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Review
. 2016 Jun;2(6):295-304.
doi: 10.1016/j.trecan.2016.05.006. Epub 2016 Jun 2.

Hypoxia: Signaling the Metastatic Cascade

Erinn B Rankin  1 , Jin-Min Nam  2 , Amato J Giaccia  3
Affiliations
Review

Hypoxia: Signaling the Metastatic Cascade

Erinn B Rankin et al. Trends Cancer. 2016 Jun.

Abstract

Hypoxia is a potent microenvironmental factor that promotes tumor metastasis. Recent studies have revealed mechanisms by which hypoxia and activation of hypoxia inducible factor (HIF)-dependent signaling promotes metastasis through the regulation of metabolic reprogramming, the stem cell phenotype, invasion, angiogenesis, immune suppression, the premetastatic niche, intravasation and/or extravasation, and resistance to apoptosis. These discoveries suggest novel paradigms in tumor metastasis and identify new opportunities for therapeutic intervention in the prevention and treatment of metastatic disease. Here, we review the impact of hypoxia and hypoxic signaling pathways in tumor and stromal cells on each step of the metastatic cascade.

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Figures

Figure 1
Figure 1. Hypoxia in the primary tumor promotes metastasis
Hypoxia within the tumor microenvironment stabilizes the hypoxia inducible factors (HIF-1 and HIF-2) in tumor and stromal cells leading to the activation of target gene programs that facilitate metastasis.
Figure 2
Figure 2. Mechanisms by which hypoxic signaling promotes metastasis to the liver
Hypoxia is a significant barrier for metastatic colonization in the liver. Disseminated colon cancer cells are dependent upon the expression of creatine kinase B (CKB) to adapt to metabolic stress associated with acute hypoxia. CKB catalyzes the phosphorylation of creatine using extracellular ATP. This allows tumor cells to generate ATP from extracellular sources of phospho-creatine during metabolic stress. Disseminated breast cancer cells also metabolically adapt to the hypoxic liver microenvironment through HIF-1 dependent upregulation of pyruvate dehydrogenase kinase 1 (PDK1). PDK1 expression promotes the generation of ATP through glycolysis by antagonizing the function of pyruvate dehydrogenase, a rate-limiting enzyme for pyruvate conversion to acetyl-coenzyme A and entry into the tricarboxylic acid cycle (TCA).
Figure 3
Figure 3. Mechanisms by which hypoxic signaling promotes metastasis to the lung
Hypoxic signaling promotes extravasation in the lung by upregulating the expression and secretion of proteins including lysyl oxidase (LOX), LOX like proteins (LOXL2 and LOXL4), and vascular endothelial growth factor (VEGF). LOX, LOXL2, and LOXL4 remodel extracellular matrix proteins, such as collagen, to recruit bone marrow derived cells (BMDCs) into the lung. BMDCs prime the lung microenvironment for metastatic colonization by producing chemokines such as stromal derived factor-1 (SDF-1) that recruit CXCR4 expressing tumor cells to the lung. HIF signaling also directly promotes tumor extravasation in the lung through the upregulation of factors that promote tumor-endothelial cell adhesions (L1 cell adhesion molecule, L1CAM) and decrease endothelial cell – cell adhesion (angiopoietin-like 4, ANGPTL4).
Figure 4
Figure 4. Mechanisms by which hypoxic signaling promotes metastasis to the bone
Tumor cells secrete factors such as lysyl oxidase (LOX) and parathyroid related protein (PTHrP) into the circulation where they precondition the bone marrow microenvironment for metastatic colonization. PTHrP and LOX modulate the activities of osteoblasts and osteoclasts to promote bone resorption and tumor growth. Additionally, HIF mediated upregulation of the chemokine receptor C-X-C motif receptor -4 (CXCR4) may promote breast tumor cell homing to the bone marrow microenvironment where the expression of its ligand, stromal derived factor-1 (SDF-1) is highly expressed by osteoblasts and other cells within the bone marrow microenvironment.
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