Role of HPV associated tumor metabolism on human macrophage phenotype

Abstract

Human papillomaviruses (HPV) are small DNA viruses that infect epithelial cells causing, depending on the virus type, benign and malignant lesions. This virus is the main etiological factor for cervical cancer, being present in virtually all cases of this disease. Cervical cancer is a serious disease that affects thousands of women each year, being the second most common cancer among women in developing countries. The high-risk oncogenic HPV promote immortalization of infected cells through degradation of p53 and pRB, which is mediated by viral oncoproteins, E6 and E7, respectively. In some cases, these immortalized cells could became tumoral cells due to accumulation of genetic damage. In most cases, the virus is eliminated naturally, but some people develop tolerance to the viral antigens which leads to persistent infection. This could lead to development of HPV- associated tumors. The E6 and E7 oncoproteins are the main mechanisms responsible for immune escape . Cells of the immune system associated with cervical lesions and cancer have regulatory phenotype and assist in the maintenance and progression of the disease . Among these, macrophages are the most frequent and increase with the progression of cervical lesion. In some types of tumors, tumor cells exhibit altered metabolism, preferably using aerobic glycolysis for energy, which result in the production of lactate and subsequent acidification of the microenvironment of the pH. The hypoxia in tumors contributes to this phenomenon by increasing the efficiency of glycolysis. The acidic pH and lactate induce a regulatory phenotype in inflammatory associated cells and are associated with tumor progression. In biopsies and cell lines derived from tumors of the cervix HIF - 1± ( hypoxia -induced factor - 1 alpha ) and monocarboxilados transporters ( MCT ) expression was observed. Due to the modulatory effects of hypoxia and lactate in cells of the immune system, it is possible that these induce suppressor phenotype in inflammatory cells associated with HPV -positive tumors. Therefore the aim of this work is to investigate the role of hypoxia and lactate in modulating the phenotype of macrophages in contact with tumor cells positive for HPV. Besides verifying changes of expression and activity of genes and signaling pathways in macrophages, with the intention of modulating them and possibly change their phenotype. Thus, we will be able to contribute to new ways to combat HPV associated cancers.