Human papillomavirus (HPV) is the causative agent of squamous cell carcinoma. The infection itself is not sufficient for the transformation of the infected cells, even if the integration of the virus in the host cell genome that cause genetic rearrangements, the activation of proto- oncogenes and other events, can generate genomic instability and increase the risk of neoplastic transformation. Tumor microenvironment (TME) is strongly correlated with chronic inflammation. Persistent infection is one possible cause of establishing chronic inflammation. Expression of cytokines and chemokines and other molecular mediators is altered thereby recruiting and differentiating into TME immune cells with a pro-tumoral phenotype. Extracellular vesicles (EVs) can load and deliver a specific package of mediators (e.g. mRNAs, microRNAs, proteins) and consequently, cancer can take advantage of this process. Based on preliminary data showing a wide deregulation of inflammatory microenvironment in prototypical cellular models of high-risk mucosal HPV-positive or cutaneous HPV-positive cells, the purpose of the project is to better characterize EVs into TME in these models. Our objective is to find mRNAs and microRNAs specifically loaded into EVs and to define their possible role principally in their cargo transfer into primary keratinocytes.
The project combines cellular and molecular biology, biotechnology and immunology knowledge with a view to expand current understanding on pathogenic mechanism of HPV infections and related tumors. The working group of the proposing researcher has already been involved in research projects on HPVs. On the basis of our background and expertise on this relevant issue of human health, the goal of the project is to characterize tumor microenvironment mainly focusing on extracellular vesicles content by using a prototypical model of E6 and E7 HPV-positive keratinocytes. Furthermore, it will be evaluated the capability of EVs internalization by primary keratinocytes. The present project mainly focuses on the study of the involvement of inflammatory microenvironment in the HPV-induced carcinogenesis, approaching the analysis of the role of the immune molecules as well as their delivery through the microvesicle cargo and its possible modification in the carcinogenesis process.
Accomplishing this task will have also relevant impact on the ongoing development of experimental strategies based on extracellular vesicles delivery, since it would represent a both original and efficient way to follow the in vivo delivery of specific biomarker molecules of the development and progression of HPV-related lesions.