Cervical cancer is the fourth most common type of cancer in females worldwide. Infection with a human papillomavirus is crucial to the etiopathogenesis of cervical cancer. The natural trajectory of HPV infection comprises HPV acquisition, HPV persistence versus clearance, and progression to precancer and invasive cancer. The majority of HPV infections are cleared and controlled by the immune system within 2 years, but some infections may become quiescent or undetectable. The persistence of high-risk HPV infection for a longer period of time enhances the risk of malignant transformation of infected cells; however, the mechanisms responsible for the persistence of infection are not yet well-understood. It is estimated that 10–15% of infections do persist, and the local microenvironment is now recognized as an important cofactor promoting infection maintenance. Extracellular vesicles (EVs) are small membrane vesicles derived from both normal cells and cancer cells. EVs contain various proteins, such as cytoskeletal proteins, adhesion molecules, heat shock proteins, major histocompatibility complex, and membrane fusion proteins. EVs derived from HPV-infected cells also contain viral proteins and nucleic acids. These biologically active molecules are transferred via EVs to target cells, constituting a kind of cell-to-cell communication. The viral components incorporated into EVs are transmitted independently of the production of infectious virions. This mode of transfer makes EVs a perfect vector for viruses and their components. EVs participate in both physiological and pathological conditions; they have also been identified as one of the mediators involved in cancer metastasis. This review discusses the potential role of EVs in remodeling the cervical cancer microenvironment which may be crucial to tumor development and the acquisition of metastatic potential. EVs are promising as potential biomarkers in cervical cancer.
The development of malignancy is closely connected with the process of cancer microenvironment remodeling. As a malignancy develops, it stimulates the creation of the suppressive microenvironment of the tumor through the presence of cells that express membrane proteins. These proteins are secreted into the cancer microenvironment, where they enable tumor growth. In patients with cancer of the cervix, the development of the disease is also linked to high-risk HPV (hr-HPV) infection. Such infections are common, and most clear spontaneously; however, a small percentage of these infections can persist and progress into precancerous cervical intraepithelial neoplasia and invasive cervical carcinoma. Consequently, it is assumed that the presence of hr-HPV infection alone is not sufficient for the development of cancer. However, chronic HPV infection is associated with the induction of the remodeling of the microenvironment of the epithelium. Furthermore, the local microenvironment is recognized as a cofactor that participates in the persistence of the HPV infection and disease progression. This review presents the selected immune evasion mechanisms responsible for the persistence of HPV infection, beginning with the delay in the virus replication process prior to the maturation of keratinocytes, the shift to the suppressive microenvironment by a change in keratinocyte immunomodulating properties, the alteration of the Th1/Th2 polarization of the immune response in the microenvironment, and, finally, the role of HLA-G antigen expression.
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