Active roles of tumor stroma in breast cancer metastasis

Abstract

Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome.

Figure 1

Schematic presentation of breast cancer progression accompanied with stromal cells. Normal breast duct is composed of a layer of epithelial cells and a layer of myoepithelial cells separated from the stroma by a basement membrane. Stromal cells include fibroblasts, BMDCs, endothelial cells, and other cells. Ductal carcinoma in situ (DCIS) is associated with luminal epithelial cells proliferation, and recruitment and expansion of stromal cells. In invasive ductal carcinoma, the myoepithelial cell layer is degraded with the underlying basement membrane and cancerous cells invade the surrounding microenvironment. Advanced breast cancer is associated with complete loss of myoepithelial cell layer and basement membrane, invasion of epithelial cells, proliferation of stromal cells, and angiogenesis.

Figure 2

Stromal cells involved in metastatic cascade. (1) Myofibroblasts, fibroblasts, and macrophages and other BMDCs play a major role in promoting primary tumor growth. (2) Intravasation is enhanced by the paracrine interactions between tumor cells and macrophages. (3) The fusion of tumor cells and macrophages is questionable (?) and may promote the survival of the tumor cells in vasculature. (4) During extravasation, direct interaction of tumor cells and macrophages enhance tumor cell egress of the vessels. (5) BMDCs and myofibroblasts stimulate tumor cell metastatic dissemination. (6) The recruitment of endothelial cells, myofibroblasts, and BMDCs to the tumor site increases vascularization.