The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness

Abstract

Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. It has been well recognized that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotypic cells are associated with therapeutic resistance and contribute to aggressive tumor growth, invasion, metastasis and believed to be the cause of tumor recurrence. Interestingly, hypoxia and HIF signaling pathway are known to play an important role in the regulation and sustenance of CSCs and EMT phenotype. However, the molecular relationship between HIF signaling pathway with the biology of CSCs and EMT remains unclear although NF-κB, PI3K/Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT. In this article, we will discuss the state of our knowledge on the role of HIF-hypoxia signaling pathway and its kinship with CSCs and EMT within the tumor microenvironment. We will also discuss the potential role of hypoxia-induced microRNAs (miRNAs) in tumor development and aggressiveness, and finally discuss the potential effects of nutraceuticals on the biology of CSCs and EMT in the context of tumor hypoxia.

Fig. 1

Hypoxia driven tumor angiogenesis. Hypoxic tumor microenvironment enhanced through desmoplasmic stroma results in activation of HIF proteins that influences aberrant miRNA expression dependent angiogenic signaling resulting in tumor angiogenesis.

Fig. 2

Hypoxia as a driver of aggressive tumor phenotype. HIF (HIF-1α and HIF-2α) activation drives two critical tumor promoting pathways (1) increase in CSC markers (Oct4, Nanog, Sox2 and Snail) and (2) EMT promoting markers (ZEB2, Snail, Twist, Wnt, Slug, Notch and TGF-β). These HIF driven pathways interact with one another leading to enrichment/enhancement in both CSC and EMT cell populations that in turn is a driver of aggressive tumor type.

Fig. 3

Potential pathways linking hypoxia to CSCs and EMT in tumor aggressiveness. Hypoxic stress increases the stability and expression of the HIFs, especially HIF-1 and 2 in the cells under tumor microenvironment. The activation of HIF signaling pathways up-regulate (1) tumor angiogenesis via the regulation of VEGF, VEGFR1, and Ang-2; (2) the maintenance of CSC phenotype and function via the regulation of Oct4, Nanog, and Sox2; (3) the induction of EMT characteristics via regulation of ZEB2, Snail, Twist, Slug, TGF-β, Wnt, and Notch; and (4) the metabolic adaptation of hypoxic stress via regulation of Glut 1,2, CAIX, LDH-5, IGF-2, and BNIP3. These regulations result in tumor growth, invasion, metastasis, treatment resistance, and recurrence. Complex interlinking of HIF pathway to NF-κB, Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways increases the contribution of HIF signaling pathway to tumor aggressiveness by the regulation of angiogenesis, CSCs, EMT, and metabolic shifts. Hypoxia also induces the altered expression of miRNAs, for examples, the up-regulation of miR-21, miR-210, and miR-373; and the down-regulation of let-7, miR-20, miR-22, and miR-101 in the tumor cells. The deregulation of the hypoxia-associated miRNAs may enhance tumor angiogenesis, CSC and EMT characteristics through the modulation of multiple signaling pathways. Natural agents such as isoflavones, curcumin, DIM, lycopene, resveratrol, and EGCG have been demonstrated to modulation of these signaling pathways, potentially by the differential regulation of hypoxia-mediated miRNAs, leading to the inhibition/attenuation of tumor aggressiveness.