Distant Relations: Macrophage Functions in the Metastatic Niche.

Tumor-associated macrophages are known contributors of tumor progression in the primary tumor via multiple mechanisms. However, recent studies have demonstrated the ability of macrophages to promote secondary tumor development by inhibiting tumoricidal immune response, initiating angiogenesis, remodeling the local matrix, and directly communicating with cancer cells. In this review, we discuss macrophage functions in establishing distant metastases including formation of the premetastatic niche, extravasation of circulating cancer cells, and colonization of secondary metastases. A more thorough understanding of metastasis-associated macrophages and their associated mechanisms of metastatic progression may lead to novel therapeutic intervention to prevent further metastatic development and tumor reseeding.

In vitro elucidation of the role of pericellular matrix in metastatic extravasation and invasion of breast carcinoma cells.

Numerous studies have demonstrated the importance of altered hyaluronan metabolism to malignant progression of multiple tumor types, including breast carcinomas. Increased hyaluronan (HA) metabolism in the stroma of primary tumors promotes activation of oncogenic signaling pathways that impact tumor initiation, growth, and invasion. Carcinoma cell synthesis and assembly of HA-rich pericellular matrices induces a stromal-independent phenotype, which is associated with cancer progression. Although the pro-tumorigenic role of stromal HA is well established, a novel but unexplored hypothesis is that carcinoma cell-associated HA pericellular matrices promote metastasis of circulating tumor cells. Here, we report the development of an in vitro assay that employs microfluidic techniques to directly measure the importance of an HA-rich pericellular matrix in the entry of carcinoma cells into ectopic sites. This model provides the capability to visualize specific steps in metastasis, which is difficult using animal models. The results show that the presence of a HA-rich pericellular matrix correlates to the invasive and metastatic potential of breast carcinoma cells. Furthermore, enzymatic removal or pharmacologic inhibition of HA synthesis significantly inhibits carcinoma cell extravasation and invasion in this model system. These results implicate pericellular HA-rich carcinoma cell associated pericellular matrices in colonization of ectopic sites by circulating tumor cells and support specific targeting of this matrix to limit metastasis in patients.