The hypoxic tumor microenvironment: A driving force for breast cancer progression

Abstract

Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality. Hypoxia-inducible factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate secondary tumors. Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Keywords: Bone metastasis; Lung metastasis; Lymph node metastasis; Mesenchymal stem cells; Microvesicles; Myeloid-derived suppressor cells; Tumor-associated macrophages.

Fig. 1

Signaling between breast cancer cells (BCCs), mesenchymal stem cells (MSCs), myeloid-derived suppressor cells (MDSCs), and tumor associated macrophages (TAMs) stimulates metastasis. Large colored arrows indicate intercellular signaling through interaction of ligand with its cognate receptor. Thin black arrows indicate intracellular signaling activated by ligand-receptor interaction. Hypoxia-inducible factors directly activate transcription of the genes encoding the three ligands (CXCL16, PGF, CSF1) and two receptors (CCR5, CXCR3) in hypoxic BCCs.

Fig. 2

Collagen biogenesis. The formation of mature collagen fibers involves three different types of post-translational modification that are mediated by prolyl hydroxylase, lysyl hydroxylase, and lysyl oxidase family members. All of the enzymes shown are products of genes that are transactivated by hypoxia-inducible factors in hypoxic breast cancer cells.

Fig. 3

Hypoxia induces collagen deposition and fiber formation that stiffen the extracellular matrix (ECM). Hypoxia also induces RhoA/ROCK1-mediated myosin light chain (MLC) phosphorylation and focal adhesion kinase (FAK) activity that are required for actin-myosin contractility and cell motility on stiff ECM. Blue oval, protein encoded by a HIF target gene; purple oval, protein that is regulated by HIF-dependent RhoA/ROCK1 signaling.

Fig. 4

HIF-1 induces transcription of the WWTR1 and SIAH1 genes to increase TAZ expression and activity in hypoxic breast cancer cells. WWTR1 encodes TAZ, whereas SIAH1 encodes a ubiquitin protein ligase that targets LATS2 for proteasomal degradation, thereby eliminating a negative regulator of TAZ nuclear localization and transcriptional activity.

Fig. 5

HIF-1 activates the transcription of genes that control multiple steps in the metastatic process. Blue, red, yellow, and orange ovals denote bulk cancer cells, cancer stem cells, bone marrow-derived cells (mesenchymal stem cells, myeloid-derived suppressor cells and tumor associated macrophages), and extracellular vesicles (exosomes and microvesicles) respectively. Cancer stem cells give rise to both stem cells and non-stem cells and can initiate secondary (metastatic) tumors.