High‑glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1α

Zhang,Lun; Zhang,Wunai; Zhang,Xin; Min,Yihe; Zhao,Yang; Wang,Baofeng; Li,Wei; Mao,Shuai; Min,Weili

doi:10.3892/or.2022.8275

High‑glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1α

Authors:
- Lun Zhang
- Wunai Zhang
- Xin Zhang
- Yihe Min
- Yang Zhao
- Baofeng Wang
- Wei Li
- Shuai Mao
- Weili Min
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Affiliations: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Chongqing Three Gorges Medical College, Chongqing 404100, P.R. China, Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: January 27, 2022 https://doi.org/10.3892/or.2022.8275
Article Number: 64
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic cancer (PC) is one of the most lethal diseases, with a 5‑year survival rate of <9%. Perineural invasion (PNI) is a common pathological hallmark of PC and is correlated with a poor prognosis in this disease. Hyperglycemia has been shown to promote the invasion and migration of PC cells; however, the effect of hyperglycemia on the PNI of PC and its underlying mechanism remains unclear. In the present study, Western blotting was utilized to detect the expression of hypoxia inducible factor 1α (HIF1α) and nerve growth factor (NGF). Transwell and wound‑healing assays were performed to detect the influence of hyperglycemia on the invasion and migration ability of PC cells. An in vitro PC‑dorsal root ganglion (DRG) co‑culture system and an in vivo PNI sciatic nerve‑infiltrating tumor model were used to evaluate the severity of PNI in hyperglycemic conditions. In the results, hyperglycemia promoted the invasion/migration ability and elevated the expression of NGF in PC by upregulating HIF1α. Moreover, in vitro short‑term hyperglycemia caused little damage on the DRG axons and accelerated both the PNI of the PC and the outgrowth of the DRGs by increasing the expression of NGF via activation of HIF1α. Indeed, in vivo long‑term hyperglycemia promoted the infiltration and growth of PC, and then disrupted the function of the sciatic nerve in a HIF1α‑dependent manner. In conclusion, a high‑glucose microenvironment promotes PNI of PC via activation of HIF1α.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Torgeson A, Garrido-Laguna I, Tao R, Cannon GM, Scaife CL and Lloyd S: Value of surgical resection and timing of therapy in patients with pancreatic cancer at high risk for positive margins. ESMO Open. 3:e0002822018. View Article : Google Scholar : PubMed/NCBI
3	Kamisawa T, Wood LD, Itoi T and Takaori K: Pancreatic cancer. Lancet. 388:73–85. 2016. View Article : Google Scholar : PubMed/NCBI
4	Liebig C, Ayala G, Wilks JA, Berger DH and Albo D: Perineural invasion in cancer: A review of the literature. Cancer. 115:3379–3391. 2009. View Article : Google Scholar : PubMed/NCBI
5	Demir IE, Ceyhan GO, Liebl F, D'Haese JG, Maak M and Friess H: Neural invasion in pancreatic cancer: The past, present and future. Cancers (Basel). 2:1513–1527. 2010. View Article : Google Scholar : PubMed/NCBI
6	Liang D, Shi S, Xu J, Zhang B, Qin Y, Ji S, Xu W, Liu J, Liu L, Liu C, et al: New insights into perineural invasion of pancreatic cancer: More than pain. Biochim Biophys Acta. 1865:111–122. 2016.PubMed/NCBI
7	Jurcak N and Zheng L: Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve. Pharmacol Ther. 200:126–134. 2019. View Article : Google Scholar : PubMed/NCBI
8	Saloman JL, Albers KM, Rhim AD and Davis BM: Can stopping nerves, stop cancer. Trends Neurosci. 39:880–889. 2016. View Article : Google Scholar : PubMed/NCBI
9	Nan L, Qin T, Xiao Y, Qian W, Li J, Wang Z, Ma J, Ma Q and Wu Z: Pancreatic stellate cells facilitate perineural invasion of pancreatic cancer via HGF/c-Met pathway. Cell Transplant. 28:1289–1298. 2019. View Article : Google Scholar : PubMed/NCBI
10	Nagakawa T, Kayahara M, Ueno K, Ohta T, Konishi I and Miyazaki I: Clinicopathological study on neural invasion to the extrapancreatic nerve plexus in pancreatic cancer. Hepatogastroenterology. 39:51–55. 1992.PubMed/NCBI
11	Scappaticcio L, Maiorino MI, Bellastella G, Giugliano D and Esposito K: Insights into the relationships between diabetes, prediabetes, and cancer. Endocrine. 56:231–239. 2017. View Article : Google Scholar : PubMed/NCBI
12	Huang Y, Cai X, Qiu M, Chen P, Tang H, Hu Y and Huang Y: Prediabetes and the risk of cancer: A meta-analysis. Diabetologia. 57:2261–2269. 2014. View Article : Google Scholar : PubMed/NCBI
13	Prizment AE, Gross M, Rasmussen-Torvik L, Peacock JM and Anderson KE: Genes related to diabetes may be associated with pancreatic cancer in a population-based case-control study in Minnesota. Pancreas. 41:50–53. 2012. View Article : Google Scholar : PubMed/NCBI
14	Li W, Zhang X, Sang H, Zhou Y, Shang C, Wang Y and Zhu H: Effects of hyperglycemia on the progression of tumor diseases. J Exp Clin Cancer Res. 38:3272019. View Article : Google Scholar : PubMed/NCBI
15	Li J, Ma Q, Liu H, Guo K, Li F, Li W, Han L, Wang F and Wu E: Relationship between neural alteration and perineural invasion in pancreatic cancer patients with hyperglycemia. PLoS One. 6:e173852011. View Article : Google Scholar : PubMed/NCBI
16	Li J, Ma J, Han L, Xu Q, Lei J, Duan W, Li W, Wang F, Wu E, Ma Q and Huo X: Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer. Cancer Biol Ther. 16:912–921. 2015. View Article : Google Scholar : PubMed/NCBI
17	Larrieta ME, Vital P, Mendoza-Rodríguez A, Cerbón M and Hiriart M: Nerve growth factor increases in pancreatic beta cells after streptozotocin-induced damage in rats. Exp Biol Med (Maywood). 231:396–402. 2006. View Article : Google Scholar : PubMed/NCBI
18	Dang C, Zhang Y, Ma Q and Shimahara Y: Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer. J Gastroenterol Hepatol. 21:850–858. 2006. View Article : Google Scholar : PubMed/NCBI
19	Li X, Wang Z, Ma Q, Xu Q, Liu H, Duan W, Lei J, Ma J, Wang X, Lv S, et al: Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin Cancer Res. 20:4326–4338. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zhou C, Qian W, Li J, Ma J, Chen X, Jiang Z, Cheng L, Duan W, Wang Z, Wu Z, et al: High glucose microenvironment accelerates tumor growth via SREBP1-autophagy axis in pancreatic cancer. J Exp Clin Cancer Res. 38:3022019. View Article : Google Scholar : PubMed/NCBI
21	Li W, Liu H, Qian W, Cheng L, Yan B, Han L, Xu Q, Ma Q and Ma J: Hyperglycemia aggravates microenvironment hypoxia and promotes the metastatic ability of pancreatic cancer. Comput Struct Biotechnol J. 16:479–487. 2018. View Article : Google Scholar : PubMed/NCBI
22	Ilic M and Ilic I: Epidemiology of pancreatic cancer. World J Gastroenterol. 22:9694–9705. 2016. View Article : Google Scholar : PubMed/NCBI
23	Xu WN, Zheng HL, Yang RZ, Jiang LS and Jiang SD: HIF-1α regulates glucocorticoid-induced osteoporosis through PDK1/AKT/mTOR signaling pathway. Front Endocrinol (Lausanne). 28:9222020. View Article : Google Scholar
24	Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK and Hruban RH: Recent progress in pancreatic cancer. CA Cancer J Clin. 63:318–348. 2013. View Article : Google Scholar : PubMed/NCBI
25	Yang YH, Liu JB, Gui Y, Lei LL and Zhang SJ: Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. World J Gastroenterol. 23:7232–7241. 2017. View Article : Google Scholar : PubMed/NCBI
26	Deborde S, Omelchenko T, Lyubchik A, Zhou Y, He S, McNamara WF, Chernichenko N, Lee SY, Barajas F, Chen CH, et al: Schwann cells induce cancer cell dispersion and invasion. J Clin Invest. 126:1538–1554. 2016. View Article : Google Scholar : PubMed/NCBI
27	Demir IE, Friess H and Ceyhan GO: Neural plasticity in pancreatitis and pancreatic cancer. Nat Rev Gastroenterol Hepatol. 12:649–659. 2015. View Article : Google Scholar : PubMed/NCBI
28	Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C, Mehta K and Pasricha PJ: Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology. 141:370–377. 2011. View Article : Google Scholar : PubMed/NCBI
29	Bressy C, Lac S, Nigri J, Leca J, Roques J, Lavaut MN, Secq V, Guillaumond F, Bui TT, Pietrasz D, et al: LIF drives neural remodeling in pancreatic cancer and offers a new candidate biomarker. Cancer Res. 78:909–921. 2018. View Article : Google Scholar : PubMed/NCBI
30	Amit M, Na'ara S, Leider-Trejo L, Binenbaum Y, Kulish N, Fridman E, Shabtai-Orbach A, Wong RJ and Gil Z: Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma. Oncogene. 36:3232–3239. 2017. View Article : Google Scholar : PubMed/NCBI
31	Pinho AV, Van Bulck M, Chantrill L, Arshi M, Sklyarova T, Herrmann D, Vennin C, Gallego-Ortega D, Mawson A, Giry-Laterriere M, et al: ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. Nat Commun. 9:50832018. View Article : Google Scholar : PubMed/NCBI
32	Cavel O, Shomron O, Shabtay A, Vital J, Trejo-Leider L, Weizman N, Krelin Y, Fong Y, Wong RJ, Amit M and Gil Z: Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res. 72:5733–5743. 2012. View Article : Google Scholar : PubMed/NCBI
33	De Oliveira T, Abiatari I, Raulefs S, Sauliunaite D, Erkan M, Kong B, Friess H, Michalski CW and Kleeff J: Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol Cancer. 11:192012. View Article : Google Scholar : PubMed/NCBI
34	Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC, Muha EA, Rhim AD and Davis BM: Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci USA. 113:3078–383. 2016. View Article : Google Scholar : PubMed/NCBI
35	Demir IE, Boldis A, Pfitzinger PL, Teller S, Brunner E, Klose N, Kehl T, Maak M, Lesina M, Laschinger M, et al: Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J Natl Cancer Inst. 106:dju1842014. View Article : Google Scholar : PubMed/NCBI
36	Meier JJ and Giese A: Diabetes associated with pancreatic diseases. Curr Opin Gastroenterol. 31:400–406. 2015. View Article : Google Scholar : PubMed/NCBI
37	Pavlova NN and Thompson CB: The emerging hallmarks of cancer metabolism. Cell Metab. 23:27–47. 2016. View Article : Google Scholar : PubMed/NCBI
38	Chen X, Wanggou S, Bodalia A, Zhu M, Dong W, Fan JJ, Yin WC, Min HK, Hu M, Draghici D, et al: A Feedforward mechanism mediated by mechanosensitive ion channel PIEZO1 and tissue mechanics promotes glioma aggression. Neuron. 100:799–815.e7. 2018. View Article : Google Scholar : PubMed/NCBI
39	Li J and Ma Q: Hyperglycemia promotes the perineural invasion in pancreatic cancer. Med Hypotheses. 71:386–389. 2008. View Article : Google Scholar : PubMed/NCBI