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

描述（由申请人提供）：肺转移是癌症患者死亡的主要原因之一，由于该疾病的侵袭性及其对当前治疗方式的耐药性，死亡率很高。尽管具有重要的临床意义，但控制肺转移发生、建立和进展的细胞和分子机制尚不清楚。然而，最近越来越多的研究开始认识到局部微环境在募集弥散性恶性肿瘤细胞和转移的发生和进展中的关键作用。我们和其他人已经观察到，从转移性人类肿瘤细胞中提取的培养基（CM）可以在目标次要器官中产生活的骨髓（BM）衍生的“转移前壁龛”。值得注意的是，这些小生境积极招募尾静脉注射的肿瘤细胞，以产生稳定的转移。这些观察结果导致了一个假设，即恶性原发肿瘤成功建立肺转移瘤必须在肺间质局部微环境募集脑转移源细胞之前。这一假设的自然延伸是，局部间质的激活是由散布在外周循环中的肿瘤分泌蛋白介导的。相反，我们也确定来自非转移细胞的CM不能诱导这些转移前壁龛的形成。我们已经确定prosaposin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）的表达来抑制转移性扩散。此外，我们已经确定，在体外实验中，丙皂苷能够抑制包含转移前生态位的细胞的迁移。因此，本研究的目的之一是确定prosaposin抑制转移前生态位形成的机制，并确定prosaposin的最小活性区域，这可能作为新型抗转移治疗药物的基础。同时，本研究的另一个主要目的是确定靶向丙皂苷以及生态位的细胞成分的治疗潜力，作为一种损害肺转移小鼠生理模型中生产性转移的开始和进展的方法。我们提出了一种综合和系统的方法，结合基于细胞的检测和肺转移的小鼠体内模型来剖析肿瘤引发的肺间质转移前生态位形成的分子机制。转移起始的靶向治疗对于可能死于肺转移的癌症患者具有巨大的希望。

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.