HIF-1 at the crossroads of hypoxia, inflammation, and cancer

Abstract

The complex cross-talk of intricate intercellular signaling networks between the tumor and stromal cells promotes cancer progression. Hypoxia is one of the most common conditions encountered within the tumor microenvironment that drives tumorigenesis. Most responses to hypoxia are elicited by a family of transcription factors called hypoxia-inducible factors (HIFs), which induce expression of a diverse set of genes that assist cells to adapt to hypoxic environments. Among the three HIF protein family members, the role of HIF-1 is well established in cancer progression. HIF-1 functions as a signaling hub to coordinate the activities of many transcription factors and signaling molecules that impact tumorigenesis. This mini review discusses the complex role of HIF-1 and its context-dependent partners under various cancer-promoting events including inflammation and generation of cancer stem cells, which are implicated in tumor metastasis and relapse. In addition, the review highlights the importance of therapeutic targeting of HIF-1 for cancer prevention.

Keywords: HIF-1; cancer stem cells; drug resistance; hypoxia; inflammation; microenvironment.

Figure 1. Hypoxia/HIF-1 links several pathways involved in tumor aggressiveness

Scheme representing cellular functions regulated by HIF-1 and showing examples of direct target genes involved in various signaling pathways. Examples of existing inhibitors and/or FDA-approved drugs, which are specific to various HIF-1 regulated genes/pathways, are shown. CXCR4, Chemokine receptor 4; Nanog; Homeobox transcription factor; Oct-4, Octamer-binding transcription factor 4; Snail, Zinc finger transcriptional repressor; Sox-2, Sex determining region Y box-2; Twist, Basic helix-loop-helix transcription factor.

Figure 2. Simplified illustration showing tumor promoting cell-cell interactions within the tumor microenvironment supported by HIF-1 activity

Hypoxia, inflammatory conditions and genetic alterations activate HIF-1 that mediates cross-talk between tumor and multiple stromal cell types through specific factors, only a few of which are shown (for details see text). Details about role of MSCs in immune suppression, EMT, and stemness can be found in this recent review.

Figure 3. Partners in Crime

Scheme summarizing the collaborators of HIF-1 in the signaling pathways associated with hypoxia adaptation, cancer progression and cancer-associated inflammation (see text for details).