Hyperoxic-hypoxic Paradox: Breast Cancer Microenvironment and an Innovative Treatment Strategy


Cite item

Full Text

Abstract

A small therapeutic range of oxygen is required for effective metabolism. As a result, hypoxia (low oxygen concentration) is one of the most potent inducers of gene expression, metabolic alterations, and regenerative processes, such as angiogenesis, stem cell proliferation, migration, and differentiation. The cellular response is controlled by sensing the increased oxygen levels (hyperoxia) or hypoxia via specific chemoreceptor cells. Surprisingly, changes in free oxygen concentration instead of absolute oxygen levels may be regarded as a deficiency of oxygen at the cellular level. Recurrent intermittent hyperoxia may trigger many mediators of cellular pathways typically generated during hypoxia. The dilemma of hyperoxic-hypoxic conditions is known as the hyperoxic-hypoxic paradox. According to the latest data, the hypoxic microenvironment, crucial during cancer formation, has been demonstrated to play a key role in regulating breast cancer growth and metastasis. Hypoxic circumstances cause breast cancer cells to respond in a variety of ways. Transcription factors are identified as hypoxia-inducible factors (HIFs) that have been suggested to be a factor in the pathobiology of breast cancer and a possible therapeutic target, driving the cellular response to hypoxia. Breast cancer has a dismal prognosis due to a high level of resistance to practically all well-known cancer management that has been related to hypoxia-based interactions between tumor cells and the stromal milieu. We attempt to review the enigma by exploring the starring roles of HIFs in breast cancer, the HIF paradox, and the hyperoxic-hypoxic enigma.

About the authors

Suman Ray

,

Email: info@benthamscience.net

Sukhes Mukherjee

Department of Biochemistry, All India Institute of Medical Science

Author for correspondence.
Email: info@benthamscience.net

References

  1. Thiemens, M.H. Oxygen origins. Nat. Chem., 2012, 4(1), 66. doi: 10.1038/nchem.1226 PMID: 22169875
  2. Michiels, C. Physiological and pathological responses to hypoxia. Am. J. Pathol., 2004, 164(6), 1875-1882. doi: 10.1016/S0002-9440(10)63747-9 PMID: 15161623
  3. Hadanny, A.; Efrati, S. The hyperoxic-hypoxic paradox. Biomolecules, 2020, 10(6), 958. doi: 10.3390/biom10060958 PMID: 32630465
  4. Todd, V.M.; Johnson, R.W. Hypoxia in bone metastasis and osteolysis. Cancer Lett., 2020, 489, 144-154. doi: 10.1016/j.canlet.2020.06.004 PMID: 32561416
  5. Johnson, R.W.; Sowder, M.E.; Giaccia, A.J. Hypoxia and bone metastatic disease. Curr. Osteoporos. Rep., 2017, 15(4), 231-238. doi: 10.1007/s11914-017-0378-8 PMID: 28597139
  6. Meneses, A.M.; Wielockx, B. PHD2: From hypoxia regulation to disease progression. Hypoxia, 2016, 4, 53-67. PMID: 27800508
  7. Corcoran, S.E.; O’Neill, L.A.J. HIF1α and metabolic reprogramming in inflammation. J. Clin. Invest., 2016, 126(10), 3699-3707. doi: 10.1172/JCI84431 PMID: 27571407
  8. Ray, S.K.; Mukherjee, S. Consequences of extracellular matrix remodeling in headway and metastasis of cancer along with novel immunotherapies: A great promise for future endeavor. Anticancer Agents Med. Chem., 2022, 22(7), 1257-1271. doi: 10.2174/1871520621666210712090017 PMID: 34254930
  9. Mukherjee, S.; Ray, S.K. Imitating hypoxia and tumor microenvironment with immune evasion by employing three dimensional in vitro cellular models: impressive tool in drug discovery. Recent Patents Anticancer Drug Discov., 2022, 17(1), 80-91. doi: 10.2174/1574892816666210728115605 PMID: 34323197
  10. Mukherjee, S.; Ray, S.K. Targeting tumor hypoxia and hypoxia-inducible factors (HIFs) for the treatment of cancer- A story of transcription factors with novel approach in molecular medicine. Curr. Mol. Med., 2022, 22(4), 285-286. doi: 10.2174/156652402204220325161921 PMID: 35603885
  11. Davis, N.M.; Sokolosky, M.; Stadelman, K.; Abrams, S.L.; Libra, M.; Candido, S.; Nicoletti, F.; Polesel, J.; Maestro, R.; D’Assoro, A.; Drobot, L.; Rakus, D.; Gizak, A.; Laidler, P.; Dulińska-Litewka, J.; Basecke, J.; Mijatovic, S.; Maksimovic-Ivanic, D.; Montalto, G.; Cervello, M.; Fitzgerald, T.L.; Demidenko, Z.N.; Martelli, A.M.; Cocco, L.; Steelman, L.S.; McCubrey, J.A. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: Possibilities for therapeutic intervention. Oncotarget, 2014, 5(13), 4603-4650. doi: 10.18632/oncotarget.2209 PMID: 25051360
  12. Hamanaka, R.B.; Chandel, N.S. Mitochondrial reactive oxygen species regulate hypoxic signaling. Curr. Opin. Cell Biol., 2009, 21(6), 894-899. doi: 10.1016/j.ceb.2009.08.005 PMID: 19781926
  13. Tam, S.Y.; Wu, V.W.C.; Law, H.K.W. Hypoxia-induced epithelial-mesenchymal transition in cancers: HIF-1α and beyond. Front. Oncol., 2020, 10, 486. doi: 10.3389/fonc.2020.00486 PMID: 32322559
  14. Echevarría, M.; Muñoz-Cabello, A.M.; Sánchez-Silva, R.; Toledo-Aral, J.J.; López-Barneo, J. Development of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expression. J. Biol. Chem., 2007, 282(41), 30207-30215. doi: 10.1074/jbc.M702639200 PMID: 17673462
  15. Choudhury, R. Hypoxia and hyperbaric oxygen therapy: A review. Int. J. Gen. Med., 2018, 11, 431-442. doi: 10.2147/IJGM.S172460 PMID: 30538529
  16. Koh, M.Y.; Darnay, B.G.; Powis, G. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol. Cell. Biol., 2008, 28(23), 7081-7095. doi: 10.1128/MCB.00773-08 PMID: 18838541
  17. Hewitson, K.S.; McNeill, L.A.; Riordan, M.V.; Tian, Y.M.; Bullock, A.N.; Welford, R.W.; Elkins, J.M.; Oldham, N.J.; Bhattacharya, S.; Gleadle, J.M.; Ratcliffe, P.J.; Pugh, C.W.; Schofield, C.J. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem., 2002, 277(29), 26351-26355. doi: 10.1074/jbc.C200273200 PMID: 12042299
  18. Belisario, D.C.; Kopecka, J.; Pasino, M.; Akman, M.; De Smaele, E.; Donadelli, M.; Riganti, C. Hypoxia dictates metabolic rewiring of tumors: Implications for chemoresistance. Cells, 2020, 9(12), 2598. doi: 10.3390/cells9122598 PMID: 33291643
  19. Herrera-Campos, A.B.; Zamudio-Martinez, E.; Delgado-Bellido, D.; Fernández-Cortés, M.; Montuenga, L.M.; Oliver, F.J.; Garcia-Diaz, A. Implications of hyperoxia over the tumor microenvironment: An overview highlighting the importance of the immune system. Cancers, 2022, 14(11), 2740. doi: 10.3390/cancers14112740 PMID: 35681719
  20. Ristescu, A.I.; Tiron, C.E.; Tiron, A.; Grigoras, I. Exploring hyperoxia effects in cancer—from perioperative clinical data to potential molecular mechanisms. Biomedicines, 2021, 9(9), 1213. doi: 10.3390/biomedicines9091213 PMID: 34572400
  21. Tiron, A.; Ristescu, I.; Postu, P.A.; Tiron, C.E.; Zugun-Eloae, F.; Grigoras, I. Long-term deleterious effects of short-term hyperoxia on cancer progression—is brain-derived neurotrophic factor an important mediator? An experimental study. Cancers, 2020, 12(3), 688. doi: 10.3390/cancers12030688 PMID: 32183322
  22. Jomova, K.; Raptova, R.; Alomar, S.Y.; Alwasel, S.H.; Nepovimova, E.; Kuca, K.; Valko, M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch. Toxicol., 2023, 97(10), 2499-2574. doi: 10.1007/s00204-023-03562-9 PMID: 37597078
  23. Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in cancer. Vasc. Health Risk Manag., 2006, 2(3), 213-219. doi: 10.2147/vhrm.2006.2.3.213 PMID: 17326328
  24. Golhani, V.; Ray, S.K.; Mukherjee, S. Role of MicroRNAs and long non-coding RNAs in regulating angiogenesis in human breast cancer: A molecular medicine perspective. Curr. Mol. Med., 2022, 22(10), 882-893. doi: 10.2174/1566524022666211217114527 PMID: 34923940
  25. Zhang, Y.; Zhang, H.; Wang, M.; Schmid, T.; Xin, Z.; Kozhuharova, L.; Yu, W.K.; Huang, Y.; Cai, F.; Biskup, E. Hypoxia in breast cancer—scientific translation to therapeutic and diagnostic clinical applications. Front. Oncol., 2021, 11, 652266. doi: 10.3389/fonc.2021.652266 PMID: 33777815
  26. Kim, J.; Bae, J.S. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm., 2016, 2016, 1-11. doi: 10.1155/2016/6058147 PMID: 26966341
  27. Baek, J.H.; Jang, J.E.; Kang, C.M.; Chung, H.Y.; Kim, N.D.; Kim, K.W. Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene, 2000, 19(40), 4621-4631. doi: 10.1038/sj.onc.1203814 PMID: 11030151
  28. Infantino, V.; Santarsiero, A.; Convertini, P.; Todisco, S.; Iacobazzi, V. Cancer cell metabolism in hypoxia: Role of HIF-1 as key regulator and therapeutic target. Int. J. Mol. Sci., 2021, 22(11), 5703. doi: 10.3390/ijms22115703 PMID: 34071836
  29. Gilkes, D.M.; Semenza, G.L. Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol., 2013, 9(11), 1623-1636. doi: 10.2217/fon.13.92 PMID: 24156323
  30. Cai, F.F.; Xu, C.; Pan, X.; Cai, L.; Lin, X.Y.; Chen, S.; Biskup, E. Prognostic value of plasma levels of HIF-1a and PGC-1a in breast cancer. Oncotarget, 2016, 7(47), 77793-77806. doi: 10.18632/oncotarget.12796 PMID: 27780920
  31. Hung, S.P.; Yang, M.H.; Tseng, K.F.; Lee, O.K. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant., 2013, 22(10), 1869-1882. doi: 10.3727/096368912X657954 PMID: 23067574
  32. Kummar, S.; Raffeld, M.; Juwara, L.; Horneffer, Y.; Strassberger, A.; Allen, D.; Steinberg, S.M.; Rapisarda, A.; Spencer, S.D.; Figg, W.D.; Chen, X.; Turkbey, I.B.; Choyke, P.; Murgo, A.J.; Doroshow, J.H.; Melillo, G. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors. Clin. Cancer Res., 2011, 17(15), 5123-5131. doi: 10.1158/1078-0432.CCR-11-0682 PMID: 21673063
  33. Wong, C.C.L.; Gilkes, D.M.; Zhang, H.; Chen, J.; Wei, H.; Chaturvedi, P.; Fraley, S.I.; Wong, C.M.; Khoo, U.S.; Ng, I.O.L.; Wirtz, D.; Semenza, G.L. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl. Acad. Sci. USA, 2011, 108(39), 16369-16374. doi: 10.1073/pnas.1113483108 PMID: 21911388
  34. Hunter, F.W.; Wouters, B.G.; Wilson, W.R. Hypoxia-activated prodrugs: Paths forward in the era of personalised medicine. Br. J. Cancer, 2016, 114(10), 1071-1077. doi: 10.1038/bjc.2016.79 PMID: 27070712

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers