Metastatic cancer cells (seeds) preferentially grow in the secondary sites with a permissive microenvironment (soil). We show that the metastatic cells can bring their own soil—stromal components in- cluding activated fibroblasts—from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that via- bility of circulating metastatic cancer cells is higher if they are in- corporated in heterotypic tumor–stroma cell fragments. Moreover, we show that these cotraveling stromal cells provide an early growth advantage to the accompanying metastatic cancer cells in the lungs. Consistent with this hypothesis, we demonstrate that partial depletion of the carcinoma-associated fibroblasts, which spontaneously spread to the lung tissue along with metastatic can- cer cells, significantly decreases the number of metastases and ex- tends survival after primary tumor resection. Finally, we show that the brain metastases from lung carcinoma and other carcinomas in patients contain carcinoma-associated fibroblasts, in contrast to primary brain tumors or normal brain tissue. Demonstration of the direct involvement of primary tumor stroma in metastasis has im- portant conceptual and clinical implications for the colonization step in tumor progression.
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