017; 177:1217-1224. [PMID: 29086420 DOI: 10.1111/bjd.15956] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2017] [Indexed: 12/14/2022]
Abstract
The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro- and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta-genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co-factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post-transplant keratinocyte cancers.
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Affiliation(s)
- C A Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, U.K
| | - A E Toland
- Cancer Biology and Genetics, The Ohio State University, Columbus, OH, U.S.A
| | - C M Proby
- Division of Cancer Research, School of Medicine, University of Dundee, Dundee, U.K
| | - S Euvrard
- Hospices Civils de Lyon, Department of Dermatology, Edouard Herriot Hospital, Lyon, France
| | - G F L Hofbauer
- Department of Dermatology, University of Zurich, Zurich, Switzerland
| | - M Tommasino
- Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France
| | - J N Bouwes Bavinck
- Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands
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32
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Mittal A, Colegio OR. Skin Cancers in Organ Transplant Recipients. Am J Transplant 2017; 17:2509-2530. [PMID: 28556451 DOI: 10.1111/ajt.14382] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/05/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023]
Abstract
Long-term utilization of immunosuppression in organ transplant recipients (OTRs) leads to decreased immune-mediated tumor surveillance and development of malignant tumors. A delicate balance needs to be maintained in the intensity of immunosuppression to keep the risk of malignancy low without jeopardizing life-saving graft function. OTRs are prone to developing skin cancers that exhibit unique epidemiologic, pathophysiologic, and prognostic characteristics. In this review, we discuss the most commonly reported skin cancers in OTRs: squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Kaposi sarcoma, Merkel cell carcinoma, and malignant melanoma (MM). Tumors in this high-risk population are aggressive and may respond poorly to standard therapies; however, new targeted therapies are promising. Checkpoint inhibitor antibodies have been used for treatment of cutaneous SCC, Merkel cell carcinoma, and MM; epidermal growth factor receptor inhibitors have been used for cutaneous SCC; hedgehog pathway inhibitors have been used for BCC; and BRAF and MEK inhibitors are being used increasingly in the management of MM. Guidelines for dermatologic screening are variable and primarily based on expert opinion. Prospective evidence-based trials by multidisciplinary groups are needed to better define surveillance schedules for pre- and posttransplant cutaneous malignancies.
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Affiliation(s)
- A Mittal
- Departments of Dermatology, Yale University School of Medicine, New Haven, CT
| | - O R Colegio
- Departments of Dermatology, Yale University School of Medicine, New Haven, CT.,Departments of Pathology, Yale University School of Medicine, New Haven, CT.,Departments of Surgery, Yale University School of Medicine, New Haven, CT.,Yale Cancer Center, Yale University School of Medicine, New Haven, CT.,Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, CT
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Abstract
OPINION STATEMENT Non-melanoma skin cancer (NMSC) is the most common malignancy in the USA, with cutaneous squamous cell carcinomas (cSCCs) constituting approximately 20 % of all NMSC. While cSCCs typically behave in an indolent fashion and can be cured with local destructive or surgical methods, a small subset metastasizes and induces significant morbidity and mortality. Identifying and aggressively treating these "high-risk" cSCCs (HRcSCCs) is thus paramount. Recent improvements in staging cSCCs appear to offer better risk stratification than earlier staging criteria. Radiologic imaging and sentinel lymph node biopsy may be beneficial in certain cases of HRcSCC, although more studies are needed before these techniques should be uniformly incorporated into management. Surgery with complete margin control, such as that offered by the Mohs micrographic technique, represents the first-line treatment for these tumors. Radiation therapy is likely most beneficial in the adjuvant setting. Chemotherapy is typically best reserved for patients with metastatic or locally advance disease that is not controllable with surgical and/or radiation therapies. Newer targeted treatments, such as EGFR inhibitors and immunotherapies may offer greater efficacy in these settings, although further evaluation is needed.
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Abstract
OBJECTIVES Nitrite inhalants (poppers) are commonly used recreational drugs among MSM and were previously associated with elevated rates of high-risk sexual behavior, HIV and human herpesvirus type 8 (HHV-8) seroconversion, and transient immunosuppressive effects in experimental models. Whether long-term popper use is associated with cancer risk among MSM in the HAART era is unclear. DESIGN Prospective cohort study of cancer risk in 3223 HIV-infected and uninfected MSM in the Multicenter AIDS Cohort Study from 1996-2010. METHODS Poisson regression models were used to examine the association between heavy popper use (defined as daily or weekly use for at least 1 year) and risk of individual cancers or composite category of virus-associated cancers. RESULTS Among all participants, heavy popper use was not associated with increased risk of any individual cancers. Among HIV-uninfected men aged 50-70, heavy popper use was associated with increased risk of virus-associated cancer with causes linked to human papillomavirus, HHV-8, and Epstein-Barr virus in models adjusted for demographics, number of sexual partners, immunological parameters (CD4 cell counts or CD4/CD8 ratios), and hepatitis B and C viruses [incidence rate ratio (IRR), 95% confidence interval (CI) 3.24, 1.05-9.96], or sexually transmitted infections (IRR 3.03, 95% CI, 1.01-9.09), as was cumulative use over a 5-year period (IRR 1.012, 95% CI 1.003-1.021; P = 0.007). There was no significant association between heavy popper use and virus-associated cancer in HIV-infected men. CONCLUSIONS Long-term heavy popper use is associated with elevated risk of some virus-associated cancers with causes related to human papillomavirus, HHV-8, and Epstein-Barr virus infections in older HIV-uninfected MSM independent of sexual behavior and immunological parameters.
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35
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Lichtenberg S, Rahamimov R, Green H, Fox BD, Mor E, Gafter U, Chagnac A, Rozen-Zvi B. The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation. Eur J Clin Pharmacol 2017; 73:819-826. [DOI: 10.1007/s00228-017-2234-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 03/03/2017] [Indexed: 02/08/2023]
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Abstract
The Notch signalling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues. The cellular processes and events that it controls are diverse, and continued investigation over recent decades has revealed how the role of Notch signalling is multifaceted and highly context dependent. Consistent with the far-reaching impact that Notch has on development and homeostasis, aberrant activity of the pathway is also linked to the initiation and progression of several malignancies, and Notch can in fact be either oncogenic or tumour suppressive depending on the tissue and cellular context. The Notch pathway therefore represents an important target for therapeutic agents designed to treat many types of cancer. In this Review, we focus on the latest developments relating specifically to the tumour-suppressor activity of Notch signalling and discuss the potential mechanisms by which Notch can inhibit carcinogenesis in various tissues. Potential therapeutic strategies aimed at restoring or augmenting Notch-mediated tumour suppression will also be highlighted.
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Affiliation(s)
- Craig S Nowell
- CMU, Department for Pathology and Immunology, University of Geneva, Rue Michel Servet, 1211 Geneva 4, Switzerland
| | - Freddy Radtke
- Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Vaud 1015, Switzerland
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Cutaneous HPV8 and MmuPV1 E6 Proteins Target the NOTCH and TGF-β Tumor Suppressors to Inhibit Differentiation and Sustain Keratinocyte Proliferation. PLoS Pathog 2017; 13:e1006171. [PMID: 28107544 PMCID: PMC5287491 DOI: 10.1371/journal.ppat.1006171] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 02/01/2017] [Accepted: 01/06/2017] [Indexed: 12/12/2022] Open
Abstract
Cutaneous beta-papillomaviruses are associated with non-melanoma skin cancers that arise in patients who suffer from a rare genetic disorder, Epidermodysplasia verruciformis (EV) or after immunosuppression following organ transplantation. Recent studies have shown that the E6 proteins of the cancer associated beta human papillomavirus (HPV) 5 and HPV8 inhibit NOTCH and TGF-β signaling. However, it is unclear whether disruption of these pathways may contribute to cutaneous HPV pathogenesis and carcinogenesis. A recently identified papillomavirus, MmuPV1, infects laboratory mouse strains and causes cutaneous skin warts that can progress to squamous cell carcinoma. To determine whether MmuPV1 may be an appropriate model to mechanistically dissect the molecular contributions of cutaneous HPV infections to skin carcinogenesis, we investigated whether MmuPV1 E6 shares biological and biochemical activities with HPV8 E6. We report that the HPV8 and MmuPV1 E6 proteins share the ability to bind to the MAML1 and SMAD2/SMAD3 transcriptional cofactors of NOTCH and TGF-beta signaling, respectively. Moreover, we demonstrate that these cutaneous papillomavirus E6 proteins inhibit these two tumor suppressor pathways and that this ability is linked to delayed differentiation and sustained proliferation of differentiating keratinocytes. Furthermore, we demonstrate that the ability of MmuPV1 E6 to bind MAML1 is necessary for papilloma formation in experimentally infected mice. Our results, therefore, suggest that experimental MmuPV1 infection in mice will be a robust and useful experimental system to model key aspects of cutaneous HPV infection, pathogenesis and carcinogenesis.
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Egawa N, Doorbar J. The low-risk papillomaviruses. Virus Res 2016; 231:119-127. [PMID: 28040475 DOI: 10.1016/j.virusres.2016.12.017] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023]
Abstract
Human Papillomavirus (HPV) research has been dominated by the study of a subset of Alpha papillomaviruses that together cause almost 5% of human cancers worldwide, with the focus being on the two most prominent of these (HPV16 and 18). These viruses are referred to as 'high-risk' (hrHPV), to distinguish them from the over 200 prevalent HPV types that more commonly cause only benign epithelial lesions. The 'low-risk' (lrHPV) term used to describe this group belies their cumulative morbidity. Persistent laryngeal papillomas, which occur rarely in children and adults, require regular surgical de-bulking to allow breathing. Such infections are not curable, and despite being caused by HPV11 (a lrHPV) are associated with 1-3% risk of cancer progression if not resolved. Similarly, the ubiquitous Beta HPV types, which commonly cause asymptomatic infections at cutaneous sites, can sometimes cause debilitating papillomatosis with associated cancer risk. Recalcitrant genital warts, which affect 1 in 200 young adults in the general population, and even the ubiquitous common warts and verrucas that most of us at some time experience, cannot be reliably eradicated, with treatment strategies advancing little over the last 100 years. The review highlights molecular similarities between high and low-risk HPV types, and focuses on the different pathways that the two groups use to ensure persistent infection and adequate virus shedding from the epithelial surface. Understanding the normal patterns of viral gene expression that underlie lesion formation, and which also prevent loss of the infected basal cells in established lesions, are particularly important when considering new treatment options. Finally, the common requirement for deregulated viral gene expression and genome persistence in development of cancers, unites both high and low-risk HPV types, and when considered alongside viral protein functions, provides us with a working understanding of the mechanisms that underlie HPV-associated pathology.
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Affiliation(s)
- Nagayasu Egawa
- Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge, UK
| | - John Doorbar
- Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge, UK.
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Soto Y, Limia CM, González L, Grá B, Hano OM, Martínez PA, Kourí V. Molecular evidence of high-risk human papillomavirus infection in colorectal tumours from Cuban patients. Mem Inst Oswaldo Cruz 2016; 111:731-736. [PMID: 27812599 PMCID: PMC5146735 DOI: 10.1590/0074-02760160217] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 08/25/2016] [Indexed: 01/15/2023] Open
Abstract
The association between colorectal cancer and human papillomavirus (HPV) infection is still unproven. The aim of this study was to investigate the presence of high-risk HPV (HR-HPV) DNA in colorectal tissues from Cuban patients. A total of 63 colorectal formalin-fixed paraffin-embedded tissues were studied (24 adenocarcinoma, 18 adenoma, and 21 colorectal tissues classified as benign colitis). DNA from colorectal samples was analysed by quantitative real-time polymerase chain reaction to detect the most clinically relevant high HR-HPV types (HPV-16, -18, -31, -33, -45, -52, and -58). Associations between histologic findings and other risk factors were also analysed. Overall, HPV DNA was detected in 23.8% (15/63) of the samples studied. Viral infections were detected in 41.7% of adenocarcinoma (10/24) and 27.7% of adenoma cases (5/18). HPV DNA was not found in any of the negative cases. An association between histological diagnosis of adenocarcinoma and HPV infection was observed (odd ratio = 4.85, 95% confidence interval = 1.40-16.80, p = 0.009). The only genotypes identified were HPV 16 and 33. Viral loads were higher in adenocarcinoma, and these cases were associated with HPV 16. This study provides molecular evidence of HR-HPV infection in colorectal adenocarcinoma tissues from Cuban patients.
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Affiliation(s)
- Yudira Soto
- Institute of Tropical Medicine Pedro Kourí, Department of Virology,
Laboratory of Sexually Transmitted Diseases,La Habana, Cuba
| | - Celia Maria Limia
- Institute of Tropical Medicine Pedro Kourí, Department of Virology,
Laboratory of Sexually Transmitted Diseases,La Habana, Cuba
| | | | | | | | - Pedro Ariel Martínez
- Institute of Tropical Medicine Pedro Kourí, Department of Virology,
Laboratory of Sexually Transmitted Diseases,La Habana, Cuba
| | - Vivian Kourí
- Institute of Tropical Medicine Pedro Kourí, Department of Virology,
Laboratory of Sexually Transmitted Diseases,La Habana, Cuba
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40
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Fogel AL, Miyar M, Teng JMC. Cutaneous Malignancies in Pediatric Solid Organ Transplant Recipients. Pediatr Dermatol 2016; 33:585-593. [PMID: 27470071 DOI: 10.1111/pde.12941] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Pediatric organ transplant recipients (POTRs) are at risk of developing malignancies due to a combination of immunosuppression, impaired DNA damage repair, and infection with oncogenic viruses. The most commonly developed malignancies in this population are skin cancers, which include nonmelanoma skin cancer, melanoma, Kaposi's sarcoma, and anogenital carcinoma. The literature shows that skin cancers account for 13% to 55% of all cancers that occur after transplantation. Given the increasing number and life expectancy of POTRs, prevention and management of skin cancer in these patients is essential, but there is a substantial knowledge gap in our understanding of the differences in skin cancer development, prevention, and management between POTRs and adult organ transplant recipients (AOTRs), for whom more data are available. Substantial differences have been observed in the patterns of malignancy development between POTRs and AOTRs, and data specific to pediatric populations are needed. The objective of this review is to provide updated information on posttransplantation skin cancer development in POTRs, including epidemiologic research on transplant patients and disease development, medication management, surveillance, and education efforts.
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Affiliation(s)
| | - Maria Miyar
- Department of Dermatology, Kaiser Permanente, San Jose, California
| | - Joyce M C Teng
- Department of Dermatology, School of Medicine, Stanford University, Stanford, California.,Department of Pediatrics, School of Medicine, Stanford University, Stanford, California
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41
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Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:7316492. [PMID: 27847554 PMCID: PMC5099458 DOI: 10.1155/2016/7316492] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 07/08/2016] [Accepted: 09/20/2016] [Indexed: 01/01/2023]
Abstract
The transcription factor Nrf2 (NF-E2 related factor 2) is a master regulator of the cell antioxidant response associated with tumor growth and resistance to cytotoxic treatments. In particular, Nrf2 induces upregulation of cytoprotective genes by interacting with the closely situated AREs (Antioxidant Response Elements) in response to endogenous or exogenous stress stimuli and takes part to several oncogenic signaling pathways. Among these, the crosstalk with Notch pathway has been shown to enhance cytoprotection and maintenance of cellular homeostasis, tissue organization by modulating cell proliferation kinetics, and stem cell self-renewal in several organs. The role of Notch and Nrf2 related pathways in tumorigenesis is highly variable and when they are both abnormally activated they can synergistically cause neoplastic proliferation by promoting cell survival, differentiation, invasion, and metastases. NFE2L2, KEAP1, and NOTCH genes family appear in the list of significantly mutated genes in tumors in both combined and individual sets, supporting the crucial role that the aberrant Nrf2-Notch crosstalk might have in cancerogenesis. In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.
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Human Papillomavirus Infection and p16 Expression in Extragenital/Extraungual Bowen Disease in Immunocompromised Patients. Am J Dermatopathol 2016; 38:751-7. [DOI: 10.1097/dad.0000000000000530] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Luff J, Rowland P, Mader M, Orr C, Yuan H. Two Canine Papillomaviruses Associated With Metastatic Squamous Cell Carcinoma in Two Related Basenji Dogs. Vet Pathol 2016; 53:1160-1163. [DOI: 10.1177/0300985816630795] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Papillomaviruses (PV) are associated with benign mucosal and cutaneous epithelial proliferations. In dogs, PV-associated pigmented plaques and papillomas can undergo malignant transformation, but this is rare, and most cases of canine squamous cell carcinoma do not arise from PV-induced precursor lesions. We describe herein the progression of pigmented plaques to invasive and metastatic squamous cell carcinoma associated with 2 canine papillomaviruses (CPV) in 2 related Basenji dogs. Immunohistochemistry for PV antigen revealed strong nuclear immunoreactivity within keratinocytes from pigmented plaques from both dogs, consistent with a productive viral infection. Polymerase chain reaction (PCR) using degenerate primers for the L1 gene revealed PV DNA sequences from 2 different CPVs. In situ hybridization for CPV revealed strong hybridization signals within the pigmented plaques and neoplastic squamous epithelial cells from both dogs. We report here progression of PV-associated pigmented plaques to metastatic squamous cell carcinoma within 2 Basenji dogs associated with 2 different CPVs.
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Affiliation(s)
- J. Luff
- North Carolina State University, Raleigh, NC, USA
| | - P. Rowland
- Histopath Consulting, Worcester, MA, USA
| | - M. Mader
- North Carolina State University, Raleigh, NC, USA
| | - C. Orr
- Animal Clinic of East Avenue, Rochester, NY, USA
| | - H. Yuan
- Georgetown University Medical School, Washington, DC, USA
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Uberoi A, Yoshida S, Frazer IH, Pitot HC, Lambert PF. Role of Ultraviolet Radiation in Papillomavirus-Induced Disease. PLoS Pathog 2016; 12:e1005664. [PMID: 27244228 PMCID: PMC4887022 DOI: 10.1371/journal.ppat.1005664] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 05/06/2016] [Indexed: 01/16/2023] Open
Abstract
Human papillomaviruses are causally associated with 5% of human cancers. The recent discovery of a papillomavirus (MmuPV1) that infects laboratory mice provides unique opportunities to study the life cycle and pathogenesis of papillomaviruses in the context of a genetically manipulatable host organism. To date, MmuPV1-induced disease has been found largely to be restricted to severely immunodeficient strains of mice. In this study, we report that ultraviolet radiation (UVR), specifically UVB spectra, causes wild-type strains of mice to become highly susceptible to MmuPV1-induced disease. MmuPV1-infected mice treated with UVB develop warts that progress to squamous cell carcinoma. Our studies further indicate that UVB induces systemic immunosuppression in mice that correlates with susceptibility to MmuPV1-associated disease. These findings provide new insight into how MmuPV1 can be used to study the life cycle of papillomaviruses and their role in carcinogenesis, the role of host immunity in controlling papillomavirus-associated pathogenesis, and a basis for understanding in part the role of UVR in promoting HPV infection in humans.
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Affiliation(s)
- Aayushi Uberoi
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Satoshi Yoshida
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Ian H. Frazer
- The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
| | - Henry C. Pitot
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- * E-mail:
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45
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Maleki Z. Human papilloma virus vaccination: Review article and an update. World J Obstet Gynecol 2016; 5:16-27. [DOI: 10.5317/wjog.v5.i1.16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 11/07/2015] [Accepted: 01/04/2016] [Indexed: 02/05/2023] Open
Abstract
Human papilloma virus (HPV) is sexually transmitted and associated with uterine cervix, vaginal, and vulvar cancers in females, oropharyngeal and anal cancer in both genders, and penile cancer in males. Moreover, genital warts are benign tumors which are HPV-related and can occur in both genders. This is a review of HPV structure, HPV infection transmission, the global impact of HPV and its associated diseases, HPV vaccines and their efficacy and safety, public acceptance of HPV vaccines, the obstacles for its acceptance and strategies to address the barriers. Cervarix (a bivalent vaccine with protection against HPV types 16 and 18) and Gardasil (a quadrivalent vaccine with protection against HPV types 6, 11, 16 and 18) are 2 recommended vaccines. The longest follow up of 9.4 years has shown efficacy and protection of the vaccine against HPV types 16 and 18. The adverse effects have been minimal and the vaccine is considered safe. Numerous studies are conducted to follow the vaccinated individuals to better understand the effect of HPV vaccine on incidence of HPV-related cancers and precancerous lesions.
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46
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Rudnick EW, Thareja S, Cherpelis B. Oral therapy for nonmelanoma skin cancer in patients with advanced disease and large tumor burden: a review of the literature with focus on a new generation of targeted therapies. Int J Dermatol 2015; 55:249-58; quiz 256, 258. [PMID: 26566923 DOI: 10.1111/ijd.12961] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 11/26/2014] [Accepted: 12/31/2014] [Indexed: 12/20/2022]
Abstract
Nonmelanoma skin cancer (NMSC) is the most common cancer in patients and includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Treatments useful for SCC and BCC include surgical, topical, and in advanced cases systemic chemo-radiation. This review of the literature aims to describe previous and current treatment options for oral therapy in locally advanced and metastatic NMSC otherwise unamenable to standard treatment. Oral Smoothened (Smo) inhibitors Vismodegib, Sonidegib, and Taladegib have shown to be effective in several trials. Oral tyrosine kinase inhibitors Erlotinib and Gefitinib, which target epidermal growth factor receptor (EGFR), have early supporting data and are currently undergoing large multicenter trials. Other less studied oral therapies which have shown at least partial efficacy include 5-Fluorouracil, capecitabine, and picropodophyllin. In vitro studies have elucidated new targets for dual combination oral therapy targeting both EGFR and insulin-like growth factor 1 receptor (IGF-1R). It is important to stratify treatment options based on patient risk of advanced disease, failure of conservative treatment, and ill-tolerated intravenous chemotherapy adverse events. Oral therapy in NMSC is useful in high risk patients with recurrent and aggressive disease who may not tolerate other systemic therapies.
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Affiliation(s)
- Eric W Rudnick
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Sumeet Thareja
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Basil Cherpelis
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
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Abstract
Several viruses with different replication mechanisms contribute to oncogenesis by both direct and indirect mechanisms in immunosuppressed subjects after solid organ transplantation, after allogeneic stem cell transplantation, or with human immunodeficiency virus (HIV) infection. Epstein-Barr virus (EBV), human papillomavirus (HPV), Kaposi sarcoma herpesvirus (KSHV), human T-cell lymphotropic virus type 1 (HTLV-1) and Merkel cell polyoma virus (MCV) are the main viruses associated with the development of cancer in immunosuppressed patients. Besides being a main cause of immunodeficiency, HIV1 has a direct pro-oncogenic effect. In this review, we provide an update on the association between the condition of acquired immunodeficiency and cancer risk, specifically addressing the contributions to oncogenesis of HPV, MCV, KSHV, HTLV-1, and EBV.
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Affiliation(s)
- A Pierangeli
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - G Antonelli
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - G Gentile
- Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
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Chockalingam R, Downing C, Tyring SK. Cutaneous Squamous Cell Carcinomas in Organ Transplant Recipients. J Clin Med 2015; 4:1229-39. [PMID: 26239556 PMCID: PMC4484997 DOI: 10.3390/jcm4061229] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 05/27/2015] [Accepted: 05/28/2015] [Indexed: 01/21/2023] Open
Abstract
Non-melanoma skin cancers represent a major cause of morbidity after organ transplantation. Squamous cell carcinomas (SCC) are the most common cutaneous malignancies seen in this population, with a 65-100 fold greater incidence in organ transplant recipients compared to the general population. In recent years, human papillomaviruses (HPV) of the beta genus have been implicated in the pathogenesis of post-transplant SCCs. The underlying mechanism of carcinogenesis has been attributed to the E6 and E7 proteins of HPV. Specific immunosuppressive medications, such as the calcineurin inhibitors and azathioprine, are associated with a higher incidence of post-transplant SCCs compared to other immunosuppressive agents. Compared to other immunosuppressives, mTOR inhibitors and mycophenolate mofetil have been associated with a decreased risk of developing post-transplant non-melanoma skin cancers. As a result, they may represent ideal immunosuppressive medications in organ transplant recipients. Treatment options for post-transplant SCCs include surgical excision, Mohs micrographic surgery, systemic retinoid therapy, adjunct topical therapy, electrodessication and curettage, and radiation therapy. This review will discuss the epidemiology, risk factors, and management options of post-transplant SCCs. In addition, the underlying mechanisms of beta-HPV mediated carcinogenesis will be discussed.
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Affiliation(s)
- Ramya Chockalingam
- Medical School, the University of Texas Health Science Center at Houston, 6431 Fannin, Houston, TX 77030, USA.
| | | | - Stephen K Tyring
- Center for Clinical Studies, 1401 Binz, Suite 200, Houston, TX 77004, USA.
- Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
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49
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Quint KD, Genders RE, de Koning MNC, Borgogna C, Gariglio M, Bouwes Bavinck JN, Doorbar J, Feltkamp MC. Human Beta-papillomavirus infection and keratinocyte carcinomas. J Pathol 2015; 235:342-54. [PMID: 25131163 DOI: 10.1002/path.4425] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/04/2014] [Accepted: 08/11/2014] [Indexed: 12/15/2022]
Abstract
Although the role of oncogenic human Alpha-papillomaviruses (HPVs) in the development of mucosal carcinomas at different body sites (eg cervix, anus, oropharynx) is fully recognized, a role for HPV in keratinocyte carcinomas (KCs; basal and squamous cell carcinomas) of the skin is not yet clear. KCs are the most common cancers in Caucasians, with the major risk factor being ultraviolet (UV) light exposure. A possible role for Beta-HPV types (BetaPV) in the development of KC was suggested several decades ago, supported by a number of epidemiological studies. Our current review summarizes the recent molecular and histopathological evidence in support of a causal association between BetaPV and the development of KC, and outlines the suspected synergistic effect of viral gene expression with UV radiation and immune suppression. Further insights into the molecular pathways and protein interactions used by BetaPV and the host cell is likely to extend our understanding of the role of BetaPV in KC.
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Affiliation(s)
- Koen D Quint
- Department of Dermatology, Leiden University Medical Centre, The Netherlands; DDL Diagnostic Laboratory, Rijswijk, The Netherlands
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50
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Reusser NM, Downing C, Guidry J, Tyring SK. HPV Carcinomas in Immunocompromised Patients. J Clin Med 2015; 4:260-81. [PMID: 26239127 PMCID: PMC4470124 DOI: 10.3390/jcm4020260] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 12/13/2014] [Accepted: 12/19/2014] [Indexed: 12/20/2022] Open
Abstract
Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide and can result in pre-malignancies or overt malignancies of the skin and mucosal surfaces. HPV-related illnesses are an important personal and public health problem causing physical, mental, sexual and financial detriments. Moreover, this set of malignancies severely affects the immunosuppressed population, particularly HIV-positive patients and organ-transplant recipients. There is growing incidence of HPV-associated anogenital malignancies as well as a decrease in the average age of affected patients, likely related to the rising number of high-risk individuals. Squamous cell carcinoma is the most common type of HPV-related malignancy. Current treatment options for HPV infection and subsequent disease manifestations include imiquimod, retinoids, intralesional bleomycin, and cidofovir; however, primary prevention with HPV vaccination remains the most effective strategy. This review will discuss anogenital lesions in immunocompromised patients, cutaneous warts at nongenital sites, the association of HPV with skin cancer in immunocompromised patients, warts and carcinomas in organ-transplant patients, HIV-positive patients with HPV infections, and the management of cutaneous disease in the immunocompromised patient.
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Affiliation(s)
- Nicole M Reusser
- Medical School, the University of Texas Health Science Center at Houston, 6431 Fannin, Houston, TX 77030, USA.
| | | | - Jacqueline Guidry
- Center for Clinical Studies, 1401 Binz, Suite 200, Houston, TX 77004, USA.
| | - Stephen K Tyring
- Medical School, the University of Texas Health Science Center at Houston, 1401 Binz, Suite 200, Houston, TX 77004, USA.
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