Initiation and evolution of the ovarian cancer microenvironment

描述（由申请人提供）：为了设计更有效的治疗和诊断干预措施，需要更好地了解突变肿瘤细胞和炎性白细胞在癌症发生和肿瘤进展过程中的双向相互作用。我们已经建立了卵巢癌的诱导遗传模型，该模型可导致晚期转移性疾病的完全外显性，并概括了人类肿瘤的炎症微环境。在C57BL6背景下的健康小鼠中，肿瘤是由Cre重组酶介导的一系列突变事件引发的。我们的新肿瘤模型在前3周经历了一个动态平衡阶段，使肿瘤的扩张得到控制，然后从第35天到第60天（逃避阶段）呈指数增长。我们将使用这个新的诱导系统来定义原始卵巢癌病变的起源和性质，以及卵巢癌起始和恶性进展过程中突变肿瘤细胞和炎性白细胞之间的串扰。我们的中心假设是卵巢癌起源于卵巢表面分化的上皮细胞，这些上皮细胞上调β -防御素以募集CCR6+CD11c+树突状细胞（DCs）。早期募集的dc反过来产生IL-6，驱动不可逆的去分化和随后的致癌转化，以及CCL3，最终诱导更多炎性dc的指数积累。在特异性目标1中，我们将阐明引发上皮性卵巢癌的细胞的有争议的性质，以及它们的解剖位置。在特异性目标2中，我们将确定从肿瘤发生初期到晚期指数肿瘤生长阶段驱动髓系白细胞募集的不同机制。在特异性目标3中，我们将确定最初由突变上皮细胞募集到原始肿瘤病变的髓系白细胞如何影响癌性转化和不可逆的恶性进展。我们的工作将在卵巢癌中定义真正的癌症干细胞的存在，以及炎性白细胞如何促进原始肿瘤病变中不可逆的癌性转化和不可逆的恶性进展，这将在该领域产生深远的影响，这可能适用于其他致死性上皮肿瘤。

DESCRIPTION (provided by applicant): 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.