Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis

Abstract

Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O2 availability induces the activity of hypoxia-inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins, which are secreted by hypoxic breast cancer cells, remodel extracellular matrix in the lungs, which leads to BMDC recruitment and metastatic niche formation.

Figure 1

Functional interactions between breast cancer cells and stromal cells that are mediated by the HIF-dependent expression of secreted factors. In response to hypoxia, HIFs are induced and activate transcription of genes encoding angiopoietin-like 4 (ANGPTL4), L1 cell adhesion molecule (L1CAM), lysyl oxidase (LOX), LOX-like 2 (LOXL2), LOXL4, platelet-derived growth factor B (PDGF-B), stem cell factor (SCF), stromal-derived factor 1 (SDF1), and vascular endothelial growth factor (VEGF). These factors promote functional interactions with blood endothelial cells (BECs), lymphatic endothelial cells (LECs) bone marrow-derived angiogenic cells (BMDACs), and other bone marrow-derived cells (BMDCs). These interactions promote angiogenesis, lymphangiogenesis, lymphatic metastasis, metastatic niche formation, and blood vessel (hematogenous) metastasis.

Figure 2

Deconvolution of steps involved in hematogenous metastasis of cancer cells. The process includes the invasion of a cancer cell into a blood vessel within the primary tumor (intravasation); survival of the cancer cell in the circulation; adherence of the cancer cell to the endothelium of a blood vessel in a distant tissue (margination); migration through the endothelium (extravasation); and cancer cell survival and proliferation at the distant site (colonization), which requires prior metastatic niche formation.