Initiation and evolution of the ovarian cancer microenvironment

描述（由申请人提供）：设计更有效的治疗和诊断干预措施需要更好地了解癌症发生和肿瘤进展期间突变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卵巢癌的可诱导遗传模型，该模型导致晚期转移性疾病的完全消退，并重现了人类肿瘤的炎症微环境。 在C57 BL 6背景下，在先前健康的小鼠中，肿瘤由Cre重组酶介导的突变事件的组合引发。 我们的新肿瘤模型通过动态平衡阶段进展，该阶段在前3周保持肿瘤扩张受到控制，随后是从约第35天到约第60天的指数生长阶段（逃避阶段）。 我们将使用这种新的诱导系统来确定原始卵巢癌病变的起源和性质，以及在卵巢癌发生和恶性进展期间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，卵巢癌的发生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CCR 6 + CD 11 c+树突状细胞（DC）。 早期募集的DC继而产生驱动不可逆的去分化和随后的致癌转化的IL-6，以及最终诱导更多炎性DC的指数积累的CCL 3。 在具体目标1中，我们将阐明引发上皮性卵巢癌的细胞的争议性质，以及它们的解剖位置。 在特定目标2中，我们将确定从肿瘤发生的最开始到晚期的指数肿瘤生长期，骨髓白细胞募集的差异机制。 在特定目标3中，我们将确定最初由突变的上皮细胞募集到原始肿瘤病变的髓样白细胞如何影响致癌转化和不可逆的恶性进展。 我们的工作将通过定义卵巢癌中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致癌转化和不可逆的恶性进展，在该领域产生深远的影响，这可能适用于其他致命的上皮肿瘤。 公共卫生相关性：上皮性卵巢癌每年杀死约15，000名美国人。 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，但非常差的5年生存率没有改变。 所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。 这种理解是迫切需要的化学预防，早期发现和有效治疗这种毁灭性的疾病，这可能适用于其他致命的上皮肿瘤的进步。

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.