Determinants of Metastatic Progression

描述（由申请人提供）：对于晚期癌症特征（如侵袭和转移）如何以及在多大程度上由靶细胞群的初始分化状态决定，仍然知之甚少。小鼠前列腺是一个独特的合适的模型，这样的研究，因为建立解剖位置的干细胞和transit-amplifying细胞区室。最近，我们建立了一种新的与p53和Rb通路缺陷相关的转移性前列腺癌的原位小鼠模型。在该模型中，肿瘤表现出管腔和神经内分泌分化的特征，并且标记有在人前列腺癌中常见的多个签名基因表达。有趣的是，所有的恶性肿瘤仅发生于前列腺导管的近端区域，该区域高度富集前列腺干/祖细胞，并且含有L-myc的复发性扩增。基于我们的初步观察，我们假设p53和Rb改变对前列腺癌发生的协同作用在干细胞隔室的背景下特别有效，并且L-myc与p53/miR-34通路合作上调Met，这代表了选择高转移细胞亚群的重要步骤。为了验证这一假设，我们提出：（1）确定p53和Rb在控制晚期癌症易感性中的作用，作为细胞分化状态的函数;（2）确定L-myc在与p53和Rb缺乏相关的前列腺癌发生中的作用。公共卫生相关性：转移进展是癌症死亡的主要原因，更好地理解决定这一过程的分子机制至关重要。p53、Rb、Myc和Met通路的改变与不良预后相关，阐明它们参与干细胞转化及其与转移表型的潜在联系可能导致开发新的诊断、预后和治疗方法。

DESCRIPTION (provided by applicant): It remains poorly understood how and to what extent advanced cancer traits, such as invasion and metastasis, are determined by the initial differentiation status of the target cell population. The mouse prostate is a uniquely suitable model for such studies because of established anatomical location of stem cell and transit-amplifying cell compartments. Recently, we have established a new autochthonous mouse model of metastatic prostate cancer associated with deficiency for p53 and Rb pathways. In this model neoplasms exhibit features of both luminal and neuroendocrine differentiation and are marked with multiple signature gene expressions commonly found in human prostate carcinomas. Intriguingly, all malignant neoplasms arise only from the proximal region of prostatic ducts, the compartment highly enriched for prostatic stem/progenitor cells, and contain recurrent amplification of L-myc. Based on our preliminary observations, we hypothesize that synergistic effects of p53 and Rb alterations on prostate carcinogenesis are particularly effective in the context of the stem cell compartment and L-myc cooperates with p53/miR-34 pathway in up-regulation of Met, which represents an essential step towards selection of a subset of highly metastatic cells. To test this hypothesis we propose (1) To determine p53 and Rb roles in controlling predisposition to advanced cancer traits as a function of cellular differentiation state and (2) to determine role of L-myc in prostate carcinogenesis associated with p53 and Rb deficiency. PUBLIC HEALTH RELEVANCE: Metastatic progression is the main cause of death from cancer and better understanding of molecular mechanisms determining this process is of critical importance. Alterations in p53, Rb, Myc and Met pathways are associated with poor prognosis and elucidation of their involvement in stem cell transformation and its potential conjunction with metastatic phenotype may lead to development of new diagnostic, prognostic and therapeutic approaches.