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，由于疾病的侵入性及其对当前治疗方式的抵抗力，死亡率很高。尽管具有临床意义，但控制肺转移的起始，建立和进展的细胞和分子机制尚不清楚。然而，最近的研究已经开始认识到局部微环境在募集传播的恶性肿瘤细胞中的关键作用。我们和其他人已经观察到，靶标二级器官中培养培养基（CM）的施用导致可行的骨髓（BM）衍生的“前转移性小丁基”。值得注意的是，这些利基积极募集的尾静脉注射肿瘤细胞以产生稳定的转移。这些观察结果导致了以下假设：在肺部基质中，局部微环境募集了BM衍生的细胞，因此必须先通过恶性原发性肿瘤来成功建立肺转移。该假设的自然扩展是，局部基质的激活是由在周围循环中分散的肿瘤分泌蛋白（S）介导的。相反，我们还确定了来自非转移细胞的CM无法诱导这些前转移性壁球的形成。我们已经确定了prosaposin是一种肿瘤分泌的蛋白质，可通过刺激p53及其靶基因的抗血管生成蛋白血小板传播1（TSP-1）来抑制转移性扩散。此外，我们已经确定，prosaposin能够抑制在体外测定中构成前转移性细分市场的细胞的迁移。因此，该提案的目的之一是确定普荷蛋白酶抑制前转移性细分市场形成并鉴定利奥氏蛋白酶的最小活性区域的机制，这可能是新型抗复位治疗剂的基础。同时，该提案的另一个主要目的是确定靶向利基市场的治疗潜力，以及小裂的细胞成分，作为一种损害肺转移生理小鼠模型的生产性转移和进展的方法。我们提出了一种综合和系统的方法，该方法结合了基于细胞的测定和肺部转移的体内小鼠模型，以剖析肺基质中肿瘤引起的前转移性小裂形成的分子机制。对于可能死于肺部转移的癌症患者，转移的治疗靶向具有巨大的希望。

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.