The Breast Tumor Microenvironment: A Key Player in Metastatic Spread

Abstract

The tumor microenvironment plays a pivotal role in the tumorigenesis, progression, and metastatic spread of many cancers including breast. There is now increasing evidence to support the observations that a bidirectional interplay between breast cancer cells and stromal cells exists within the tumor and the tumor microenvironment both at the primary tumor site and at the metastatic site. This interaction occurs through direct cell to cell contact, or by the release of autocrine or paracrine factors which can activate pro-tumor signaling pathways and modulate tumor behavior. In this review, we will highlight recent advances in our current knowledge about the multiple interactions between breast cancer cells and neighboring cells (fibroblasts, endothelial cells, adipocytes, innate and adaptive immune cells) in the tumor microenvironment that coordinate to regulate metastasis. We also highlight the role of exosomes and circulating tumor cells in facilitating breast cancer metastasis. We discuss some key markers associated with stromal cells in the breast tumor environment and their potential to predict patient survival and guide treatment. Finally, we will provide some brief perspectives on how current technologies may lead to the development of more effective therapies for the clinical management of breast cancer patients.

Keywords: breast cancer; circulating tumor cells; exosomes; metastasis; prolactin inducible protein; tumor microenvironment.

Figure 1

The tumor microenvironment (TME) and breast cancer progression. At the onset of tumor initiation, the developing tumor is exposed to growth-suppressive signals from the inflammatory process, which is primarily modulated by cytotoxic T-lymphocytes, M1 macrophages and fibroblasts. The BC cells overcome these mechanisms by educating host stroma cells to acquire pro-tumorigenic features. Cytokines (TGF-β, IL-1β and TNF-α) released from the inflammatory process then modulate the differentiation of normal fibroblasts to cancer-associated fibroblasts (CAFs). The latter, in turn, secrete extracellular matrix proteins and soluble factors (TGF-β, CXCL12, IL-6) that stimulate epithelial to mesenchymal transition (EMT), tumor growth and progression. Neutrophils can induce EMT and promote tumor progression through cytokines release. Adipocytes secrete high-energy metabolites to fuel tumor growth. Tumor-associated macrophages (primarily M2 macrophages) support various processes within the TME, including BC growth and invasion by secreting pro-tumorigenic cytokines and growth factors. During tumor expansion, activated cytokines in the environment (CXCL5-CXCR2, TGF-β) stimulate the recruitment of regulatory T cells (T_reg) and myeloid-derived suppressor cells (MDSCs) which disrupt immune surveillance by inhibiting cytotoxic T lymphocytes, M1 macrophages and natural killer cells. BC cells can also escape immune surveillance by overexpressing the PD-L1 ligand. Such orchestrated events in the primary tumor allow tumor cells to acquire a mobile and invasive phenotype. Secreted factors (MMPs, VEGF) further facilitate tumor cells intravasation into the circulation. There, BC cells interact with platelets and M2 macrophages to support their survival by inhibiting immune recognition. Platelets escort tumor cells to the secondary sites, where it interacts with endothelial cells and promote extravasation. The preferred site of metastasis can be influenced by the subtype of the BC (Created with BioRender.com, accessed on 12 September 2021).

Figure 2

Host stromal cells at the metastatic site promote the establishment of the breast tumor. (A) In the bone microenvironment, chemoattractant released by osteoblasts recruit circulating tumor cells (CTCs) from the circulation to extravasate into the bone stroma. Once in the bone environment, interactions between BC cells and osteoblasts occur via JAG1/Notch and CAFs (through TGF-β), facilitating bone metastasis. There, BC cells then secrete factors to promote osteolysis, resulting in the release of factors that stimulate tumor growth, and thereby generating a vicious cycle. (B) In the lung capillaries, the expression of FAK, E-Selectin, VCAM1 and MMPs are involved in tumor extravasation to the lung parenchyma. Tumor cells now have the capacity to recruit monocytes from the circulation to differentiate into M2 macrophages, which then secrete pro-metastatic factors (VEGF, IL-1β). BC cells also secrete exosomes that stimulate CAF to release cytokines, growth factors and ECM components to create a pro-tumorigenic niche. (C) Once within the confines of the brain, tumor cells produce cathepsin S, MMPs and VEGF to overcome the blood-brain barrier in order to colonize the brain. They then stimulate astrocytes to secrete IL-6, IGF-1 and TGF-β that result in tumor expansion. Exosomes are also secreted by BC cells that stimulate microglia to support metastasis through WNT signaling. BC cells also take advantage of neurotransmitters secreted by neurons as bio-precursors to generate NADH that support tumor growth in the brain. (D) To promote their extravasation into the liver stroma, BC cells secrete exosomes that stimulate Kupffer cells to produce S100A8 resulting in liver-specific metastasis. BC cells also modulate M2 macrophages which also promote tumor extravasation. Hepatic stellate cells, secrete HGF, TGF-β and, PDGF to induce liver metastasis. Interaction of BC cell enriched in claudin-2 and hepatocytes also result in liver metastasis establishment (Created with BioRender.com, accessed on 12 September 2021).