Determinants of Metastatic Progression

描述（由申请人提供）：目前尚不清楚如何以及在多大程度上晚期癌症特征，如侵袭和转移，是由靶细胞群的初始分化状态决定的。小鼠前列腺是一个独特的适合于这类研究的模型，因为干细胞和转运扩增细胞区室的解剖位置已经确定。最近，我们建立了一种新的转移性前列腺癌小鼠模型，该模型与p53和Rb通路缺乏相关。在这个模型中，肿瘤表现出管腔和神经内分泌分化的特征，并以人类前列腺癌中常见的多个特征基因表达为标志。有趣的是，所有恶性肿瘤仅发生在前列腺导管的近端区域，该区域高度富集前列腺干/祖细胞，并含有复发性L-myc扩增。根据我们的初步观察，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室的背景下特别有效，L-myc与p53/miR-34途径合作上调Met，这是选择高转移细胞亚群的重要一步。为了验证这一假设，我们提出(1)确定p53和Rb作为细胞分化状态的功能在控制晚期癌症特征易感中的作用；(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：转移性进展是癌症死亡的主要原因，更好地了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有关，阐明它们在干细胞转化中的作用及其与转移表型的潜在关联可能会导致新的诊断、预后和治疗方法的发展。

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.