Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jan;17(1):30-54.
doi: 10.1111/jcmm.12004. Epub 2013 Jan 10.

Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells

Murielle Mimeault  1 , Surinder K Batra
Affiliations

Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells

Murielle Mimeault et al. J Cell Mol Med. 2013 Jan.

Abstract

Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3'-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency-associated transcription factors (Oct-3/4, Nanog and Sox-2), glycolysis- and epithelial-mesenchymal transition (EMT) programme-associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self-renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Cellular events and signalling elements involved in the regulation of the stabilization and activation of hypoxia-inducible factors. The increase in the stability and activation of HIFs, HIF-1α and HIF-2α, in cancer cells including cancer stem/progenitor cells, which may be induced via different growth factor and cytokine pathways under normoxic and hypoxic conditions, hypoxic microenvironment and inflammation are illustrated. The potential cellular signalling elements modulated through the up-regulation of HIFs and which can contribute to high self-renewal, altered glycolytic metabolism, invasion, metastases, treatment resistance and disease relapse are also indicated. BCRP/ABCG2: breast cancer resistance protein; CAIX: carbonic anhydrase; EGFR: epidermal growth factor receptor; GLUT: glucose transporter; IL-6: interleukin-6; MAPK: mitogen-activated protein kinase; MCT-4: monocarboxylate transporter-4; MIC-1: macrophage inhibitory cytokine-1; MMPs: metalloproteinases; mTOR: molecular target of rapamycin; NF-κB: nuclear factor-κB; RTK: receptor tyrosine kinase; PI3K: phosphatidylinositol 3′-kinase; PGK1: phosphoglycerate kinase 1; PKM: pyruvate kinase M; P-gp: P-glycoprotein; ROS: reactive oxygen species; TGF-β: transforming growth factor-β; TNF-α: tumour necrosis factor-α; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor.
Fig. 2
Fig. 2
Proposed model of malignant transforming events associated with cancer progression and metastases driving hypoxia and enhanced expression of HIFs in cancer stem/progenitor cells. Genetic and epigenetic alterations occurring in tissue-resident adult stem/progenitor cells during intense injury, oxidative stress, inflammation and/or ageing may result in their malignant transformation into tumourigenic cancer stem/progenitor cells also designated cancer-initiating cells that are able to generate the bulk mass of heterogeneous and differentiated cancer cells within tumour. The scheme also shows the potential localization of clusters of cancer stem/progenitor cells expressing HIFs at the hypoxic region near a necrotic areas and invasive front of the primary tumour. The enhanced expression of HIFs in highly tumourigenic cancer stem/progenitor cells and their differentiated progenies, which may be induced under hypoxia or sustained activation of growth factor pathways and PI3K/Akt/mTOR under normoxic and hypoxic conditions, may promote the EMT programme, altered metabolic pathways and re-expression of stem cell-like markers such as Oct-3/4, Sox-2 and Nanog and pro-angiogenic factor VEGF. These molecular transforming events in turn may contribute to the acquisition of a more malignant behaviour and migratory ability by cancer cells and tumour neovascularization. Moreover, bi-directional cross-talks between cancer cells and stromal myofibroblasts found within their local tumour microenvironment also may promote their gain of more aggressive phenotypes. Hence, highly tumourigenic and migratory cancer stem/progenitor cells with stem cell-like properties that survive under stressful conditions, including low oxygen tension and nutrient deprivation, during primary cancer progression and reach the invasive front of primary tumour can be involved in dissemination and metastatic spread at near lymph nodes and distant tissues. The disseminated cancer stem/progenitor cells that are able to survive in their novel microenvironment prevalent at metastatic sites can give rise to the total mass of differentiated cancer cells forming secondary tumours. The preferential migration of cancer cells to pre-metastatic niches induced by different soluble factors released from primary tumour and bone marrow-derived cells (BMDCs) at distant sites is also illustrated.
Fig. 3
Fig. 3
Scheme showing the potential molecular events induced in cancer cells in the hypoxic tumour microenvironment. The intracellular consequences of decreased oxygen level (hypoxia) in cancer cells including the switch of mitochondrial oxidative phosphorylation to anaerobic glycolysis and enhanced nuclear translocation of HIF-α subunit are illustrated. The enhanced stabilization and activation of HIF-1α and HIF-2α and their formation of nuclear heterodimers with HIF-β receptor in cancer cells under hypoxia that in turn may result in the transcriptional activation of numerous gene products involved in anaerobic glycolysis, pH regulation, self-renewal, survival and induction of angiogenic switch and metastases are indicated. The enhanced cellular accumulation and activation of HIF-α protein subunit which may be induced through the stimulation of different receptor tyrosine kinases (RTKs) in cancer cells under normoxic and hypoxic conditions are also illustrated. Particularly, the stimulation of RTKs may lead to the sustained activation of phosphatidylinositol 3′-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) pathway that in turn may induce the translational machinery and HIF protein synthesis and/or enhanced stabilization of HIF-α subunit. Moreover, the activation of RTKs may result in the stimulation of nuclear factor-kappaB (NF-κB) that in turn can induce the transcriptional up-regulation of HIFs. ABCG2/BCRP: breast cancer resistance protein; CAIX: carbonic anhydrase IX; COX-2: clyooxygenase-2; ECM: extracellular matrix; FOXO3A: forehead 3A; GLUT: glucose transporter; HIFs: hypoxia-inducible factors; IAP: inhibitor of apoptosis protein; IL-6: interleukin-6; MAPK: mitogen-activated protein kinase; MCT: monocarboxylate transporter; MIC-1: macrophage inhibitory cytokine-1; MMPs: matrix metalloproteinases; pHe: extracellular pH; pHi: intracellular pH; PGK1: phosphoglycerate kinase 1; PKM: pyruvate kinase M; VEGF: vascular endothelial growth factor.
Fig. 4
Fig. 4
Proposed model of potential transforming events occurring in hypoxic cancer cells during epithelial cancer progression and bone metastasis. The up-regulated expression levels of stem cell-like phenotypes, HIFs, CXC chemokine receptor (CXCR4) and occurrence of the EMT programme in prostate or breast cancer cells within the hypoxic region at the invasive front of the primary tumour may lead to their invasion and dissemination through the peripheral circulation and homing at distant metastatic sites. More specifically, circulating prostate or breast cancer cells expressing high level of CXCR4 can preferentially disseminate and home to specific metastatic sites such as bones at least in part through the chemoattractant gradient formed by stromal cell-derived factor-1 (SDF-1) released by endothelial cells. The hypoxia-adapted prostate or breast cancer cells may compete with long-term haematopoietic stem cells (LT-HSCs) to occupy the hypoxic endosteal niche within BM and survive under a dormant state for a short or long period of time. The activation of dormant prostate or breast cancer cells may occur through the release of different growth factors and cytokines by cancer cells and stromal host cells under specific microenvironmental conditions. The activated prostate or breast cancer cells can give rise to the total tumour cell mass and skeletal metastasis formation. The bone metastases of prostate cancer cells are predominantly associated with the formation of osteoblastic lesions (bone formation), whereas bone metastases of breast cancer cells are generally related with the formation of osteolytic lesions (bone destruction).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1 alpha in common human cancers and their metastases. Cancer Res. 1999;59:5830–5. - PubMed
    1. Cangul H, Salnikow K, Yee HZ, et al. Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect. 2002;110:783–8. - PMC - PubMed
    1. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16:1151–62. - PubMed
    1. Mathieu J, Zhang Z, Zhou W, et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res. 2011;71:4640–52. - PMC - PubMed
    1. Jubb AM, Buffa FM, Harris AL. Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis. J Cell Mol Med. 2010;14:18–29. - PMC - PubMed

Publication types

MeSH terms

Substances