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，需要更好地了解癌症起始和肿瘤进展过程中突变的肿瘤细胞和炎性白细胞之间的双向相互作用。我们已经建立了一个可诱导的卵巢癌遗传模型，该模型导致终末转移疾病，完全外露，并重述了人类肿瘤的炎性微环境。在C57BL6背景的健康小鼠中，肿瘤是由Cre重组酶介导的一系列突变事件引发的。我们的新肿瘤模型经历了动态平衡阶段，即在最初的3周内控制肿瘤的扩张，随后是从~35天到~60天的指数增长阶段(逃逸阶段)。我们将使用这一新的诱导系统来确定原始卵巢癌病变的起源和性质，以及在卵巢癌启动和恶性进展过程中突变的肿瘤细胞和炎性白细胞之间的相互作用。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，它上调β-防御素以招募CCR6+CD11c+树突状细胞(DC)。早期招募的DC继而产生IL-6，推动不可逆转的去分化和随后的致癌转化，还产生CCL3，最终导致更多炎症性DC的指数聚集。在具体目标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。在特定的目标2中，我们将确定从肿瘤发生的最初阶段到肿瘤后期的指数生长阶段，驱动髓系白细胞募集的不同机制。在具体目标3中，我们将确定突变的上皮细胞最初招募的髓系白细胞对原始肿瘤病变的影响如何影响致癌转化和不可逆转的恶性进展。我们的工作将在该领域产生深远的影响，明确卵巢癌中真癌干细胞的存在，以及炎性白细胞如何促进原始肿瘤病变的不可逆致癌转化和不可逆的恶性进展，这可能适用于其他致命的上皮性肿瘤。 公共卫生相关性：每年约有15,000名美国人死于卵巢上皮癌。在过去的30年里，尽管对细胞周期和肿瘤细胞突变进行了广泛的研究，但非常糟糕的5年存活率并没有改变。提出的目标的实现将提供关于早期卵巢癌微环境中发生的事件的第一条线索。这一认识对于推动化学预防、早期发现和有效治疗这种破坏性疾病是迫切需要的，这种疾病可能适用于其他致命的上皮性肿瘤。

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. PUBLIC HEALTH RELEVANCE: 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.