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

肺脏中肿瘤引发的转移前生态位形成的分子机制

• 批准号: 8598461
• 负责人: Vivek Mittal
• 金额: $ 51.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598461
• 关键词: Angiogenesis Inhibitors; Animals; Biological Assay; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cancer Patient; Cause of Death; Cells; Clinical; Conditioned Culture Media; Disease; Disease Resistance; Endothelial Cells; Fibroblasts; Gene Targeting; Grant; Human; ITGAM gene; Immunocompetent; In Vitro; Lung; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Maps; Mediating; Metastatic Neoplasm to the Lung; Metastatic to; Migration Assay; Modality; Modeling; Molecular; Mus; Nature; Neoplasm Metastasis; Organ; Peripheral; Physiological; Primary Neoplasm; Principal Investigator; Proteins; Recruitment Activity; Relative (related person); Resistance; Role; Site; Stromal Cells; Structure of parenchyma of lung; Tail; Therapeutic; Therapeutic Agents; Thrombospondin 1; Time; Transgenic Mice; Tumor-Secreted Protein; Vascular Endothelial Growth Factor Receptor-1; Veins; Work; Xenograft Model; base; cell motility; cellular targeting; diphtheria toxin receptor; in vitro Assay; in vivo; lymph nodes; mortality; mouse model; mutant; neoplastic cell; neutralizing antibody; novel; prevent; prostate cancer cell; public health relevance; small hairpin RNA; therapeutic target; tumor; tumor xenograft

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.

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，由于疾病的侵袭性及其对当前治疗方式的抗性，死亡率很高。尽管临床上的重要性，细胞和分子机制，管理的启动，建立和发展的肺转移仍然不清楚。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中的关键作用，这些细胞在转移的开始和进展中。我们和其他人已经观察到，施用来自转移性人肿瘤细胞的培养条件培养基（CM）导致靶次级器官中的活的骨髓（BM）衍生的“转移前小生境”。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这样的假设，即恶性原发性肿瘤肺转移的成功建立必须通过肺间质中局部微环境的BM衍生细胞的募集来进行。这一假设的自然延伸是局部基质的活化由散布在外周循环中的肿瘤分泌蛋白介导。相反，我们还确定了来自非转移性细胞的CM不能诱导这些转移前小生境的形成。我们已经确定了鞘脂激活蛋白原作为一种肿瘤分泌蛋白，通过刺激p53及其靶基因，抗血管生成蛋白血小板反应蛋白-1（TSP-1）的表达来抑制转移扩散。此外，我们已经确定，鞘脂激活蛋白原是能够抑制细胞的迁移，包括在体外试验中的转移前的小生境。因此，这个建议的一个目的是确定的机制，其中鞘脂激活蛋白原抑制转移前的小生境形成，并确定最小的活性区域的鞘脂激活蛋白原，这可能是新的抗转移治疗剂的基础。同时，该提议的另一个主要目的是确定靶向鞘脂激活蛋白原以及小生境的细胞组分作为在肺转移的生理小鼠模型中损害生产性转移起始和进展的方法的治疗潜力。我们提出了一个综合的和系统的方法，结合细胞为基础的检测和体内小鼠模型的肺转移，解剖肿瘤引发的转移前生态位形成的肺间质的分子机制。转移起始的治疗靶向对于可能死于肺转移的癌症患者具有巨大的前景。

项目成果

Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth.

• DOI: 10.1158/0008-5472.can-10-1142
• 发表时间: 2010-09-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Mellick AS;Plummer PN;Nolan DJ;Gao D;Bambino K;Hahn M;Catena R;Turner V;McDonnell K;Benezra R;Brink R;Swarbrick A;Mittal V
• 通讯作者: Mittal V

PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression.

• DOI: 10.1038/s41467-022-35649-9
• 发表时间: 2022-12-27
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sui, Lufei;Wang, Suming;Ganguly, Debolina;El Rayes, Tyler P. P.;Askeland, Cecilie;Borretzen, Astrid;Sim, Danielle;Halvorsen, Ole Johan;Knutsvik, Goril;Arnes, Jarle;Aziz, Sura;Haukaas, Svein;Foulkes, William D. D.;Bielenberg, Diane R. R.;Ziemys, Arturas;Mittal, Vivek;Brekken, Rolf A. A.;Akslen, Lars A. A.;Watnick, Randolph S. S.
• 通讯作者: Watnick, Randolph S. S.