Hypoxia-inducible factors: cancer progression and clinical translation

Abstract

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.

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     Not in our library10.1038/367645a0

118. 118.

     Hu T, et al. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 2008;68(16):6533-6540.

     Not in our library10.1158/0008-5472.can-07-6642

119. 119.

     Leis O, et al. Sox2 expression in breast tumors and activation in breast cancer stem cells. Oncogene. 2012;31(11):1354-1365.

     Not in our library10.1038/onc.2011.338

120. 120.

     Santaliz-Ruiz LE, et al. Emerging role of NANOG in tumorigenesis and cancer stem cells. Int J Cancer. 2014;135(12):2741-2748.

     Not in our library10.1002/ijc.28690

121. 121.

     Yu F, et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene. 2011;30(18):2161-2172.

     Not in our library10.1038/onc.2010.591

122. 122.

     Conley SJ, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A. 2012;109(8):2784-2789.

     Not in our library10.1073/pnas.1018866109

123. 123.

     Xiang L, et al. Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype. Oncotarget. 2014;5(24):12509-12527.

     Not in our library10.18632/oncotarget.2997

124. 124.

     Samanta D, et al. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci U S A. 2014;111(5):E5429-E5438.

     Not in our library10.1073/pnas.1421438111

125. 125.

     Creighton CJ, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820-13825.

     Not in our library10.1073/pnas.0905718106

126. 126.

     Mathieu J, et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res. 2011;71(13):4640-4652.

     Not in our library10.1158/0008-5472.can-10-3320

127. 127.

     Lan J, et al. Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment. Proc Natl Acad Sci U S A. 2018;115(41):E9640-E9648.

     Not in our library10.1073/pnas.1809695115

128. 128.

     Lu H, et al. Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci U S A. 2015;112(33):E4600-E4609.

     Not in our library10.1073/pnas.1513433112

129. 129.
     Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment · 2017

     Not checked
130. 130.

     Lu H, et al. Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness. J Clin Invest. 2020;130(9):4607-4623.

     Not in our library10.1172/jci138577

131. 131.

     Lu H, et al. Reciprocal regulation of DUSP9 and DUSP16 expression by HIF-1 controls ERK and p38 MAP kinase activity and mediates chemotherapy-induced breast cancer stem cell enrichment. Cancer Res. 2018;78(15):4191-4202.

     Not in our library10.1158/0008-5472.can-18-0270

132. 132.
     Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells · 2016

     No notice
133. 133.

     Zhang H, et al. HIF-1-regulated expression of calreticulin promotes breast tumorigenesis and progression through Wnt/β-catenin pathway activation. Proc Natl Acad Sci U S A. 2021;118(44):e2109144118.

     Not in our library10.1073/pnas.2109144118

134. 134.

     Lu H, et al. HIF-1 recruits NANOG as a coactivator for TERT gene transcription in hypoxic breast cancer stem cells. Cell Rep. 2021;36(13):109757.

     Not in our library10.1016/j.celrep.2021.109757

135. 135.

     Shay JW, Wright SE. Telomeres and telomerase in normal and cancer stem cells. FEBS Lett. 2010;584(17):3819-3825.

     Not in our library10.1016/j.febslet.2010.05.026

136. 136.

     Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31(6):539-544.

     Not in our library10.1038/nbt.2576

137. 137.

     Krishnamachary B, et al. Hypoxia regulates CD44 and its variant isoforms through HIF-1α in triple negative breast cancer. PLoS One. 2012;7(8):e44078.

     Not in our library10.1371/journal.pone.0044078

138. 138.

     Pennacchietti S, et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3(4):347-361.

     Not in our library10.1016/s1535-6108(03)00085-0

139. 139.

     Zhang H, et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci U S A. 2015;112(45):E6215-E6223.

     Not in our library10.1073/pnas.1520032112

140. 140.

     Jonasch E, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036-2046.

     Not in our library10.1056/nejmoa2103425

141. 141.

     Zou W. Immunosuppressive networks in the tumor microenvironment and their therapeutic relevance. Nat Rev Cancer. 2005;5(4):263-274.

     Not in our library10.1038/nrc1586

142. 142.
     Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction · 2016

     No notice
143. 143.

     Parks SK, et al. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer. 2013;13(9):611-623.

     Not in our library10.1038/nrc3579

144. 144.

     Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr. 2007;39(3):231-234.

     Not in our library10.1007/s10863-007-9081-2

145. 145.

     Brand A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24(5):657-671.

     Not in our library10.1016/j.cmet.2016.08.011

146. 146.

     Chang CH, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229-1241.

     Not in our library10.1016/j.cell.2015.08.016

147. 147.

     Fischer K, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109(9):3812-3819.

     Not in our library10.1182/blood-2006-07-035972

148. 148.

     Ottensmeier CH, et al. Upregulated glucose metabolism correlates inversely with CD8+ T-cell infiltration and survival in squamous cell carcinoma. Cancer Res. 2016;76(14):4136-4148.

     Not in our library10.1158/0008-5472.can-15-3121

149. 149.

     Bannud N, et al. Hypoxia supports differentiation of terminally exhausted T cells. Front Immunol. 2021;12:660944.

     Not in our library10.3389/fimmu.2021.660944

150. 150.

     Liikanen I, et al. Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells. J Clin Invest. 2021;131(7):e143729.

     Not in our library10.1172/jci143729

151. 151.

     Hatfield SM, Sitkovsky MV. Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy. J Clin Invest. 2020;130(11):5629-5637.

     Not in our library10.1172/jci137554

152. 152.

     Jayaprakash P, et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest. 2018;128(11):5137-5149.

     Not in our library10.1172/jci96268

153. 153.

     Samanta D, et al. Chemotherapy induces enrichment of CD47+/CD73+/PDL1+ immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci U S A. 2018;115(6):E1239-E1248.

     Not in our library10.1073/pnas.1718197115

154. 154.
     BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy · 2020

     Not checked
155. 155.

     Semenza GL. Pharmacologic targeting of hypoxia-inducible factors. Annu Rev Pharmacol Toxicol. 2019;59:379-403.

     Not in our library10.1146/annurev-pharmtox-010818-021637

156. 156.

     Kong D, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005;65(19):9047-9055.

     Not in our library10.1158/0008-5472.can-05-1235

157. 157.

     Liu YV, et al. RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α. Mol Cell. 2007;25(2):207-217.

     Not in our library10.1016/j.molcel.2007.01.001

158. 158.

     Xiang L, et al. Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer. J Mol Med (Berl). 2014;92(2):151-164.

     Not in our library10.1007/s00109-013-1102-5

159. 159.

     Mabjeesh NJ, et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell. 2003;3(4):363-375.

     Not in our library10.1016/s1535-6108(03)00077-1

160. 160.

     Welsh S, et al. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1α. Mol Cancer Ther. 2004;3(3):233-244.

     Not in our library

161. 161.

     Yeo EJ, et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst. 2003;95(7):516-525.

     Not in our library10.1093/jnci/95.7.516

162. 162.

     Chen W, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112-117.

     Not in our library10.1038/nature19796

163. 163.

     Cho H, et al. On-target efficiency of a HIF-2α antagonist in preclinical kidney cancer models. Nature. 2016;539:107-111.

     Not in our library10.1038/nature19795

164. 164.

     Wallace EM, et al. A small-molecule antagonist of HIF-2α is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76(18):5491-5500.

     Not in our library10.1158/0008-5472.can-16-0473

165. 165.

     Choueiri TK, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805.

     Not in our library10.1038/s41591-021-01324-7

166. 166.

     Courtney KD, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36(9):867-874.

     Not in our library10.1200/jco.2017.74.2627

167. 167.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

168. 168.

     Zhang H, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11(5):407-420.

     Not in our library10.1016/j.ccr.2007.04.001

169. 169.

     Hoefflin R, et al. Therapeutic effects of inhibition of sphingosine-1-phosphate signaling in HIF-2α-inhibitor-resistant clear cell renal cell carcinoma. Cancers. 2021;13(19):4801.

     Not in our library10.3390/cancers13194801

170. 170.

     Wu D, et al. Structural integration in hypoxia-inducible factors. Nature. 2015;524(7565):303-308.

     Not in our library10.1038/nature14883

171. 171.

     El-Serag HB, et al. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118-1127.

     Not in our library10.1056/nejmra1001683

172. 172.

     Llovet JM, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.

     Not in our library10.1038/s41572-020-00240-3

173. 173.

     Lai E, et al. Introducing immunotherapy for advanced hepatocellular carcinoma patients: too early or too fast? Crit Rev Oncol Hematol. 2021;157:103167.

     Not in our library10.1016/j.critrevonc.2020.103167

174. 174.

     McKeown SR. Defining normoxia, physoxia, and hypoxia in tumors—implications for treatment response. Br J Radiol. 2014;87(1035):20130676.

     Not in our library10.1259/bjr.20130676

175. 175.

     Xu R, et al. LY-294002 enhances the chemosensitivity of liver cancer to oxaliplatin by blocking the PI3K/AKT/HIF-1α pathway. Mol Med Rep. 2021;24(1):508.

     Not in our library10.3892/mmr.2021.12147

176. 176.

     Cao S, et al. Protein expression of hypoxia-inducible factor 1α and hepatocellular carcinoma: a systematic review with meta-analysis. Clin Res Hepatol Gastroenterol. 2014;38(5):598-603.

     Not in our library10.1016/j.clinre.2014.04.004

177. 177.

     Salman S, et al. HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy. J Clin Invest. 2022;132(9):e156774.

     Not in our library10.1172/jci156774

Cited by papers we hold 4

• Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer · 2024
  No notice
• Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions · 2023
  No notice
• Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer · 2023
  No notice
• The role of lipid metabolic reprogramming in tumor microenvironment · 2023
  No notice

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