Stromal Cell Recruitment and the Pathogenesis of Metastasis

基质细胞的募集和转移的发病机制

• 批准号: 8555485
• 负责人: ROBERT A WEINBERG
• 金额: $ 20.53万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555485
• 关键词: Animals; Antibodies; Automobile Driving; Behavior; Biological; Blood Circulation; Breast Cancer Cell; Breast Carcinoma; CSF3 gene; Carcinoma; Cells; Chemotactic Factors; Complex; Disseminated Malignant Neoplasm; Endocrine; Enzyme-Linked Immunosorbent Assay; Epithelial; Extravasation; Human; Implant; Laboratories; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mesenchymal; Mus; Myeloid Cells; Nature; Neoplasm Metastasis; Organ; Paracrine Communication; Pathogenesis; Play; Primary Neoplasm; Production; Recruitment Activity; Relapse; Research; Role; Signal Transduction; Snails; Source; Spleen; Splenectomy; Splenomegaly; Stromal Cells; Testing; Tumor Volume; cancer cell; cell stroma; cell type; extracellular; implantation; in vivo; macrophage; malignant state; monocyte; neoplastic cell; neutrophil; paracrine; programs; release factor; success; trait; transcription factor; tumor; tumor progression

The acquisition of highly malignant traits by carcinoma cells enables their invasion and metastatic dissemination. In many, and possibly all carcinomas, these traits are conferred by a cell-biological program termed the epithelial-mesenchymal transition (EMT). The EMT program is induced in carcinoma cells, usually reversibly, by contextual signals that they receive, largely if not entirely from the adjacent reactive stroma that is present in many highly progressed tumors. While the intracellular signaling circuits that enable activation of EMT programs have come into view, the nature of the extracellular, contextual signals that activate these programs in carcinoma cells is still obscure as are the cellular origins of these signals. This Indicates that the ultimate governors of malignant progression - the stromal cells and the signals that they release - are still poorly understood. The proposed research derives from the convergence of two lines of research in the Pi's laboratory. First. Twist - an EMT-inducing transcription factor - is responsible for the malignant behavior of highly aggressive 4T1 mouse mammary carcinoma cells; its expression is induced in vivo, ostensibly by signals that the implanted 4T1 cells receive from the stromal cells that they recruit. Second, these carcinoma cells induce splenomegaly in tumor-bearing syngeneic mouse hosts. Rather than being an epiphenomenon of tumor pathogenesis, this splenomegaly plays a causal role in 4T1 tumor formation, since in the absence of a functional spleen (achieved by splenectomy), the expression of the Twist and Snail EMT-TFs and their ability to spawn metastases are all significantly reduced. Hence, the local malignant state of these tumors, and likely many other tumors, is controlled by systemic factors, in this case myeloid cells recruited from the spleen. These dynamics suggest that certain carcinomas, such as the 4T1 tumors studied here, induce splenomegaly; the myeloid cells that collect In the spleen may then be recruited via the circulation into the tumor-associated stroma, where these cells proceed to release heterotypic signals that induce an EMT in the 4T1 cells, enabling the latter to metastasize. Importantly for the proposed research, the spleens of these mice should represent a rich source of the myeloid cells that participate in the induction of the EMT and thus in the triggering of metastatic relapse. The research that is proposed will examine these cells as well as others that are recruited into the tumor-associated stroma in order to develop a list of the functionally important, malignancy-promoting cells in the tumor-associated stroma and to uncover the EMT-inducing paracrine signals that they release.

癌细胞对高度恶性特征的获取可实现其侵袭和转移性 传播。在许多（甚至所有癌）中，这些特征是由细胞生物学程序赋予的 称为上皮 - 间质转变（EMT）。 EMT程序在癌细胞中诱导，通常 可逆地，通过他们收到的上下文信号，很大程度上甚至不是完全来自相邻的反应性基质 存在于许多高度进展的肿瘤中。而细胞内信号传导电路可以激活 EMT程序已经开始了，细胞外，上下文信号的性质激活这些信号 癌细胞中的程序仍然是晦涩的，这些信号的细胞起源也是如此。这表明 恶性进展的最终调速器 - 基质细胞及其释放的信号 - 仍然是 理解不佳。 提出的研究源于PI实验室中两条研究线的收敛。第一的。 扭曲 - 诱导EMT的转录因子 - 负责高度侵略性的恶性行为 4T1小鼠乳腺癌细胞；它的表达在体内诱导，表面上是通过信号表明 植入的4T1细胞从其募集的基质细胞中接收。其次，这些癌细胞诱导 具有肿瘤的同性小鼠宿主中的脾肿大。而不是作为肿瘤的表皮 发病机理，这种脾肿大在4T1肿瘤形成中起因果作用，因为在没有A的情况下 功能性脾脏（通过脾切除术实现），扭曲和蜗牛EMT-TF的表达及其能力 产卵转移均大大减少。因此，这些肿瘤的局部恶性状态，可能 许多其他肿瘤受系统因素控制，在这种情况下，从脾脏募集的髓样细胞。 这些动力学表明某些癌，例如这里研究的4T1肿瘤，诱导 脾肿大;然后可以通过循环招募在脾脏中收集的髓样细胞 肿瘤相关的基质，这些细胞继续释放诱导EMT的异型信号 4T1细胞，使后者能够转移。重要的是，对于拟议的研究，这些小鼠的脾脏 应代表参与EMT诱导的髓样细胞的丰富来源，因此 触发转移性复发。提出的研究将检查这些细胞以及其他细胞 被招募到与肿瘤相关的基质中，以制定功能上重要的列表 肿瘤相关的基质中的恶性细胞，并发现EMT诱导的旁分泌信号 他们释放。