Abstract
Pancreatic cancer (PC) remains one of the most extremely lethal malignancies worldwide due to late diagnosis and early metastasis, with a 1-year overall survival rate of approximately 20%. The hypoxic microenvironment, induced by intratumoral hypoxia, promotes tumor invasion and progression, leading to chemotherapy or radiotherapy resistance and eventual mortality after treatment of PC. However, the role of the hypoxic microenvironment in PC is complicated and requires further investigation. In this article, we review recent advances regarding the regulation of malignant behaviors in PC, which provide insight into the potential of hypoxic microenvironment activation therapy for the therapeutic agents.
Similar content being viewed by others
Abbreviations
- ATP:
-
Adenosine triphosphate
- CAF:
-
Cancer-associated fibroblast
- CODD:
-
C-terminal oxygen-dependent degradation domain
- CSC:
-
Cancer stem cell
- ECM:
-
Extracellular matrix
- EMT:
-
Epithelial to mesenchymal transition
- ENO1:
-
Enolase 1
- HIF:
-
Hypoxia-inducible factor
- MDR1:
-
Multidrug resistance 1
- MIIP:
-
Migration and invasion inhibitory protein
- NODD:
-
N-terminal oxygen-dependent degradation domain
- PC:
-
Pancreatic cancer
- PDK1:
-
Pyruvate dehydrogenase kinase 1
- PHD:
-
Proline hydroxylase domain
- ROS:
-
Reactive oxygen species
- VEGF:
-
Vascular endothelial growth factor
References
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11):2913–2921. https://doi.org/10.1158/0008-5472.CAN-14-0155
Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M (2000) Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 48(4):919–922. https://doi.org/10.1016/s0360-3016(00)00803-8
Colbert LE, Fisher SB, Balci S, Saka B, Chen Z, Kim S, El-Rayes BF, Adsay NV, Maithel SK, Landry JC, Curran WJ Jr (2015) High nuclear hypoxia-inducible factor 1 alpha expression is a predictor of distant recurrence in patients with resected pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 91(3):631–639. https://doi.org/10.1016/j.ijrobp.2014.11.004
Chen J, Luo H, Liu Y, Zhang W, Li H, Luo T, Zhang K, Zhao Y, Liu J (2017) Oxygen-self-produced nanoplatform for relieving hypoxia and breaking resistance to sonodynamic treatment of pancreatic cancer. ACS Nano 11(12):12849–12862. https://doi.org/10.1021/acsnano.7b08225
Ye LY, Zhang Q, Bai XL, Pankaj P, Hu QD, Liang TB (2014) Hypoxia-inducible factor 1alpha expression and its clinical significance in pancreatic cancer: a meta-analysis. Pancreatology 14(5):391–397. https://doi.org/10.1016/j.pan.2014.06.008
Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271(30):17771–17778. https://doi.org/10.1074/jbc.271.30.17771
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23(24):9361–9374. https://doi.org/10.1128/mcb.23.24.9361-9374.2003
Tamama K, Kawasaki H, Kerpedjieva SS, Guan J, Ganju RK, Sen CK (2011) Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem 112(3):804–817. https://doi.org/10.1002/jcb.22961
Israel M, Schwartz L (2011) The metabolic advantage of tumor cells. Mol Cancer 10:70. https://doi.org/10.1186/1476-4598-10-70
Yang J, Ren B, Yang G, Wang H, Chen G, You L, Zhang T, Zhao Y (2019) The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol Life Sci. https://doi.org/10.1007/s00018-019-03278-z
Smith H, Board M, Pellagatti A, Turley H, Boultwood J, Callaghan R (2016) The effects of severe hypoxia on glycolytic flux and enzyme activity in a model of solid tumors. J Cell Biochem 117(8):1890–1901. https://doi.org/10.1002/jcb.25488
Wise DR, Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35(8):427–433. https://doi.org/10.1016/j.tibs.2010.05.003
Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, Miyazawa H, Yamaguchi Y, Miura M, Jenkins DM, Choi H, Kim JW, Asagiri M, Cowburn AS, Abe H, Soma K, Koyama K, Katoh M, Sayama K, Goda N, Johnson RS, Manabe I, Nagai R, Komuro I (2016) HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 7:11635. https://doi.org/10.1038/ncomms11635
Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R, Giaccia AJ (2003) Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22(37):5907–5914. https://doi.org/10.1038/sj.onc.1206703
Wu X, Qiao B, Liu Q, Zhang W (2015) Upregulation of extracellular matrix metalloproteinase inducer promotes hypoxia-induced epithelial-mesenchymal transition in esophageal cancer. Mol Med Rep 12(5):7419–7424. https://doi.org/10.3892/mmr.2015.4410
Wu Z, Liu X, Liu L, Deng H, Zhang J, Xu Q, Cen B, Ji A (2014) Regulation of lncRNA expression. Cell Mol Biol Lett 19(4):561–575. https://doi.org/10.2478/s11658-014-0212-6
Lai XL, Huang YH, Li YS, Li GN, Wang LP, Sun R, Ma YS, Feng SY, Chang ZY, Wang XH, Fu D, Han X, Cong XL, Li WP (2015) Differential expression profiling of microRNAs in para-carcinoma, carcinoma and relapse human pancreatic cancer. Clin Transl Oncol 17(5):398–408. https://doi.org/10.1007/s12094-014-1249-8
Hwang HW, Mendell JT (2007) MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer 96(Suppl):R40–44
Liu B, Yang H, Taher L, Denz A, Grutzmann R, Pilarsky C, Weber GF (2018) Identification of prognostic biomarkers by combined mRNA and miRNA expression microarray analysis in pancreatic cancer. Transl Oncol 11(3):700–714. https://doi.org/10.1016/j.tranon.2018.03.003
Niu Y, Jin Y, Deng SC, Deng SJ, Zhu S, Liu Y, Li X, He C, Liu ML, Zeng Z, Chen HY, Zhong JX, Ye Z, Wang CY, Zhao G (2018) MiRNA-646-mediated reciprocal repression between HIF-1alpha and MIIP contributes to tumorigenesis of pancreatic cancer. Oncogene 37(13):1743–1758. https://doi.org/10.1038/s41388-017-0082-2
Pan L, Zhou L, Yin W, Bai J, Liu R (2018) miR-125a induces apoptosis, metabolism disorder and migrationimpairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission. Int J Oncol 53(1):124–136. https://doi.org/10.3892/ijo.2018.4380
Duguang L, Jin H, Xiaowei Q, Peng X, Xiaodong W, Zhennan L, Jianjun Q, Jie Y (2017) The involvement of lncRNAs in the development and progression of pancreatic cancer. Cancer Biol Ther 18(12):927–936. https://doi.org/10.1080/15384047.2017.1385682
Chandra Gupta S, Nandan Tripathi Y (2017) Potential of long non-coding RNAs in cancer patients: from biomarkers to therapeutic targets. Int J Cancer 140(9):1955–1967. https://doi.org/10.1002/ijc.30546
Deng SJ, Chen HY, Ye Z, Deng SC, Zhu S, Zeng Z, He C, Liu ML, Huang K, Zhong JX, Xu FY, Li Q, Liu Y, Wang CY, Zhao G (2018) Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription. Oncogene 37(44):5811–5828. https://doi.org/10.1038/s41388-018-0382-1
Li H, Wang X, Wen C, Huo Z, Wang W, Zhan Q, Cheng D, Chen H, Deng X, Peng C, Shen B (2017) Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia-induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer. Mol Cancer 16(1):169. https://doi.org/10.1186/s12943-017-0738-0
Ou ZL, Zhang M, Ji LD, Luo Z, Han T, Lu YB, Li YX (2019) Long noncoding RNA FEZF1-AS1 predicts poor prognosis and modulates pancreatic cancer cell proliferation and invasion through miR-142/HIF-1alpha and miR-133a/EGFR upon hypoxia/normoxia. J Cell Physiol. https://doi.org/10.1002/jcp.28188
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. https://doi.org/10.1056/NEJMoa1304369
Vaccaro V, Sperduti I, Milella M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 365(8):768–769. https://doi.org/10.1056/NEJMc1107627author reply 769
Chiorean EG, Cheung WY, Giordano G, Kim G, Al-Batran SE (2019) Real-world comparative effectiveness of nab-paclitaxel plus gemcitabine versus FOLFIRINOX in advanced pancreatic cancer: a systematic review. Ther Adv Med Oncol 11:1758835919850367. https://doi.org/10.1177/1758835919850367
Thomas D, Radhakrishnan P (2019) Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol Cancer 18(1):14. https://doi.org/10.1186/s12943-018-0927-5
Gilkes DM, Semenza GL, Wirtz D (2014) Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer 14(6):430–439. https://doi.org/10.1038/nrc3726
Katagiri T, Kobayashi M, Yoshimura M, Morinibu A, Itasaka S, Hiraoka M, Harada H (2018) HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog. Oncotarget 9(12):10525–10535. https://doi.org/10.18632/oncotarget.24156
Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62(12):3387–3394
Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56. https://doi.org/10.1016/j.gde.2009.10.009
Abdalla MY, Ahmad IM, Rachagani S, Banerjee K, Thompson CM, Maurer HC, Olive KP, Bailey KL, Britigan BE, Kumar S (2019) Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition. Transl Res 207:56–69. https://doi.org/10.1016/j.trsl.2018.12.008
Wang L, Bi R, Yin H, Liu H, Li L (2019) ENO1 silencing impaires hypoxia-induced gemcitabine chemoresistance associated with redox modulation in pancreatic cancer cells. Am J Transl Res 11(7):4470–4480
Chen N, Chen X, Huang R, Zeng H, Gong J, Meng W, Lu Y, Zhao F, Wang L, Zhou Q (2009) BCL-xL is a target gene regulated by hypoxia-inducible factor-1{alpha}. J Biol Chem 284(15):10004–10012. https://doi.org/10.1074/jbc.M805997200
Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, Miller C, Demonacos C, Stratford IJ, Dive C (2004) 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 24(7):2875–2889. https://doi.org/10.1128/mcb.24.7.2875-2889.2004
Trollmann R, Richter M, Jung S, Walkinshaw G, Brackmann F (2014) Pharmacologic stabilization of hypoxia-inducible transcription factors protects developing mouse brain from hypoxia-induced apoptotic cell death. Neuroscience 278:327–342. https://doi.org/10.1016/j.neuroscience.2014.08.019
Nagaraju GP, Zakka KM, Landry JC, Shaib WL, Lesinski GB, El-Rayes BF (2019) Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer. Int J Cancer 145(6):1529–1537. https://doi.org/10.1002/ijc.32227
Bolderson E, Richard DJ, Zhou BB, Khanna KK (2009) Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin Cancer Res 15(20):6314–6320. https://doi.org/10.1158/1078-0432.CCR-09-0096
Blanco FF, Jimbo M, Wulfkuhle J, Gallagher I, Deng J, Enyenihi L, Meisner-Kober N, Londin E, Rigoutsos I, Sawicki JA, Risbud MV, Witkiewicz AK, McCue PA, Jiang W, Rui H, Yeo CJ, Petricoin E, Winter JM, Brody JR (2016) The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells. Oncogene 35(19):2529–2541. https://doi.org/10.1038/onc.2015.325
Yoshida GJ, Saya H (2016) Therapeutic strategies targeting cancer stem cells. Cancer Sci 107(1):5–11. https://doi.org/10.1111/cas.12817
Ning X, Shu J, Du Y, Ben Q, Li Z (2013) Therapeutic strategies targeting cancer stem cells. Cancer Biol Ther 14(4):295–303. https://doi.org/10.4161/cbt.23622
Rodriguez-Aznar E, Wiesmuller L, Sainz B Jr, Hermann PC (2019) EMT and stemness-key players in pancreatic cancer stem cells. Cancers. https://doi.org/10.3390/cancers11081136
Gzil A, Zarebska I, Bursiewicz W, Antosik P, Grzanka D, Szylberg L (2019) Markers of pancreatic cancer stem cells and their clinical and therapeutic implications. Mol Biol Rep. https://doi.org/10.1007/s11033-019-05058-1
Chen S, Zhang J, Chen J, Wang Y, Zhou S, Huang L, Bai Y, Peng C, Shen B, Chen H, Tian Y (2019) RER1 enhances carcinogenesis and stemness of pancreatic cancer under hypoxic environment. J Exp Clin Cancer Res 38(1):15. https://doi.org/10.1186/s13046-018-0986-x
Roper K, Corbeil D, Huttner WB (2000) Retention of prominin in microvilli reveals distinct cholesterol-based lipid micro-domains in the apical plasma membrane. Nat Cell Biol 2(9):582–592. https://doi.org/10.1038/35023524
Maeda K, Ding Q, Yoshimitsu M, Kuwahata T, Miyazaki Y, Tsukasa K, Hayashi T, Shinchi H, Natsugoe S, Takao S (2016) CD133 modulate HIF-1alpha expression under hypoxia in EMT phenotype pancreatic cancer stem-like cells. Int J Mol Sci. https://doi.org/10.3390/ijms17071025
Greeno E, Borazanci E, Gockerman J, Korn R, Saluja A, Von Hoff D (2015) Abstract CT207: Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide. Can Res 75(15 Supplement):CT207. https://doi.org/10.1158/1538-7445.am2015-ct207
Noel P, Von Hoff DD, Saluja AK, Velagapudi M, Borazanci E, Han H (2019) Triptolide and its derivatives as cancer therapies. Trends Pharmacol Sci 40(5):327–341. https://doi.org/10.1016/j.tips.2019.03.002
Zhou Y, Zhou Y, Yang M, Wang K, Liu Y, Zhang M, Yang Y, Jin C, Wang R, Hu R (2019) Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway. Redox Biol 22:101131. https://doi.org/10.1016/j.redox.2019.101131
Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F, Li J, Wang X, Gao S, Qian D, Huang C, Hao J (2015) Inhibition of HIF-1alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget 6(4):2250–2262. https://doi.org/10.18632/oncotarget.2948
Lang M, Wang X, Wang H, Dong J, Lan C, Hao J, Huang C, Li X, Yu M, Yang Y, Yang S, Ren H (2016) Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma. Cancer Lett 378(2):87–96. https://doi.org/10.1016/j.canlet.2016.05.016
Funding
This study was jointly funded by the National Science Foundation for Distinguished Young Scholars of China (No. 81625016), the National Natural Science Foundation of China (No. 81602085 and 81902428) and the Shanghai Sailing Program (No. 17YF1402500 and 19YF1409400).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tan, Z., Xu, J., Zhang, B. et al. Hypoxia: a barricade to conquer the pancreatic cancer. Cell. Mol. Life Sci. 77, 3077–3083 (2020). https://doi.org/10.1007/s00018-019-03444-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-019-03444-3