A better understanding of the bi-directional interaction between mutated tumor cells and inflammatory leukocytes during cancer initiation and neoplastic progression is required for the design of more effective therapeutic and diagnostic interventions. We have generated an inducible genetic model of ovarian carcinoma that leads to terminal metastatic disease complete penetrance and recapitulates the inflammatory microenvironment of human tumors. Tumors are initiated by a combination of mutational events mediated by Cre recombinase in previously healthy mice in a C57BL6 background. Our new tumor model progresses through a phase of dynamic equilibrium that keeps tumor expansion in check for the first 3 weeks, followed by a phase of exponential growth from ~day 35 to ~day 60 (evasion phase). We will use this new inducible system to define the origin and nature of primordial ovarian cancer lesions and the cross-talk between mutated tumor cells and inflammatory leukocytes during ovarian cancer initiation and malignant progression. Our central hypothesis is that ovarian cancer initiation arises from differentiated epithelial cells from the ovarian surface that upregulate beta-defensins to recruit CCR6+CD11c+ dendritic cells (DCs). Early recruited DCs in turn produce IL-6 that drives irreversible dedifferentiation and subsequent oncogenic transformation, and also CCL3 that eventually induces the exponential accumulation of more inflammatory DCs.
In Specific Aim 1, we will elucidate the debated nature of the cells that initiate epithelial ovarian cancer, as well as their anatomic location.
In Specific Aim 2, we will determine the differential mechanisms driving the recruitment of myeloid leukocytes from the very beginning of tumorigenesis to the exponential tumor growth phase at late stages.
In Specific Aim 3, we will establish how myeloid leukocytes initially recruited by mutated epithelial cells to primordial tumor lesions impact oncogenic transformation and irreversible malignant progression. Our work will exert a profound effect in the field by defining the existence of true cancer stem cells in ovarian cancer, and how inflammatory leukocytes promote irreversible oncogenic transformation in primordial tumor lesions and irreversible malignant progression, which may be applicable to other lethal epithelial tumors.
Epithelial ovarian cancer kills ~15,000 Americans per year. Over the last 30 years, despite extensive research into the cell cycle and tumor cell mutations, the very poor 5- year survival rates are unchanged. The accomplishment of the proposed aims will provide the first clue about the events taking place in the microenvironment of incipient ovarian carcinomas. This understanding is urgently required for the advancement towards chemoprevention, early detection and effective treatment of this devastating disease, which may be applicable to other lethal epithelial tumors.
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