Abstract
Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy.
Highlights
Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs
While the overall number of disseminated tumor cells is reduced in clodronate liposome treated animals[36,49,57], of the cells that do disseminate, there is a significant reduction in the fraction that are positive for NR2F1 in circulating tumor cells (CTCs) and in disseminated tumor cells found in the lungs, as well as in the primary tumor, compared to control animals (Fig. 8d)
Studying the fate of individual DTCs in an intact organ such as the lung has been a major challenge for metastasis research because, until recently, it has not been possible to follow individual DTCs in the lung over time
Summary
Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Metastasis causes approximately 90% of cancer-related mortality[1] It is the endpoint of a complex and dynamic cascade of steps in which tumor cells migrate within the primary tumor, intravasate, disseminate via the circulatory system, arrest at a secondary site, extravasate, survive, and reinitiate growth to form secondary tumors[2]. Specific primary tumor microenvironments, such as hypoxia, can prime those primary tumor cells that are destined to become DTCs to have divergent fates in target organs[21]. Despite these advances, it is not known what influence the primary tumor has on the early steps of the metastatic cascade in the secondary site
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