Malignant cells facilitate lung metastasis by bringing their own soil

Abstract

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 including activated fibroblasts-from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that viability of circulating metastatic cancer cells is higher if they are incorporated 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 cancer cells, significantly decreases the number of metastases and extends 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 important conceptual and clinical implications for the colonization step in tumor progression.

Pericyte–fibroblast transition promotes tumor growth and metastasis

“…Loss of pericytes from tumor vessels may either permit tumor cell intravasation and PFT or hijack tumor cells for intravasation, and perhaps even the formation of the initial metastatic niches in distal tissues and organs. Indeed, it has been described that tumors can carry their own fibroblasts as "soil" for them to "seed" and grow in distal organs (42). Therefore, pericytes play dynamic roles in cancer invasion and metastasis.…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Notably, some of the early signalling that contributes to pre-metastatic niche formation may originate from passenger fibroblasts, accompanying the disseminating tumour cells to the secondary site. Support for this comes from two recent reports demonstrating that metastatic Lewis lung carcinoma cells and human pancreatic cancer cells provide their own stromal components, including activated fibroblasts, from primary sites to the metastatic organs [111].…”

Emerging roles of the tumor-associated stroma in promoting tumor metastasis

“…41,42 Moreover, CTCs appear to contain clusters of heterogeneous cell populations composed of platelets, leukocytes and mesenchymal cells. [43][44][45] The half-life of CTCs in the circulation is short, i.e., measured in hours, which is partially related to their fast clearance from the circulation and/or apoptosis. 46 To date, whether CTCs and DTCs extracted from either patients or mouse tumor models are capable of forming metastases when introduced into recipient mice has not been shown.…”

“…Sampling of the blood from these mice when tumors reached approximately 10 mm in diameter showed that 80% of isolated ds-Red+ CTCs traveled as single cells, while some ds-Red+CTCs formed clusters containing viable GFP + host stromal cells. 44 In addition, mice having GFP + cells specifically in their skin were generated by the parabiosis skin transplantation and ds-Red + macrophages (28%). Furthermore, human mammary CAFs were injected subcutaneously together with murine LLC1 cells into recipient mice and allowed to metastasize with carcinoma cells into the lung.…”

“…Furthermore, human mammary CAFs were injected subcutaneously together with murine LLC1 cells into recipient mice and allowed to metastasize with carcinoma cells into the lung. 44 To abolish support from CAFs for metastatic colonization, mice were systemically treated with diphtheria toxin after primary tumor resection. 44 This toxin is described as being 1,000 times more potent at killing human cells than murine cells.…”