Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Review

The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment

Authors: Asieh Emami Nejad, Simin Najafgholian, Alireza Rostami, Alireza Sistani, Samaneh Shojaeifar, Mojgan Esparvarinha, Reza Nedaeinia, Shaghayegh Haghjooy Javanmard, Marjan Taherian, Mojtaba Ahmadlou, Rasoul Salehi, Bahman Sadeghi, Mostafa Manian

Published in: Cancer Cell International | Issue 1/2021

Login to get access

Abstract

Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.
Literature
1.
2.
3.
Folkman J. What is the evidence that tumors are angiogenesis dependent? JNCI J Natl Cancer Inst. 1990;82(1):4–7.PubMedCrossRef
4.
Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49(23):6449–65.PubMed
5.
Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, et al. Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and-independent mechanisms and contributes to drug resistance. Mol Cell Biol. 2004;24(7):2875–89.PubMedPubMedCentralCrossRef
6.
Rouschop KM, Van Den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Investig. 2010;120(1):127–41.PubMedCrossRef
7.
Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3(4):347–61.PubMedCrossRef
8.
9.
Goldmann E. The growth of malignant disease in man and the lower animals, with special reference to the vascular system. Thousand Oaks: SAGE Publications; 1908.CrossRef
10.
Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Investig. 2010;120(3):694–705.PubMedCrossRefPubMedCentral
11.
Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83.PubMedPubMedCentralCrossRef
12.
13.
14.
Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metabol. 2005;1(6):401–8.CrossRef
15.
Bristow RG, Hill RP. Hypoxia and metabolism: hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008;8(3):180.CrossRefPubMed
16.
Yotnda P, Wu D, Swanson AM. Hypoxic tumors and their effect on immune cells and cancer therapy. Immunotherapy of Cancer. Berlin: Springer; 2010. p. 1–29.
17.
18.
19.
20.
21.
Carmeliet P, Dor Y, Herbert J-M, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394(6692):485.PubMedCrossRef
22.
Wang GL, Jiang B-H, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci. 1995;92(12):5510–4.PubMedCrossRefPubMedCentral
23.
Ohh M, Park CW, Ivan M, Hoffman MA, Kim T-Y, Huang LE, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein. Nat Cell Biol. 2000;2(7):423.PubMedCrossRef
24.
Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.PubMedCrossRef
25.
Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001;11(3):293–9.PubMedCrossRef
26.
Holmquist-Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer cell. 2006;10(5):413–23.PubMedCrossRef
27.
28.
29.
30.
31.
32.
Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat Rev. 2011;37(1):63–74.PubMedCrossRef
33.
Williams KJ, Cowen RL, Stratford IJ. Hypoxia and oxidative stress in breast cancer Tumour hypoxia–therapeutic considerations. Breast Cancer Res. 2001;3(5):328.PubMedPubMedCentralCrossRef
34.
Zölzer F, Streffer C. Increased radiosensitivity with chronic hypoxia in four human tumor cell lines. Int J Radiat Oncol Biol Phys. 2002;54(3):910–20.PubMedCrossRef
35.
Chan N, Koritzinsky M, Zhao H, Bindra R, Glazer PM, Powell S, et al. Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res. 2008;68(2):605–14.PubMedCrossRef
36.
Miao H, Wu N, Luan C, Yang X, Zhang R, Lv N, et al. Quantitation of intestinal Fusobacterium and butyrate- producing bacteria in patients with colorectal adenomas and colorectal cancer. Wei sheng wu xue bao Acta MicrobiolSin. 2014;54(10):1228–34.
37.
Rofstad EK, Gaustad JV, Egeland TA, Mathiesen B, Galappathi K. Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer. 2010;127(7):1535–46.PubMedCrossRef
38.
Bhaskara VK, Mohanam I, Rao JS, Mohanam S. Intermittent hypoxia regulates stem-like characteristics and differentiation of neuroblastoma cells. PLoS ONE. 2012;7(2):e30905.PubMedPubMedCentralCrossRef
39.
Martinive P, Defresne F, Bouzin C, Saliez J, Lair F, Grégoire V, et al. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications for anticancer therapies. Cancer Res. 2006;66(24):11736–44.PubMedCrossRef
40.
41.
Seo BR, DelNero P, Fischbach C. In vitro models of tumor vessels and matrix: engineering approaches to investigate transport limitations and drug delivery in cancer. Adv Drug Deliv Rev. 2014;69:205–16.PubMedCrossRef
42.
43.
Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16(10):1151–62.PubMedCrossRef
44.
Less JR, Posner MC, Skalak TC, Wolmark N, Jain RK. Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation. 1997;4(1):25–33.PubMedCrossRef
45.
Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO 2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997;3(2):177.CrossRefPubMed
46.
Hanahan D, Christofori G, Naik P, Arbeit J. Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models. Eur J Cancer. 1996;32(14):2386–93.CrossRef
47.
Goonewardene T, Sowter H, Harris A. Hypoxia-induced pathways in breast cancer. Microsc Res Tech. 2002;59(1):41–8.PubMedCrossRef
48.
Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989;339(6219):58.CrossRefPubMed
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
Kubota Y, Takubo K, Suda T. Bone marrow long label-retaining cells reside in the sinusoidal hypoxic niche. Biochem Biophys Res Commun. 2008;366(2):335–9.PubMedCrossRef
62.
63.
64.
65.
Kim H, Lin Q, Glazer PM, Yun Z. The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Res. 2018;20(1):16.PubMedPubMedCentralCrossRef
66.
67.
68.
69.
Chang WH, Lai AG. Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion. Br J Cancer. 2019;121:666–6783.PubMedPubMedCentralCrossRef
70.
71.
72.
73.
74.
75.
76.
77.
Colwell N, Larion M, Giles AJ, Seldomridge AN, Sizdahkhani S, Gilbert MR, et al. Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells. Neurooncology. 2017;19(7):887–96.
78.
Schöning JP, Monteiro M, Gu W. Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia-inducible factors HIF 1α and HIF 2α. Clin Exp Pharmacol Physiol. 2017;44(2):153–61.PubMedCrossRef
79.
Bae K-M, Dai Y, Vieweg J, Siemann DW. Hypoxia regulates SOX2 expression to promote prostate cancer cell invasion and sphere formation. Am J Cancer Res. 2016;6(5):1078.PubMedPubMedCentral
80.
Hajizadeh F, Okoye I, Esmaily M, Chaleshtari MG, Masjedi A, Azizi G, et al. Hypoxia inducible factors in the tumor microenvironment as therapeutic targets of cancer stem cells. Life Sci. 2019;237:116952.PubMedCrossRef
81.
82.
Markiewicz A, Welnicka-Jaskiewicz M, Seroczynska B, Skokowski J, Majewska H, Szade J, et al. Epithelial-mesenchymal transition markers in lymph node metastases and primary breast tumors - relation to dissemination and proliferation. Am J Transl Res. 2014;6(6):793–808.PubMedPubMedCentral
83.
84.
85.
86.
87.
Akbar MW, Isbilen M, Belder N, Canli SD, Kucukkaraduman B, Turk C, et al. A stemness and EMT based gene expression signature identifies phenotypic plasticity and is A predictive but not prognostic biomarker for breast cancer. J Cancer. 2020;11(4):949.PubMedPubMedCentralCrossRef
88.
Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, et al. A microRNA signature of hypoxia. Mol Cell Biol. 2007;27(5):1859–67.PubMedPubMedCentralCrossRef
89.
Cascio S, D’Andrea A, Ferla R, Surmacz E, Gulotta E, Amodeo V, et al. miR-20b modulates VEGF expression by targeting HIF‐1α and STAT3 in MCF‐7 breast cancer cells. J Cell Physiol. 2010;224(1):242–9.PubMed
90.
Liu M, Wang D, Li N. MicroRNA-20b downregulates HIF-1α and Inhibits the proliferation and invasion of osteosarcoma cells. Oncol Res Featur Preclin Clin Cancer Ther. 2016;23(5):257–66.
91.
Wu Q, Yang Z, Wang F, Hu S, Yang L, Shi Y, et al. MiR-19b/20a/92a regulates the self-renewal and proliferation of gastric cancer stem cells. J Cell Sci. 2013;126(18):4220–9.PubMed
92.
Shao Q, Xu J, Guan X, Zhou B, Wei W, Deng R, et al. In vitro and in vivo effects of miRNA-19b/20a/92a on gastric cancer stem cells and the related mechanism. Int J Med Sci. 2018;15(1):86.PubMedPubMedCentralCrossRef
93.
Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103(7):2257–61.PubMedCrossRefPubMedCentral
94.
Hua Z, Lv Q, Ye W, Wong CKA, Cai G, Gu D, et al. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS ONE. 2006;1(1):e116.PubMedPubMedCentralCrossRef
95.
96.
97.
Anwar SL, Sari DNI, Kartika AI, Fitria MS, Tanjung DS, Rakhmina D, et al. Upregulation of circulating MiR-21 expression as a potential biomarker for therapeutic monitoring and clinical outcome in breast cancer. Asian Pac J Cancer Prev. 2019;20(4):1223–8.PubMedPubMedCentralCrossRef
98.
Liu B, Su F, Chen M, Li Y, Qi X, Xiao J, et al. Serum miR-21 and miR-125b as markers predicting neoadjuvant chemotherapy response and prognosis in stage II/III breast cancer. Human Pathol. 2017;64:44–52.CrossRef
99.
100.
Tu H-F, Lin S-C, Chang K-W. MicroRNA aberrances in head and neck cancer: pathogenetic and clinical significance. Curr Opin Otolaryngol Head Neck Surg. 2013;21(2):104–11.PubMedCrossRef
101.
Mamoori A, Gopalan V, Smith RA, Lam AKY. Modulatory roles of microRNAs in the regulation of different signalling pathways in large bowel cancer stem cells. Biol Cell. 2016;108(3):51–64.PubMedCrossRef
102.
103.
Nedaeinia R, Sharifi M, Avan A, Kazemi M, Nabinejad A, Ferns GA, et al. Inhibition of microRNA-21 via locked nucleic acid-anti-miR suppressed metastatic features of colorectal cancer cells through modulation of programmed cell death 4. Tumor Biol. 2017;39(3):1010428317692261. https://​doi.​org/​10.​1177/​1010428317692261​.CrossRef
104.
Zhang Z, Li Z, Gao C, Chen P, Chen J, Liu W, et al. miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Investig. 2008;88(12):1358–66.PubMedCrossRef
105.
106.
107.
Liu L-Z, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, et al. MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS ONE. 2011;6(4):e19139.PubMedPubMedCentralCrossRef
108.
Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S, et al. Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS ONE. 2012;7(12):e50165.PubMedPubMedCentralCrossRef
109.
Jiao X, Qian X, Wu L, Li B, Wang Y, Kong X, et al. microRNA: the impact on cancer stemness and therapeutic resistance. Cells. 2020;9(1):8.CrossRef
110.
111.
Li J, Zhang Y, Zhao J, Kong F, Chen Y. Overexpression of miR-22 reverses paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells. Mol Cell Biochem. 2011;357(1–2):31–8.PubMed
112.
Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, et al. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer. 2010;103(8):1215–20.PubMedPubMedCentralCrossRef
113.
Li J, Liang S, Yu H, Zhang J, Ma D, Lu X. An inhibitory effect of miR-22 on cell migration and invasion in ovarian cancer. Gynecol Oncol. 2010;119(3):543–8.PubMedCrossRef
114.
Nakamura M, Hayashi M, Konishi H, Nunode M, Ashihara K, Sasaki H, et al. MicroRNA–22 enhances radiosensitivity in cervical cancer cell lines via direct inhibition of c–Myc binding protein, and the subsequent reduction in hTERT expression. Oncol Lett. 2020;19(3):2213–22.PubMedPubMedCentral
115.
Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell. 2013;154(2):311–24.PubMedPubMedCentralCrossRef
116.
Song SJ, Pandolfi PP. miR-22 in tumorigenesis. Cell Cycle (Georgetown Tex). 2014;13(1):11–2.CrossRef
117.
Tsuchiya N, Izumiya M, Ogata-Kawata H, Okamoto K, Fujiwara Y, Nakai M, et al. Tumor suppressor miR-22 determines p53-dependent cellular fate through post-transcriptional regulation of p21. Cancer Res. 2011;71(13):4628–39.PubMedPubMedCentralCrossRef
118.
Bao B, Li Y, Ahmad A, Azmi S, Bao A, Ali G, et al. Targeting CSC-related miRNAs for cancer therapy by natural agents. Curr Drug Targets. 2012;13(14):1858–68.PubMedPubMedCentralCrossRef
119.
Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, et al. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012;72(1):335–45.PubMedCrossRef
120.
Cao P, Deng Z, Wan M, Huang W, Cramer SD, Xu J, et al. MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1α/HIF-1β. Mol Cancer. 2010;9(1):108.PubMedPubMedCentralCrossRef
121.
Zhang J-g, Guo J-F, Liu D-L, Liu Q, Wang J-J. MicroRNA-101 exerts tumor-suppressive functions in non-small cell lung cancer through directly targeting enhancer of zeste homolog 2. J Thorac Oncol. 2011;6(4):671–8.PubMedCrossRef
122.
Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6(11):846–56.PubMedCrossRef
123.
124.
Datta J, Smith A, Lang JC, Islam M, Dutt D, Teknos TN, et al. microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ. Oncogene. 2012;31(36):4045–53.PubMedCrossRef
125.
Yamakuchi M, Lotterman CD, Bao C, Hruban RH, Karim B, Mendell JT, et al. P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proc Natl Acad Sci. 2010;107(14):6334–9.PubMedCrossRefPubMedCentral
126.
Chen H, Chen Q, Fang M, Mi Y. microRNA-181b targets MLK2 in HL-60 cells. Sci China Life Sci. 2010;53(1):101–6.PubMedCrossRef
127.
Wang B, Hsu S-H, Majumder S, Kutay H, Huang W, Jacob ST, et al. TGFβ-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010;29(12):1787–97.PubMedCrossRef
128.
Wang X, Meng Q, Qiao W, Ma R, Ju W, Hu J, et al. miR-181b/Notch2 overcome chemoresistance by regulating cancer stem cell-like properties in NSCLC. Stem Cell Res Ther. 2018;9(1):327.PubMedPubMedCentralCrossRef
129.
Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, et al. hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res. 2008;1236:185–93.PubMedCrossRef
130.
Liu W, Cai T, Li L, Chen H, Chen R, Zhang M, et al. MiR-200a regulates nasopharyngeal carcinoma cell migration and invasion by targeting MYH10. J Cancer. 2020;11(10):3052.PubMedPubMedCentralCrossRef
131.
Cong N, Du P, Zhang A, Shen F, Su J, Pu P, et al. Downregulated microRNA-200a promotes EMT and tumor growth through the wnt/β-catenin pathway by targeting the E-cadherin repressors ZEB1/ZEB2 in gastric adenocarcinoma. Oncol Rep. 2013;29(4):1579–87.PubMedCrossRef
132.
Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9(6):582–9.PubMedPubMedCentralCrossRef
133.
Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138(3):592–603.PubMedPubMedCentralCrossRef
134.
Tang T, Yang Z, Zhu Q, Wu Y, Sun K, Alahdal M, et al. Up-regulation of miR-210 induced by a hypoxic microenvironment promotes breast cancer stem cell metastasis, proliferation, and self-renewal by targeting E-cadherin. FASEB J. 2018;32(12):6965–81.CrossRef
135.
Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, et al. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clinical Cancer Res. 2008;14(5):1340–8.CrossRef
136.
Kulshreshtha R, Davuluri R, Calin GA, Ivan M. A microRNA component of the hypoxic response. Cell Death Differ. 2008;15(4):667–71.PubMedCrossRef
137.
138.
Huang Q, Gumireddy K, Schrier M, Le Sage C, Nagel R, Nair S, et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 2008;10(2):202–10.PubMedCrossRef
139.
Wang LQ, Yu P, Li B, Guo YH, Liang ZR, Zheng LL, et al. miR-372 and miR‐373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways. Mol Oncol. 2018;12(11):1949–64.PubMedPubMedCentralCrossRef
140.
Place RF, Li L-C, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci. 2008;105(5):1608–13.PubMedCrossRefPubMedCentral
141.
Berx G, Van Roy F. The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res. 2001;3(5):289.PubMedPubMedCentralCrossRef
142.
Chang C-J, Hsu C-C, Chang C-H, Tsai L-L, Chang Y-C, Lu S-W, et al. Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep. 2011;26(4):1003–10.PubMed
143.
Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S, et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE. 2010;5(8):e12445.PubMedPubMedCentralCrossRef
144.
Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, Philip PA, et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69(16):6704–12.PubMedPubMedCentralCrossRef
145.
Sun X, Xu C, Xiao G, Meng J, Wang J, Tang SC, et al. Breast cancer stem-like cells are sensitized to tamoxifen induction of self-renewal inhibition with enforced Let-7c dependent on Wnt blocking. Int J Mol Med. 2018;41(4):1967–75.PubMedPubMedCentral
146.
Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PloS ONE. 2012;7(3):e33729.PubMedPubMedCentralCrossRef
147.
Lu J, He M-L, Wang L, Chen Y, Liu X, Dong Q, et al. MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res. 2011;71(1):225–33.PubMedCrossRef
148.
Li G, Liu H, Zhang X, Liu X, Zhang G, Liu Q. The protective effects of microRNA-26a in steroid-induced osteonecrosis of the femoral head by repressing EZH2. . Cell Cycle (GeorgetownTex). 2020;19(5):551–66.CrossRef
149.
Ma D-N, Chai Z-T, Zhu X-D, Zhang N, Zhan D-H, Ye B-G, et al. MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. J Hematol Oncol. 2016;9(1):1.PubMedPubMedCentralCrossRef
150.
Peng X, Kang Q, Wan R, Wang Z. MiR-26a/HOXC9 dysregulation promotes metastasis and stem cell-like phenotype of gastric cancer. Cell Physiol Biochem. 2018;49(4):1659–76.PubMedCrossRef
151.
152.
153.
154.
155.
156.
Sun H, Wang S, Yan S, Zhang Y, Nelson PJ, Jia H, et al. Therapeutic strategies targeting cancer stem cells and their microenvironment. Front Oncol. 2019;9:1104.PubMedPubMedCentralCrossRef
157.
Chiche J, Brahimi-Horn MC, Pouysségur J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med. 2010;14(4):771–94.PubMedCrossRef
158.
159.
160.
Najafi M, Farhood B, Mortezaee K, Kharazinejad E, Majidpoor J, Ahadi R. Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance. J Cancer Res Clin Oncol. 2020;146(1):19–31.PubMedCrossRef
161.
Shiraishi A, Tachi K, Essid N, Tsuboi I, Nagano M, Kato T, et al. Hypoxia promotes the phenotypic change of aldehyde dehydrogenase activity of breast cancer stem cells. Cancer Sci. 2017;108(3):362–72.PubMedPubMedCentralCrossRef
162.
Kim R-J, Park J-R, Roh K-J, Choi A-R, Kim S-R, Kim P-H, et al. High aldehyde dehydrogenase activity enhances stem cell features in breast cancer cells by activating hypoxia-inducible factor-2α. Cancer Lett. 2013;333(1):18–31.PubMedCrossRef
163.
164.
165.
Cho IJ, Lui PP, Obajdin J, Riccio F, Stroukov W, Willis TL, et al. Mechanisms, hallmarks, and implications of stem cell quiescence. Stem Cell Rep. 2019;12(6):1190–200.CrossRef
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
Czekay R-P, Aertgeerts K, Curriden SA, Loskutoff DJ. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol. 2003;160(5):781–91.PubMedPubMedCentralCrossRef
180.
181.
Foekens JA, Peters HA, Look MP, Portengen H, Schmitt M, Kramer MD, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res. 2000;60(3):636–43.PubMed
182.
Andreasen P, Egelund R, Petersen H. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci CMLS. 2000;57(1):25–40.PubMedCrossRef
183.
184.
185.
186.
187.
188.
Wong CCL, Gilkes DM, Zhang H, Chen J, Wei H, Chaturvedi P, et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci. 2011;108(39):16369–74.PubMedCrossRefPubMedCentral
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
Sitkovsky M, Lukashev D. Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat Rev Immunol. 2005;5(9):712.PubMedCrossRef
199.
200.
Chiu DK-C, Tse AP-W, Xu IM-J, Di Cui J, Lai RK-H, Li LL, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun. 2017;8(1):517.PubMedPubMedCentralCrossRef
201.
Corzo CA, Condamine T, Lu L, Cotter MJ, Youn J-I, Cheng P, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207(11):2439–53.PubMedPubMedCentralCrossRef
202.
Noman MZ, Janji B, Hu S, Wu JC, Martelli F, Bronte V, et al. Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. Cancer Res. 2015;75(18):3771–87.PubMedCrossRef
203.
204.
Liu G, Bi Y, Shen B, Yang H, Zhang Y, Wang X, et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1α–dependent glycolysis. Cancer Res. 2014;74(3):727–37.PubMedCrossRef
205.
Andrea C, Damya L, Mathias W, Rizzolio S, Nicklas B, Marco M, et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013;24:695–709.CrossRef
206.
207.
Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104(8):2224–34.PubMedCrossRef
208.
Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513(7519):559.PubMedPubMedCentralCrossRef
209.
Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res. 2010;70(19):7465–75.PubMedPubMedCentralCrossRef
210.
Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan L-J, et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120(8):2699–714.PubMedPubMedCentralCrossRef
211.
212.
213.
214.
Xu L, Xie K, Mukaida N, Matsushima K, Fidler IJ. Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. Cancer Res. 1999;59(22):5822–9.PubMed
215.
216.
217.
218.
Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76(6):1367–80.PubMedPubMedCentralCrossRef
219.
Jung HS, Gu J, Kim J-E, Nam Y, Song JW, Kim HK. Cancer cell–induced neutrophil extracellular traps promote both hypercoagulability and cancer progression. PLoS ONE. 2019;14(4):e0216055.PubMedPubMedCentralCrossRef
220.
221.
222.
223.
Chang C-H, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229–41.PubMedPubMedCentralCrossRef
224.
225.
226.
Laplagne C, Domagala M, Le Naour A, Quemerais C, Hamel D, Fournié J-J, et al. Latest advances in targeting the tumor microenvironment for tumor suppression. Int J Mol Sci. 2019;20(19):4719.PubMedCentralCrossRef
227.
228.
229.
230.
231.
232.
233.
Karhausen J, Haase VH, Colgan SP. Inflammatory hypoxia: role of hypoxia-inducible factor. Cell Cycle (Georgetown Tex). 2005;4(2):256–8.CrossRef
234.
235.
Hsiao H-W, Hsu T-S, Liu W-H, Hsieh W-C, Chou T-F, Wu Y-J, et al. Deltex1 antagonizes HIF-1α and sustains the stability of regulatory T cells in vivo. Nat Commun. 2015;6:6353.PubMedCrossRef
236.
237.
238.
239.
Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, et al. Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible factor-2 alpha, is regulated by von Hippel–Lindau gene mutation status. Eur Urol. 2016;70(4):623–32.PubMedCrossRef
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
Velásquez SY, Killian D, Schulte J, Sticht C, Thiel M, Lindner HA. Short term hypoxia synergizes with interleukin 15 priming in driving glycolytic gene transcription and supports human natural killer cell activities. J Biol Chem. 2016;291(25):12960–77.PubMedPubMedCentralCrossRef
250.
Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updates. 2007;10(1–2):13–29.CrossRef
251.
Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updates. 2011;14(3):191–201.CrossRef
252.
253.
254.
255.
Vaupel P, Kelleher DK, Höckel M, editors. Oxygenation status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Seminars in oncology. New York: Elsevier; 2001.
256.
Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002;62(12):3387–94.PubMed
257.
258.
259.
Vaupel P, Mayer A, Höckel M. Tumor hypoxia and malignant progression. Methods in enzymology. New York: Elsevier; 2004. p. 335–54.
260.
261.
262.
263.
264.
Graham K, Unger E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int J Nanomed. 2018;13:6049.CrossRef
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
Molls M, Anscher MS, Nieder C, Vaupel P. The impact of tumor biology on cancer treatment and multidisciplinary strategies. Berlin: Springer; 2009.CrossRef
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
Lee Y-Y, Jeon H-K, Hong JE, Cho YJ, Ryu JY, Choi J-J, et al. Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma. Oncotarget. 2015;6(33):35040.PubMedPubMedCentralCrossRef
287.
288.
289.
290.
291.
292.
Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, et al. Inhibiting glycolytic metabolism enhances CD8 + T cell memory and antitumor function. J Clin Investig. 2013;123(10):4479–88.PubMedCrossRefPubMedCentral
293.
Bosticardo M, Ariotti S, Losana G, Bernabei P, Forni G, Novelli F. Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur J Immunol. 2001;31(9):2829–38.PubMedCrossRef
294.
Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al editors. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in cancer biology. Berlin: Elsevier; 2017.
295.
296.
297.
298.
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
332.
333.
334.
335.
336.
337.
338.
339.
340.
341.
Metadata
Title
The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment
Authors
Asieh Emami Nejad
Simin Najafgholian
Alireza Rostami
Alireza Sistani
Samaneh Shojaeifar
Mojgan Esparvarinha
Reza Nedaeinia
Shaghayegh Haghjooy Javanmard
Marjan Taherian
Mojtaba Ahmadlou
Rasoul Salehi
Bahman Sadeghi
Mostafa Manian
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01719-5

Other articles of this Issue 1/2021

Cancer Cell International 1/2021 Go to the issue

Primary research

ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384), a PI3K inhibitor in colorectal cancer cells

Review

Biogenesis, cellular effects, and biomarker value of circHIPK3

Primary research

NCK1-AS1 promotes the progression of melanoma by accelerating cell proliferation and migration via targeting miR-526b-5p/ADAM15 axis

Primary research

A seven-gene prognostic signature predicts overall survival of patients with lung adenocarcinoma (LUAD)

Primary research

Immunological significance of prognostic alternative splicing signature in hepatocellular carcinoma

Primary research

VWCE as a potential biomarker associated with immune infiltrates in breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits