Stromal Cell Recruitment and the Pathogenesis of Metastasis

癌细胞获得高度恶性的特征使其能够侵袭和转移 传播。在许多，甚至可能是所有的癌症中，这些特征是由细胞生物学程序赋予的 称为上皮-间充质转化(EMT)。EMT程序通常是在癌细胞中诱导的 可逆地，通过它们接收的上下文信号，很大程度上(如果不是全部)来自相邻的反应间质 存在于许多高度进展的肿瘤中。而细胞内的信令电路能够激活 EMT程序已经进入人们的视野，激活这些信号的细胞外、上下文信号的性质 癌细胞中的程序仍然不清楚，这些信号的细胞来源也是如此。这表明， 恶性进展的终极控制因素--基质细胞及其释放的信号--仍然 人们对此知之甚少。 这项拟议的研究源于国际和平研究所实验室的两条研究路线的汇合。第一。 Twist是一种EMT诱导的转录因子，与高度侵袭性的恶性行为有关 4T1小鼠乳腺癌细胞；其表达是在体内诱导的，表面上是由以下信号诱导的 移植的4T1细胞从它们招募的基质细胞中接收。第二，这些癌细胞诱导 荷瘤同基因小鼠的脾肿大。与其说是肿瘤的附带现象，不如说 在发病机制上，这种脾肿大在4T1肿瘤的形成中起因果作用，因为在缺乏 脾功能(脾切除获得)、扭转和蜗牛EMT-TF的表达及其能力 产卵转移均显著减少。因此，这些肿瘤的局部恶性状态，很可能 许多其他肿瘤是由全身因素控制的，在这种情况下，髓系细胞从脾招募而来。 这些动力学表明，某些癌症，如这里研究的4T1肿瘤，会诱发 脾肿大；聚集在脾中的髓系细胞然后可能通过循环被招募到 在肿瘤相关间质中，这些细胞继续释放异型信号，从而在 4T1细胞，使后者发生转移。对于拟议的研究来说，重要的是这些小鼠的脾 应该代表丰富的髓系细胞来源，这些细胞参与了EMT的诱导，从而在 引发转移性复发。拟议的研究将检查这些细胞以及其他 被招募到与肿瘤相关的间质中以形成功能上重要的列表， 肿瘤相关间质中促恶性细胞及揭示EMT诱导的旁分泌信号 被他们释放的人。

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.