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.

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Clinically, both HIF-1a and CAIX up-regulation have been associated with poor overall and relapse-free survival. 96 A paper by Wicha and colleagues at the University of Michigan Comprehensive Cancer Center (Ann Arbor, MI, USA) demonstrated how antiangiogenic therapy with either bevacizumab or sunitinib could increase cancer stem cells in orthotropic breast xenograft models by making tumours more hypoxic, thereby activating HIF-1a. These findings suggest that combining antiangiogenic therapy with inhibitors of HIF-1a will be an improvement over antiangiogenic therapy alone.…”

“…Surface marker studies confirmed that hypoxia induces stem cell-like phenotypes and thus leads to tumour aggressiveness and poor prognosis. 96 Conversely, cancer stem cells use induced hypoxia to protect from DNA damage by reduction of reactive oxygen species. This can be achieved by activating HIF-1a, which is preferentially expressed in cancer stem cells compared with other cancer cells in the same tissue.…”

“…114 Other evidence of the role of HIF-1 in cancer stem cell regulation is covered in a review by Sarkar and colleagues at Wayne State University (Detroit, MI, USA). 96 In brief, activation of HIF-1 enhances the expression of stem cell-associated genes such as Oct4, Nanog, c-Myc, Notch-1, and CD133 pathways. Moreover, factors downstream of HIF-1 such as CAIX can regulate the acidic microenvironment of surrounding cancer stem cells.…”

“…93,94 Other HIF-1a endogenous regulators include the von Hippel-Lindau (VHL) tumour suppressor protein, which facilitates its degradation through the ubiquitin pathway. 95 Other endogenous inhibitors of HIF-1a are listed in Bao et al 96 They include oxygen-sensitive factorinhibition HIF (FIH); p53; phosphatase and tensin homologue (PTEN) and liver kinase B1 (LKB1). Recent studies showed the role of miRNAs in regulating HIF-1a expression.…”

“…Inhibition and knockdown of both HIF-1a and HIF-2a increased tumour sensitivity to radiotherapy. 96 A meta-analysis study of more than 4800 patients connected hypoxic modification of radiotherapy and improved therapeutic benefit in patients with head and neck cancer. 128 Janssen et al synthesized an RGD-peptide (described in Section 8.2.2) labeled with radioactive Yttrium-90 ( 90 Y) to target the a v b 3 integrins on the endothelium associated with OVCAR-3 ovarian tumour xenografts.…”