Determinants of Metastatic Progression

描述(由申请人提供)：目前尚不清楚晚期癌症特征，如侵袭和转移，在多大程度上以及如何由目标细胞群体的初始分化状态决定。小鼠前列腺是这类研究唯一合适的模型，因为干细胞和转运放大细胞室在解剖学上已经确定了位置。最近，我们建立了一种新的与P53和Rb通路缺陷相关的前列腺癌转移小鼠模型。在这个模型中，肿瘤表现出腔内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标志性基因表达为标志。有趣的是，所有的恶性肿瘤都只发生在前列腺管的近端，该区域高度富含前列腺干/祖细胞，并含有周期性的L-myc扩增。根据我们的初步观察，我们假设P53和Rb基因改变在前列腺癌发生中的协同作用在干细胞区块的背景下特别有效，而L-myc的过度表达可能是选择具有神经内分泌分化的高转移细胞亚群的关键步骤。为了验证这一假说，我们建议(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。转移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和Myc通路的改变与预后不良有关，阐明它们在干细胞转化中的作用及其与转移表型的潜在联系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 to what extent and how 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 stem cell compartment, while L-myc overexpression may be an essential step towards selection of a subset of highly metastatic cells with neuroendocrine differentiation. 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 roles of L-myc in prostate carcinogenesis associated with p53 and Rb deficiency. 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 and Myc 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.