Molecular mechanisms of tumor-initiated premetastatic niche formation in lung str

描述(申请人提供)：肺转移是癌症患者死亡的主要原因之一，由于这种疾病的侵袭性及其对当前治疗方式的抵抗力，其死亡率很高。尽管肺转移具有重要的临床意义，但控制肺转移发生、建立和发展的细胞和分子机制仍不清楚。然而，最近的研究已经开始认识到局部微环境在募集播散性恶性肿瘤细胞在转移的启动和进展中的关键作用。我们和其他人已经观察到，给予转移性人类肿瘤细胞的培养条件培养液(CM)会在靶器官的次级器官中产生活性的骨髓(BM)来源的“转移前利基”。值得注意的是，这些利基积极招募尾静脉注射的肿瘤细胞来产生稳定的转移。这些观察结果导致了一种假设，即在恶性原发肿瘤成功建立肺转移之前，肺间质中的局部微环境必须招募骨髓来源的细胞。这一假设的自然延伸是局部间质的激活是由肿瘤分泌蛋白(S)介导的，这些蛋白散布在外周循环中。相反，我们也已经确定，来自非转移细胞的CM不能诱导这些转移前利基的形成。我们已经确定丙皂苷是一种肿瘤分泌蛋白，通过刺激P53及其靶基因-抗血管生成蛋白血栓反应蛋白-1(TSP-1)的表达来抑制转移扩散。此外，我们在体外实验中确定了丙皂苷能够抑制构成转移前生态位的细胞的迁移。因此，这项建议的目的之一是确定丙皂苷抑制转移前生态位形成的机制，并确定丙皂苷的最小活性区域，这可能是新型抗转移治疗药物的基础。同时，这项建议的另一个主要目的是确定靶向丙皂苷以及利基细胞成分的治疗潜力，以此作为一种方法来损害生理性肺转移小鼠模型中生产性转移的启动和进展。我们提出了一种综合和系统的方法，结合基于细胞的分析和活体小鼠肺转移模型来剖析肿瘤启动的肺间质转移前生态位形成的分子机制。肿瘤转移启动的靶向治疗对于可能死于肺转移的癌症患者具有巨大的前景。

DESCRIPTION (provided by applicant): Lung metastasis is one of the leading causes of death in cancer patients, with a high mortality due to the invasive nature of the disease and its resistance to current treatment modalities. Despite the clinical importance, the cellular and molecular mechanisms that govern the initiation, establishment and progression of pulmonary metastasis remain unclear. However, more recent studies have begun to recognize the critical role of the local microenvironments in recruiting the disseminated malignant tumor cells in the initiation and progression of metastasis. We and others have observed that administration of culture conditioned media (CM) from metastatic human tumor cells results in viable bone marrow (BM)-derived "premetastatic niches" in target secondary organs. Notably, these niches actively recruited tail vein injected tumor cells to generate stable metastases. These observations led to the hypothesis that successful establishment of pulmonary metastases by malignant primary tumors must be preceded by the recruitment of BM-derived cells by the local microenvironment in the lung stroma. The natural extension of this hypothesis is that the activation of the local stroma is mediated by tumor-secreted protein(s) that are disseminated in the peripheral circulation. Conversely, we have also determined that CM from non-metastatic cells is unable to induce the formation of these premetastatic niches. We have identified prosaposin as a tumor-secreted protein that inhibits metastatic spread by stimulating the expression of p53 and its target gene, the antiangiogenic protein thrombospondin-1 (Tsp-1). Furthermore, we have determined that prosaposin is able to inhibit the migration of cells that comprise the premetastatic niche in an in vitro assay. Thus, one aim of this proposal is to determine the mechanism by which prosaposin inhibits premetastatic niche formation and to identify the minimal active region of prosaposin, which may serve as the basis for novel anti-metastatic therapeutic agents. Meanwhile, the other major aim of this proposal is to determine the therapeutic potential of targeting prosaposin as well as cellular components of the niche as an approach to impair productive metastasis initiation and progression in physiological mouse models of pulmonary metastasis. We propose an integrated and systematic approach that combines cell-based assays and in vivo mouse models of pulmonary metastasis to dissect the molecular mechanisms of tumor-initiated premetastatic niche formation in the lung stroma. Therapeutic targeting of metastasis initiation has tremendous promise for cancer patients who are likely to die of pulmonary metastasis.