Hypoxic control of metastasis

Abstract

Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.

Fig. 1. Mechanisms of HIF-1 and HIF-2 activation in tumor cells

Hypoxia is a common mechanism of HIF activation in cancer. Under normoxic conditions, PHD enzymes (also called EGLN 1–3) utilize oxygen as a substrate to hydroxylate key proline residues located within the HIF-α subunit. This hydroxylation event mediates pVHL binding and subsequent ubiquitination and degradation by the 26S proteasome. Under conditions of hypoxia or loss of pVHL, HIF-α is stabilized and translocates to the nucleus, where it heterodimerizes with ARNT and binds to hypoxia response elements (HREs) within regulatory regions of target genes. The HIF heterodimer activates gene expression at these sites upon cofactor (p300/CBP) recruitment. PRC2-mediated histone methylation can inhibit the activation of HIF target genes involved in metastasis. HIF activity can also be induced in tumor cells through mechanisms that enhance HIF-α production (TORC1, YB-1) or prevent its degradation (UCHL1, WSB1).

Fig. 2. HIF signaling regulates multiple steps within the metastatic cascade

Highlighted in brackets are direct target genes of HIF that promote each step of metastasis (to the lung, in the example shown). ECM, extracellular matrix; BMDC, bone marrow–derived cell.

Fig. 3. Mechanisms of metabolic reprogramming in liver metastasis

The liver microenvironment is hypoxic. Pimonidazole staining (brown) demonstrates areas of hypoxia in the liver (middle panel). Metastatic tumor cells enter hypoxic regions of the liver and must metabolically adapt to survive the metabolic stress associated with hypoxia. Disseminated breast cancer cells (right) metabolically adapt by increasing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and promoting glycolytic reprogramming. Disseminated colon cancer cells (left) metabolically adapt by increasing the expression and secretion of creatine kinase brain-type (CKB). This enzyme controls the amount of rapidly mobilized high-energy phosphates by catalyzing the transfer of a high-energy phosphate group from ATP to the metabolite creatine, producing phosphocreatine. Under conditions of metabolic stress, such as hypoxia, tumor cells utilize phosphocreatine stores as a source of high-energy phosphate that can be transferred to ADP to generate ATP.