Breast cancer stem cells, cytokine networks, and the tumor microenvironment

Abstract

Many tumors, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment - including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune cells - through networks of cytokines and growth factors. Since these components have a direct influence on CSC properties, they represent attractive targets for therapeutic development.

Figure 1. The tumor microenvironment.

Elevated levels of cytokines and growth factors produced by tumor cells enhance the proliferation and survival of CSCs, induce angiogenesis, and recruit tumor-associated macrophages, neutrophils, and mast cells, which secrete additional growth factors, forming a positive feedback loop that promotes tumor cell invasion and metastasis.

Figure 2. Cytokines secreted by cells in the tumor microenvironment regulate BCSC self renewal.

Tumor-associated fibroblasts (TAFs) and macrophages (TAMs) and MSCs have been shown to secrete IL-6, IL-8, and CXCL7, which in turn activate Stat3/NF-κB signaling, leading to self renewal of BCSCs. This generates a positive feedback loop between the tumor microenvironment and tumor cells.