Abstract
Infection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (βHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of βHPVs in actinic keratoses than in cancerous lesions, it is currently discussed that these viruses play a carcinogenic role in cancer initiation. In vitro assays performed to characterize the cell transforming activities of high-risk HPV types of genus alphapapillomavirus have markedly contributed to the present knowledge on their oncogenic functions. However, these assays failed to detect oncogenic functions of βHPV early proteins. They were not suitable for investigations aiming to study the interactive role of βHPV positive epidermis with mesenchymal cells and the extracellular matrix. This review focuses on βHPV gene functions with special focus on oncogenic mechanisms that may be relevant for skin cancer development.
Highlights
Keratinocyte derived squamous cell carcinoma (SCC) is the most common metastatic skin cancer, and its incidence is increasing worldwide [1]
This review focuses on βHPV gene functions with special focus on oncogenic mechanisms that may be relevant for skin cancer development
Tumors that did form progressed more rapidly to invasive carcinoma, implying a requirement for elevated α3β1 cell surface presence during tumor initiation and early growth [24]. These findings and our observations provide some evidence that α3β1 integrin and fibronectin may represent mediators of invasion during the initiation of the invasion cascade by βHPV
Summary
Keratinocyte derived squamous cell carcinoma (SCC) is the most common metastatic skin cancer, and its incidence is increasing worldwide [1]. To study the effect of cutaneous HPV gene expression on keratinocytes, organotypic cultures based on a collagen type I matrix were repopulated with 3T3 mouse fibroblasts and primary keratinocytes expressing the E6/E7 genes of βHPV types HPV5, 12, 15, 17, 20, and 38 as well as the high-risk αHPV type HPV16 These cultures showed varying degrees of dysregulated keratinocyte differentiation but lacked the features of cancer progression including the key step of basement membrane invasion for any of the HPV types analyzed. Tumors that did form progressed more rapidly to invasive carcinoma, implying a requirement for elevated α3β1 cell surface presence during tumor initiation and early growth [24] These findings and our observations provide some evidence that α3β1 integrin and fibronectin may represent mediators of invasion during the initiation of the invasion cascade by βHPV. Studies on the cross-talk between α3β1 with other fibronectin binding integrins may shed light on the underlying mechanism leading to keratinocyte invasion
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