The Influence of the Cancer Microenvironment on the Process of Metastasis

Metastasis of breast cancer is a multistep process that requires cancer cells to invade stroma at the primary site, gain access to vasculature, survive in the circulation, extravasate into the parenchyma of the secondary site, and survive and proliferate at the secondary site. During each of these steps, the microenvironment surrounding the cancer cells is believed to be an active participant. The cancer microenvironment also varies during the metastatic process. At the primary tumor in the breast, invasive cancer cells are surrounded by fibroblasts, extracellular matrix (ECM), cellular constituents of the vasculature, inflammatory/immune cells, and adipose tissue. Metastasizing cancer cells are exposed to a completely different microenvironment within the circulatory system. The cancer microenvironment at the secondary site is, again, very different from the microenvironment of the breast and varies depending on the sites of metastasis. At the primary and metastatic sites, the interaction between tumor cells and their surrounding milieu is reciprocal; the tumor cells influence the stroma and vice versa, ultimately fueling tumor progression. The papers in this issue discuss the dynamics of the interactions of tumor cells and their microenviron-ment, detailing how tumor cells manipulate their milieu and, conversely, how the reactive tumor microenvironment influences tumor cell plasticity, invasion, metastasis, and cancer therapy. Z. I. Khamis et al. provide a thorough summary of the roles of the tumor stroma and tumor microenvironment in the various steps involved in the metastatic process, as well as in the development of breast cancer in their paper " Active roles of tumor stroma in breast cancer metastasis. " The authors discuss research findings related to the contribution of various constituents of the tumor microenvironment, including inflammatory cells, fibroblasts, extracellular matrix, and blood vessels, in the metastatic process. They also include a discussion of the signaling pathways utilized by cancer cells to modify the stroma and ECM. This review serves as an excellent overview for this issue. Two papers in this issue discuss the cancer cells themselves and how characteristics or functions of the cancer cells influence the tumor microenvironment. Just as the microenvironment signals to the cancer cells, the cancer cells alter the microenvironment to promote tumor progression and metastasis. J. E. Chu and A. L. Allan in their paper " The role of cancer stem cells in the organ tropism of breast cancer metastasis: a mechanistic balance between the " seed " and the " soil? " " have exhaustively …