人类乳头瘤病毒在癌肿的作用

目前积累的资料表明,人类乳头瘤病毒不仅与良性肿瘤也与恶性肿瘤有关。它可能在皮肤肿瘤的恶变中具有重要意义。本文分析发现于不同解剖部位(包括皮肤)恶性肿瘤中的人类乳头瘤病毒的潜在致癌性。     

人类乳头瘤病毒相关的皮肤和粘膜肿瘤

对人类乳头瘤病毒生物学特性、人类乳头瘤病毒相关肿瘤模型的发病机理及相关皮肤粘膜肿瘤的临床特征作一简要介绍,并探讨了相关的治疗内容。     

人类乳头瘤病毒相关的皮肤和粘膜肿瘤

对人类乳头瘤病毒生物学特性，人类乳头瘤病毒相关肿瘤模型的发病机理及相关皮肤粘膜肿瘤的临床特征作一简要介绍，并探讨了相关的治疗内容。     

高危型人类乳头瘤病毒的致瘤分子机制

高危型人类乳头瘤病毒 (16 ,18等 )感染已被证实可导致生殖系统、皮肤和口腔等的恶性肿瘤病变。随着分子生物学技术的进一步发展 ,人类对肿瘤的发病机制的认识也越来越深入。本文旨从细胞周期调控与细胞凋亡 ,端粒与端粒酶 ,病毒逃逸分子机制等几个方面综述高危型人类乳头瘤病毒的致瘤分子机制     

高危型人类乳头瘤病毒的致瘤分子机制

高危型人类乳头瘤病毒（16，18等）感染已被证实可导致生殖系统、皮肤和口腔等的恶性肿瘤病变。随着分子生物学技术的进一步发展，人类对肿瘤的发病机制的认识也越来越深入。本文旨从细胞周期调控与细胞 凋亡，端粒与端粒酶，病毒逃逸分子机制等几个方面综述高危型人类乳头瘤病毒的致瘤分子机制。     

病毒感染与皮肤肿瘤的相关性

病毒感染与皮肤肿瘤的发展密切相关，约有15%的皮肤肿瘤可能由病毒感染诱发。目前研究显示参与人类肿瘤的病毒主要包括7种病毒，不同的病毒致癌的分子机制亦各不相同，其中人乳头瘤病毒(human papilloma virus, HPV)、爱泼斯坦-巴尔病毒(Epstein-Barr virus, EBV)、卡波西肉瘤相关疱疹病毒(Kaposi′s sarcoma-associated herpes virus, KSHV)、默克尔细胞多瘤病毒(Merkel cell polyomavirus, MCV)、人类T细胞嗜淋巴细胞病毒1型(human T lymphotropic virus, HTLV-1)与皮肤肿瘤密切相关。本文将从流行病学、分子机制的角度阐述致癌病毒与皮肤肿瘤之间的因果关系，从病毒感染的角度探讨皮肤肿瘤新的诊断及治疗思路。     

β人乳头瘤病毒与皮肤鳞状细胞癌的相关性研究进展

人乳头瘤病毒根据侵犯部位的不同可分为黏膜型和皮肤型.皮肤型人乳头瘤病毒多为β人乳头瘤病毒,其与皮肤鳞状细胞癌的相关性尚有争议.近年来随着皮肤鳞状细胞癌发病率的增加,其发病机制及β人乳头瘤病毒与皮肤鳞状细胞癌的病因学关系引起了重视.流行病学资料显示,β人乳头瘤病毒与皮肤鳞状细胞癌相关,但是也有部分证据不支持.随着研究的深入,有研究指出,β人乳头瘤病毒可能作为协同致癌因子诱导皮肤鳞状细胞癌的产生,但不参与肿瘤的维持发展过程.     

HPV感染与皮肤癌

实验研究证实 ,皮肤癌组织中可检测到人乳头瘤病毒DNA ,特别是人乳头瘤病毒 16 /18型。人乳头瘤病毒 16型的基因产物E6、E7蛋白可与肿瘤抑制蛋白p5 3、PRb结合 ,使p5 3丧失对损伤DNA的修复功能 ,而且人乳头瘤病毒阳性的黑素瘤患者预后不佳。人乳头瘤病毒感染可加重皮肤癌的恶性度。综述了皮肤恶性肿瘤与人乳头瘤病毒感染的相关性     

人类乳头瘤病毒感染的实验室研究

人类乳头瘤病毒(human papillomavirus, HPV)可引起人类皮肤粘膜的多种增殖性损害,其中发生于肛周生殖器部位的尖锐湿疣近年来在成倍地增加.目前,随着分子杂交方法的应用,已明确某些类型的HPV与肿瘤的发生有密切关系,因此对HPV的研究也日益深入.现将HPV感染的有关实验室研究综述如下.     

HPV感染与皮肤癌

实验研究证实，皮肤癌组织中可检测到人乳头瘤病毒DNA，特别是人乳头瘤病毒16／18型，人乳头瘤病毒16型的基因产物E6，E7蛋白可与肿瘤抑制蛋白p53,PRb结合，使P53丧失对损伤DNA的修复功能，而且人乳头瘤病毒阳性的黑素瘤患者预后不佳，人乳头瘤病毒感染可加重皮肤癌的恶性度，综述了皮肤恶性肿瘤与人乳头瘤病毒感染的相关性。     

Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms

Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation in various skin diseases including, premature aging of the skin and melanoma and non-melanoma skin cancers. Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of these harmful events in the UV-exposed skin. A wide variety of polyphenols or phytochemicals, most of which are dietary supplements, have been reported to possess substantial skin photoprotective effects. This review article summarizes the photoprotective effects of some selected polyphenols, such as green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, on UV-induced skin inflammation, oxidative stress and DNA damage, etc., with a focus on mechanisms underlying the photoprotective effects of these polyphenols. The laboratory studies conducted in animal models suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.     

Presence of human papilloma virus type 16 DNA sequences in human nonmelanoma skin cancers

The presence of human papillomaviruses (HPV) has been shown to be associated with the development and progression of invasive cancers of the genital tract, skin, and head and neck. In this study we analyzed 37 human nonmelanoma skin cancers (21 squamous cell carcinomas and 16 basal cell carcinomas) for the presence of HPV sequences. The polymerase chain reaction (PCR) was employed using primers designed to amplify DNA encoding the E6-E7 region of HPV types 6b/11, 16, and 18. HPV type 6b/11 and 18 sequences were absent from the DNA of all 37 tumors examined. However, HPV type 16 sequences were detected in four of 21 squamous cell carcinomas (SCC) (19%) and three of 16 basal cell carcinomas (BCC) (19%) as indicated on agarose gel electrophoresis by the presence of a single specific DNA band of predicted length. Furthermore, HPV type 16 sequences were absent in the DNA of normal skin from these seven skin cancer patients. The presence of HPV type 16 sequences in the seven skin tumors was confirmed by dot blot hybridization of PCR-amplified material to 32P-labeled HPV type 16, but not to HPV type 6/11 or 18-specific probes. These data indicate that HPV type 16, but not 6b/11 or 18, is associated with development of some human nonmelanoma skin cancers.     

Human papillomavirus and skin cancer

Human papillomavirus (HPV) appears to be the most ubiquitous of the human viruses. Over 100 HPV types have been identified. A minority of HPV cause cutaneous warts and mucosal condylomata. The HPV that cause mucosal condylomata put the patient at various degrees of risk for developing cancers, particularly cervical cancer. The majority of HPV infect the skin of normal and immunocompromised individuals. In normal people, most of these HPV appear to establish a latent infection of the skin, most likely as normal flora residing in hair follicles; however, in patients with various systemic and localized depressions of cell-mediated immunity, some HPV infections appear to be involved in the development of nonmelanotic skin cancer and its precursor lesions in skin, usually in sunlight-exposed areas. Circumstantial evidence suggests that these HPV may have a role in promoting proliferative lesions of the skin, although their sites of active infection and mode of transmission to susceptible individuals remain unknown.     

The human papillomavirus type 8 E2 gene encodes a transforming activity sufficient for skin tumor formation in transgenic mice

Infections with beta-genus human papillomaviruses (HPVs) have been associated with nonmelanoma skin cancers, particularly in immunocompromised patients and individuals with a rare genetic disease, epidermodysplasia verruciformis (EV). Using a transgenic mouse model, Herbert Pfister's group determined that expression of the HPV8 E2 gene results in skin cancer development and that this process is greatly accelerated by UV irradiation (Pfefferle et al., 2008, this issue).     

Erkrankungen durch humane Papillomviren (HPV)

Human papillomaviruses (HPV) are non‐enveloped tumor viruses with a double stranded DNA approximately 8 kilobases in length. The viral genome is enclosed by a spherical capsid with icosahedral symmetry and a diameter of about 55 nm. More than 100 HPV types have been identified. They infect the squamous epithelia of skin and mucosa and usually cause benign papillomas or warts. Persistent infection with high‐risk oncogenic HPV causes all cervical cancers, most anal cancers, and a subset of vulvar, vaginal, penile and oropha‐ryngeal cancers. In recent years cutaneous beta‐HPV types have been associated with the pathogenesis of non‐melanoma skin cancers. Two prophylactic HPV vaccines based on virus‐like particles (VLP) are licensed. These are up to 100% effective in preventing HPV 16 and HPV 18 infections and associated genital lesions in women, who have not been previously infected with these types. One vaccine also prevents genital warts caused by HPV 6 and HPV 11.     

Advances in antiviral therapy

Infections with five of the herpesviruses (herpes simplex virus 1 [HSV-1], HSV-2, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus) are treated with topical or systemic antiviral therapies. There are more than 100 genotypes of human papillomaviruses (HPVs), which may manifest as warts, skin cancers, cervical cancer, anogenital cancers, and upper digestive tract cancers. Molluscum contagiosum (MC) is a common, benign viral infection of the skin. Immunomodulating agents, such as imiquimod, act on HPV and MC indirectly by inducing host immune responses, such as cytokines and cell-mediated immunity, and thereby reduce recurrences. There are multiple vaccines available for certain viral diseases and others in development for HSV-2 and HPV.     

Hautkrebs und Berufserkrankung

Although it is universally accepted that UV light exposure can cause malignant skin tumors, UV-induced skin cancers are not recognized as an occupational disease in Germany. Exposure to natural or artificial UV light occurs in many work places, so that the induction of occupational skin cancers is certainly plausible. In recent years, a special clause in the occupational disability rules has recognized some cases of UV-induced skin cancers. We discuss the nature of occupational UV exposure, explore preventative measures and review the data regarding occupational UV-induced skin tumors. After evaluating recent publications, we conclude that for squamous cell carcinoma the epidemiological proof of an at least doubled risk (RR >2) due to occupational UV radiation can be given. The clear dose response relationship supports these epidemiological findings. For the individual risk assessment, an attributive UV radiation >40% due to occupational factors must exist. Under those circumstances, squamous cell carcinoma should be recognized and compensated as an occupational disease.     

Cross-sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation

Approximately three million non-melanoma skin cancers (NMSCs) are diagnosed worldwide each year, although this number is likely an underestimate given that these cancers are not always recorded in cancer registries. Studies have suggested that skin (cutaneous) infections with human papillomaviruses (HPV) and polyomaviruses (HPyV) may play a role in the development of some NMSC types. Suppression of the immune system is also a risk factor for NMSC. This study, from the U.S.A, aimed to understand the relationship between T-regulatory (Treg) cells, cells which suppress immune response, and cutaneous viral infections. Blood, skin swabs and eyebrow hairs were collected from 352 patients who underwent skin cancer screening and did not have cancer detected. The researchers examined whether the skin swabs (SSW) and eyebrow hairs (EBH) contained genetic material (DNA) corresponding to 98 cutaneous HPV types (including beta HPV and gamma HPV) and 5 HPyV types. The blood samples were analyzed to determine proportions of different types of Treg cell populations in circulation (in the blood). The researchers found no association between total percent of circulating Treg cells and beta HPV or HPyV infection. However, two types of Treg cells were found at lower levels in those that had gamma HPV infection in their EBH and/or SSW. Those two types were CLA⁺ Treg cells (known to travel to the skin) and effector CD27^-CD45RA^-FOXP3⁺CD4⁺ Treg cells (known to become active when exposed to a foreign viral infection). The study results suggest that gamma HPV infection may stimulate Treg cells to move from circulation into the skin tissues.     

Betapapillomavirus in multiple non‐melanoma skin cancers of Netherton syndrome: Case report and published work review

Netherton syndrome (NS) is a rare genetic disease presenting with ichthyosiform erythroderma, hair alterations and atopy. NS is due to SPINK5 gene mutations, which cause absent or decreased expression of the encoded protein lymphoepithelial Kazal‐type‐related inhibitor (LEKTI) in all stratified epithelia. We report a 43‐year‐old man affected with NS, who developed several squamous and basal cell carcinomas on the face, ears and scalp and papillomatous lesions of hips, groin and genitoanal area. Molecular analysis of the SPINK5 gene revealed homozygosity for the recurrent mutation c.238dupG. Human papillomavirus (HPV) DNA detection and genotyping on patient skin carcinomas and hyperplastic lesions found betapapillomavirus DNA in 10 of 12 (83%) carcinomas and in a hip papilloma, with multiple betapapillomavirus types being identified. Immunohistochemistry showed upregulated expression of p16^INK4a protein in nine of 12 (75%) patient carcinomas, in line with findings reported in HPV‐related cancers. LEKTI and filaggrin immunostaining was strongly decreased in patient skin. A published work search for NS cases with skin cancers and HPV infection identified 15 NS patients, five of them showing mucosal or cutaneous HPV infection. Overall, our results confirm the increased susceptibility to skin carcinomas of some NS patients and provide further evidence of an association between HPV and non‐melanoma skin cancers in NS. The highly impaired skin barrier function, hallmark of NS, could facilitate HPV infection, in turn increasing the risk for cancer development.     

Differential p53-mediated responses to solar-simulated radiation in human papillomavirus type 16-infected keratinocytes

In immunocompromised patients, cooperative effects of human papillomavirus (HPV) and ultraviolet (UV) radiation have been postulated in the development of non-melanoma skin cancers. The tumor suppressor p53 is a key component of the cellular response to genotoxic agents, such as UV radiation. We have previously demonstrated that in HPV16-infected cells, a higher E6* level was associated with a higher resistance to UV and oxidative stress. Using the two same SKv cell lines, the aim of the present study was to investigate p53 and p21 expression and cell death in HPV-infected keratinocytes in response to UV irradiation and to determine the role of HPV oncoprotein levels on the p53-mediated cellular response. We demonstrated that the weakly E6*-expressing level SKv-e cell line presented both higher cytotoxicity and apoptosis to UV. This high sensitivity was associated with both p53 and p21 nuclear accumulation, while a high E6* level and resistance were associated with no p53 accumulation and a p21 nuclear down-regulation after UV. Moreover, in SKv-e cell line, p21 promoter activation was p53 dependent. Our results suggest that an alteration and/or a modulation of the p53-p21 pathway in response to UV could be determinant for HPV-infected keratinocyte survival and HPV-associated carcinogenic process.