Malignant cells facilitate lung metastasis by bringing their own soil

TLDR

Metastatic cancer cells preferentially colonize secondary sites that provide a permissive microenvironment, or “soil,” for tumor growth. The authors aim to show that metastatic cells can transport their own stromal microenvironment to the lungs. They demonstrate that metastatic cells carry activated fibroblasts and other stromal components from the primary tumor to the lung tissue. Analysis of tumor efferent blood revealed that circulating metastatic cells incorporated into tumor‑stroma fragments have higher viability and give an early growth advantage in the lungs, depletion of these carcinoma‑associated fibroblasts reduces metastases and prolongs survival, and CAFs are also found in brain metastases, highlighting the essential role of primary tumor stroma in metastatic colonization.

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.