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

Oncogene. 2013 Aug 29;32(35):4057-63. doi: 10.1038/onc.2012.578. Epub 2012 Dec 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Bone Marrow Cells / physiology
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / pathology*
  • Cell Communication
  • Cell Movement
  • Cell Proliferation
  • Endothelial Cells / physiology
  • Humans
  • Hypoxia-Inducible Factor 1 / physiology*
  • Lipoxygenase / physiology
  • Lymphangiogenesis*
  • Lymphatic Metastasis
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / etiology*
  • Stromal Cells / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • endothelial PAS domain-containing protein 1
  • Lipoxygenase