This proposal is in response to Program Announcement PA-04-057 from the NCI to stimulate research on malignancies in AIDS. We will conduct experiments designed to address an under explored area of cervical cancer, a cancer which, in HIV-positive women is an AIDS-defining illness. This proposal is responsive to two areas of study. Within the Biomarkers, Diagnostics, and Therapeutics area, the experiments described herein have the potential to improve in vitro and in vivo assays for pre-clinical evaluations. Within the area of Etiology, Pathogenesis, and Immunology, we will be expanding the knowledge base of the mechanism of human papillomavirus (HPV)-mediated tumor initiation and promotion. We have chosen to use the R21 mechanism since our proposed experiments are in the realm of novel exploratory/developmental research. Here we will focus on how HPVs alter the microenvironment in such a way as to promote tumor development. Since HIV positive individuals are at increased risk for HPV infection, dysplasia, and cancer, this avenue of research is particularly pertinent to PA-04-057. The experiments are supported by recent published data from our laboratory that show that HPVs can reprogram their host cells to favor the synthesis and secretion of angiogenic inducers, cytokines which could subsequently act on endothelial cells to recruit a blood supply to the infected tissue. Preliminary data presented in this proposal also show that conditioned media from the HPV-expressing cells alter endothelial cell behavior both in vitro and in vivo.
In Specific Aim 1 we will use the in vivo Matrigel model to establish the origin of endothelial cells recruited by the HPV-induced factors.
In Specific Aim 2 we will identify the HPV-induced factors which are required for this response. By combining the expertise of an HPV virologist and a tumor microenvironment expert, we hope to provide novel insights into the activities of these oncogenic viruses. The outcome could have both prognostic and therapeutic implications and the potential to be translated from the bench to the bedside. Human papillomaviruses, as causative agents of cervical cancer, have a major public health impact. This proposal offers the potential of identifying new biomarkers for early diagnosis and monitoring of disease progression. ? ? ?
| Roman, Ann; Munger, Karl (2013) The papillomavirus E7 proteins. Virology 445:138-68 |
| Walker, Joanna; Smiley, Lucy Clare; Ingram, David et al. (2011) Expression of human papillomavirus type 16 E7 is sufficient to significantly increase expression of angiogenic factors but is not sufficient to induce endothelial cell migration. Virology 410:283-90 |
