Caracterização de alvos moleculares em tumores associados ao Papilomavírus Humano

Abstract

Cervical cancer is caused by a persistent infection by some of the oncogenic types of Human Papillomavirus (HPV) and continues to be a public health problem, especially in developing countries. By Peptide Phage Display peptide sequences were selected with binding affinity to cell lines or to HPV-associated tumors. Among them, it was possible to identify sequences contained in molecules important for the progression of tumors, such as α-mannosidase and tryptase, enzymes that play an important role in tumor progression. To characterize the effect of αmannosidase II inhibition on cervical tumor therapy in mice, we used the drug Swainsonina (SW), previously described as an inhibitor of this enzyme. We tested the effect of this drug by treating animals inoculated with tumor cells expressing HPV16 E6 and E7 oncogenes. We observed that Swainsonine treated animals had significantly faster tumor growth than control animals.Investigating the mechanisms behind this effect, we found that although SW partially modulates tumor-associated macrophages, the treatment induces the accumulation of cells with suppressive myeloderivative phenotype in the animals spleens, enhancing the tolerogenic effect of tumors on the immune system. Therefore, we suggest caution in the use of this drug for the therapy of patients with HPV + tumors. Another arm of the study was to evaluate the role of tryptase, which is produced by mast cells, in the inflammatory infiltrate. For this we standardized a co-culture model of tumor spheroids of the TC-1 lineage with the murine mast cell line PT18.Through this model we could observe that the tumoral lineage can induce mast cell degranulation independently of antibodies. In addition, when co-cultured, the tumoral lineage appears to be increasing the half-life of mast cells and stimulating the proliferation of these. In in vivo experiments we observed that tumors induced with PT18 and TC-1 cells grew faster than tumors induced only with TC-1. Tumor immunophenotyping revealed an increase in CD31 + cells and in the total inflammatory infiltrate of tumors induced with co-culture. Justifying the fact that they grow faster, suggesting that mast cells can have both proliferative effects and the process of tumor angiogenesis.