Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells.
TLDR
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.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.read more
Citations
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Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.
Suzanne A. Eccles,Eric O. Aboagye,Simak Ali,Annie S. Anderson,Jo Armes,Fedor Berditchevski,Jeremy P. Blaydes,Keith Brennan,Nicola J. Brown,Helen E. Bryant,Nigel J Bundred,Joy Burchell,Anna Campbell,Jason S. Carroll,Robert Clarke,Charlotte E. Coles,Gary Cook,Angela Cox,Nicola J. Curtin,Lodewijk V. Dekker,Isabel dos Santos Silva,Stephen W. Duffy,Douglas F. Easton,Diana Eccles,Dylan R. Edwards,Joanne Edwards,D. G. R. Evans,Deborah Fenlon,James M. Flanagan,Claire Foster,William M. Gallagher,Montserrat Garcia-Closas,Julia Margaret Wendy Gee,Andy J. Gescher,Vicky Goh,Ashley M. Groves,Amanda J. Harvey,Michelle Harvie,Bryan T. Hennessy,Stephen Edward Hiscox,Ingunn Holen,Sacha J Howell,Anthony Howell,Gill Hubbard,Nicholas J. Hulbert-Williams,Myra S. Hunter,Bharat Jasani,Louise J. Jones,Timothy J. Key,Cliona C. Kirwan,Anthony Kong,Ian Kunkler,Simon P. Langdon,Martin O. Leach,David J. Mann,John Marshall,Lesley Ann Martin,Stewart G. Martin,Jennifer E. Macdougall,David Miles,William R. Miller,Joanna R. Morris,Sue Moss,Paul B. Mullan,Rachel Natrajan,James P B O'Connor,Rosemary O'Connor,Carlo Palmieri,Paul D.P. Pharoah,Emad A. Rakha,Elizabeth Reed,Simon P. Robinson,Erik Sahai,John M. Saxton,Peter Schmid,Matthew J. Smalley,Valerie Speirs,Robert Stein,John Stingl,Charles H. Streuli,Andrew Tutt,Galina Velikova,Rosemary A. Walker,Christine J. Watson,Kaye J. Williams,Leonie S. Young,Alastair M. Thompson +86 more
TL;DR: With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
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HIF-1 at the crossroads of hypoxia, inflammation, and cancer.
TL;DR: 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 are discussed.
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