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HPV and tumor microenvironment


Carcinomas are malignant tumors originated from epithelial cells. Tumor stroma is formed by other cell types such as fibroblasts, endothelial cells, pericytes, adipocytes and leukocytes that can be identified both around and within the tumor. Besides, the complexity of these structures is increased by the presence of the cellular matrix, cytokines, chemokines and growth factors secreted by the different cell types present. This combination creates a unique tumor microenvironment which may modify the properties of the transformed cells. The products of the E6 and E7 genes of human papillomavirus (HPV) are pleiotropic proteins that exert different effects on the host cells. These proteins collaborate to immortalize human keratinocytes and they alter the cell cycle and the differentiation program of these cells inducing the accumulation of mitotic defects. Moreover, E6 and E7 promote several mechanisms of immune evasion. However, most of the HPV infections are transient and are cleared by the action of the cell-mediated immune response. On the other hand, women with cervical cancer exhibit tolerance to HPV antigens which has been associated to the presence of regulatory T cells (Treg) and, to a less extent, of infiltrating macrophages. Finally, several studies have shown that high-risk HPV oncoproteins induce VEGF synthesis in keratinocytes. The increase in angiogenic activity is a fundamental step in tumor progression that may be favored not only by malignant cells, but also by infiltrating macrophages and myeloid cells, as well as by local endothelial cells and pericytes. Therefore, the study of the interactions between HPV-oncogenes expressing cells and the other cellular and non-cellular elements that constitute and regulate the tumor environment may contribute to the better understanding of the pathologic processes associated to the infection by these viruses. (AU)

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Scientific publications (10)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DA SILVA CARDEAL, LAURA BEATRIZ; BOCCARDO, ENRIQUE; TERMINI, LARA; RABACHINI, TATIANA; ANDREOLI, MARIA ANTONIETA; DI LORETO, CELSO; LONGATTO FILHO, ADHEMAR; VILLA, LUISA LINA; MARIA-ENGLER, SILVYA STUCHI. HPV16 Oncoproteins Induce MMPs/RECK-TIMP-2 Imbalance in Primary Keratinocytes: Possible Implications in Cervical Carcinogenesis. PLoS One, v. 7, n. 3, . (08/58817-4, 08/03232-1)
OLIVEIRA, LUCAS BOENO; LOUVANTO, KAROLINA; RAMANAKUMAR, AGNIHOTRAM V.; FRANCO, EDUARDO L.; VILLA, LUISA L.; STUDY, LUDWIG-MCGILL COHORT. Polymorphism in the promoter region of the Toll-like receptor 9 gene and cervical human papillomavirus infection. JOURNAL OF GENERAL VIROLOGY, v. 94, n. 8, p. 1858-1864, . (08/03232-1, 10/18388-7)
CABECA, TATIANE KAREN; ABREU, ALICE DE MELLO; ANDRETTE, RAFAEL; LINO, VANESCA DE SOUZA; MORALE, MIRIAN GALLIOTE; AGUAYO, FRANCISCO; TERMINI, LARA; VILLA, LUISA LINA; LEPIQUE, ANA PAULA; BOCCARDO, ENRIQUE. HPV-Mediated Resistance to TNF and TRAIL Is Characterized by Global Alterations in Apoptosis Regulatory Factors, Dysregulation of Death Receptors, and Induction of ROS/RNS. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 1, . (11/14416-9, 08/03232-1, 10/20002-0, 08/57889-1)
OLIVEIRA, LUCAS BOENO; HAGA, ISMAR R.; VILLA, LUISA LINA. Human papillomavirus (HPV) 16 E6 oncoprotein targets the Toll-like receptor pathway. JOURNAL OF GENERAL VIROLOGY, v. 99, n. 5, p. 667-675, . (08/03232-1, 10/18388-7)
STONE, SIMONE CARDOZO; MARQUES ROSSETTI, RENATA ARIZA; BOLPETTI, ALINE; BOCCARDO, ENRIQUE; DE ARAUJO SOUZA, PATRICIA SAVIO; LEPIQUE, ANA PAULA. HPV16-associated tumors control myeloid cell homeostasis in lymphoid organs, generating a suppressor environment for T cells. Journal of Leukocyte Biology, v. 96, n. 4, p. 619-631, . (08/03232-1, 10/20010-2)
RABACHINI, TATIANA; BOCCARDO, ENRIQUE; ANDRADE, RUBIANA; PEREZ, KATIA REGINA; NONOGAKI, SUELY; CUCCOVIA, IOLANDA MIDEA; VILLA, LUISA LINA. HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner. BMC CANCER, v. 18, . (10/20002-0, 08/57889-1, 08/03232-1)
PINHEIRO, CELINE; GARCIA, EDUARDO A.; MORAIS-SANTOS, FILIPA; SCAPULATEMPO-NETO, CRISTOVAM; MAFRA, ALLINI; STEENBERGEN, RENSKE D. M.; BOCCARDO, ENRIQUE; VILLA, LUISA L.; BALTAZAR, FATIMA; LONGATTO-FILHO, ADHEMAR. Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix. BMC CANCER, v. 14, . (08/03232-1)
MORALE, MIRIAN GALLIOTE; ABJAUDE, WALASON DA SILVA; SILVA, ALINE MONTENEGRO; VILLA, LUISA LINA; BOCCARDO, ENRIQUE. HPV-transformed cells exhibit altered HMGB1-TLR4/MyD88-SARM1 signaling axis. SCIENTIFIC REPORTS, v. 8, . (14/21361-4, 10/20002-0, 11/14416-9, 08/57889-1, 08/03232-1)
DISCACCIATI, MICHELLE G.; GIMENES, FABRCIA; PENNACCHI, PAULA C.; FAIAO-FLORES, FERNANDA; ZEFERINO, LUIZ C.; DERCHAIN, SOPHIE M.; TEIXEIRA, JULIO C.; COSTA, MARIA C.; ZONTA, MARCO; TERMINI, LARA; et al. MMP-9/RECK Imbalance: A Mechanism Associated with High-Grade Cervical Lesions and Genital Infection by Human Papillomavirus and Chlamydia trachomatis. CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, v. 24, n. 10, p. 1539-1547, . (08/03232-1, 12/09746-2)
PINHEIRO, CELINE; GARCIA, EDUARDO A.; MORAIS-SANTOS, FILIPA; MOREIRA, MARISE A. R.; ALMEIDA, FABIO M.; JUBE, LUIZ F.; QUEIROZ, GERALDO S.; PAULA, ELBIO C.; ANDREOLI, MARIA A.; VILLA, LUISA L.; et al. Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas. BMC CANCER, v. 15, . (08/03232-1)

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