Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL‑8 production in pancreatic cancer

Imafuji,Hiroyuki; Matsuo,Yoichi; Ueda,Goro; Omi,Kan; Hayashi,Yuichi; Saito,Kenta; Tsuboi,Ken; Morimoto,Mamoru; Koide,Shuji; Ogawa,Ryo; Hara,Masayasu; Takahashi,Hiroki; Takiguchi,Shuji

doi:10.3892/or.2019.7105

Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL‑8 production in pancreatic cancer

Authors:
- Hiroyuki Imafuji
- Yoichi Matsuo
- Goro Ueda
- Kan Omi
- Yuichi Hayashi
- Kenta Saito
- Ken Tsuboi
- Mamoru Morimoto
- Shuji Koide
- Ryo Ogawa
- Masayasu Hara
- Hiroki Takahashi
- Shuji Takiguchi
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Affiliations: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Mizuho‑cho, Mizuhoku, Nagoya, Aichi 467‑8601, Japan
Published online on: April 9, 2019 https://doi.org/10.3892/or.2019.7105
Pages: 3508-3516

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Abstract

Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem‑R). To elucidate the mechanism of Gem‑R, two Gem‑R PaCa cell lines were established from AsPC‑1 and MIA PaCa‑2 cells. It was demonstrated that expression of interleukin‑8 (IL‑8) mRNA was significantly upregulated in Gem‑R PaCa cells by cDNA microarray and RT‑qPCR analyses. Increased IL‑8 secretion by Gem‑R cells was confirmed by cytokine array and enzyme‑linked immunosorbent assay. Moreover, we found that co‑culture with Gem‑R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti‑CXCR2 (main receptor for IL‑8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL‑8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem‑R increased IL‑8 production and consequently increased tumor angiogenesis, the IL‑8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem‑R.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Ilic M and Ilic I: Epidemiology of pancreatic cancer. World J Gastroenterol. 22:9694–9705. 2016. View Article : Google Scholar : PubMed/NCBI
3	Niedergethmann M, Alves F, Neff JK, Heidrich B, Aramin N, Li L, Pilarsky C, Grützmann R, Allgayer H, Post S, et al: Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model. Br J Cancer. 97:1432–1440. 2007. View Article : Google Scholar : PubMed/NCBI
4	Kamisawa T, Wood LD, Itoi T and Takaori K: Pancreatic cancer. Lancet. 388:73–85. 2016. View Article : Google Scholar : PubMed/NCBI
5	Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H and Kleeff J: Preoperative/neoadjuvant therapy in pancreatic cancer: A systematic review and meta-analysis of response and resection percentages. PLoS Med. 7:e10002672010. View Article : Google Scholar : PubMed/NCBI
6	Wong HH and Lemoine NR: Pancreatic cancer: Molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol. 6:412–422. 2009. View Article : Google Scholar : PubMed/NCBI
7	Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 15:2403–2413. 1997. View Article : Google Scholar : PubMed/NCBI
8	Raman D, Baugher PJ, Thu YM and Richmond A: Role of chemokines in tumor growth. Cancer Lett. 256:137–165. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kulbe H, Levinson NR, Balkwill F and Wilson JL: The chemokine network in cancer-much more than directing cell movement. Int J Dev Biol. 48:489–496. 2004. View Article : Google Scholar : PubMed/NCBI
10	Baggiolini M, Walz A and Kunkel SL: Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. 84:1045–1049. 1989. View Article : Google Scholar : PubMed/NCBI
11	Kuwada Y, Sasaki T, Morinaka K, Kitadai Y, Mukaida N and Chayama K: Potential involvement of IL-8 and its receptors in the invasiveness of pancreatic cancer cells. Int J Oncol. 22:765–771. 2003.PubMed/NCBI
12	Brat DJ, Bellail AC and Van Meir EG: The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol. 7:122–133. 2005. View Article : Google Scholar : PubMed/NCBI
13	Konno H, Ohta M, Baba M, Suzuki S and Nakamura S: The role of circulating IL-8 and VEGF protein in the progression of gastric cancer. Cancer Sci. 94:735–740. 2003. View Article : Google Scholar : PubMed/NCBI
14	Todorović-Raković N and Milovanović J: Interleukin-8 in breast cancer progression. J Interferon Cytokine Res. 33:563–570. 2013. View Article : Google Scholar : PubMed/NCBI
15	Lin Y, Huang R, Chen L, Li S, Shi Q, Jordan C and Huang RP: Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays. Int J Cancer. 109:507–515. 2004. View Article : Google Scholar : PubMed/NCBI
16	Shi J and Wei PK: Interleukin-8: A potent promoter of angiogenesis in gastric cancer. Oncol Lett. 11:1043–1050. 2016. View Article : Google Scholar : PubMed/NCBI
17	Ning Y, Manegold PC, Hong YK, Zhang W, Pohl A, Lurje G, Winder T, Yang D, LaBonte MJ, Wilson PM, et al: Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int J Cancer. 128:2038–2049. 2011. View Article : Google Scholar : PubMed/NCBI
18	Jia L, Li F, Shao M, Zhang W, Zhang C, Zhao X, Luan H, Qi Y, Zhang P, Liang L, et al: IL-8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells. Oncol Lett. 15:1350–1356. 2018.PubMed/NCBI
19	Srivastava SK, Bhardwaj A, Arora S, Tyagi N, Singh AP, Carter JE, Scammell JG, Fodstad Ø and Singh S: Interleukin-8 is a key mediator of FKBP51-induced melanoma growth, angiogenesis and metastasis. Br J Cancer. 112:1772–1781. 2015. View Article : Google Scholar : PubMed/NCBI
20	Matsuo Y, Raimondo M, Woodward TA, Wallace MB, Gill KR, Tong Z, Burdick MD, Yang Z, Strieter RM, Hoffman RM and Guha S: CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer. Int J Cancer. 125:1027–1037. 2009. View Article : Google Scholar : PubMed/NCBI
21	Matsuo Y, Sawai H, Funahashi H, Takahashi H, Sakamoto M, Yamamoto M, Okada Y, Hayakawa T and Manabe T: Enhanced angiogenesis due to inflammatory cytokines from pancreatic cancer cell lines and relation to metastatic potential. Pancreas. 28:344–352. 2004. View Article : Google Scholar : PubMed/NCBI
22	Osugi T, Oshima Y, Fujio Y, Funamoto M, Yamashita A, Negoro S, Kunisada K, Izumi M, Nakaoka Y, Hirota H, et al: Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart. J Biol Chem. 277:6676–6681. 2002. View Article : Google Scholar : PubMed/NCBI
23	Bishop ET, Bell GT, Bloor S, Broom IJ, Hendry NF and Wheatley DN: An in vitro model of angiogenesis: Basic features. Angiogenesis. 3:335–344. 1999. View Article : Google Scholar : PubMed/NCBI
24	Matsuo Y, Ochi N, Sawai H, Yasuda A, Takahashi H, Funahashi H, Takeyama H, Tong Z and Guha S: CXCL8/IL-8 and CXCL12/SDF-1alpha co-operatively promote invasiveness and angiogenesis in pancreatic cancer. Int J Cancer. 124:853–861. 2009. View Article : Google Scholar : PubMed/NCBI
25	Ohhashi S, Ohuchida K, Mizumoto K, Fujita H, Egami T, Yu J, Toma H, Sadatomi S, Nagai E and Tanaka M: Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer. Anticancer Res. 28:2205–2212. 2008.PubMed/NCBI
26	Minami K, Shinsato Y, Yamamoto M, Takahashi H, Zhang S, Nishizawa Y, Tabata S, Ikeda R, Kawahara K, Tsujikawa K, et al: Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. J Pharmacol Sci. 127:319–325. 2015. View Article : Google Scholar : PubMed/NCBI
27	Waters JA, Matos J, Yip-Schneider M, Aguilar-Saavedra JR, Crean CD, Beane JD, Dumas RP, Suvannasankha A and Schmidt CM: Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts. Surgery. 158:881–889. 2015. View Article : Google Scholar : PubMed/NCBI
28	Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse ML, Fölsch UR and Schäfer H: Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 22:3243–3251. 2003. View Article : Google Scholar : PubMed/NCBI
29	Zheng C, Jiao X, Jiang Y and Sun S: ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells. J Int Med Res. 41:300–306. 2013. View Article : Google Scholar : PubMed/NCBI
30	Wang R, Cheng L, Xia J and Wang Z, Wu Q and Wang Z: Gemcitabine resistance is associated with epithelial-mesenchymal transition and induction of HIF-1α in pancreatic cancer cells. Curr Cancer Drug Targets. 14:407–417. 2014. View Article : Google Scholar : PubMed/NCBI
31	Chen M, Xue X, Wang F, An Y, Tang D, Xu Y, Wang H, Yuan Z, Gao W, Wei J, et al: Expression and promoter methylation analysis of ATP-binding cassette genes in pancreatic cancer. Oncol Rep. 27:265–269. 2012.PubMed/NCBI
32	Quint K, Tonigold M, Di Fazio P, Montalbano R, Lingelbach S, Rückert F, Alinger B, Ocker M and Neureiter D: Pancreatic cancer cells surviving gemcitabine treatment express markers of stem cell differentiation and epithelial-mesenchymal transition. Int J Oncol. 41:2093–2102. 2012. View Article : Google Scholar : PubMed/NCBI
33	Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T, Chen Y, Han X and Wu K: The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 31:61–71. 2016. View Article : Google Scholar : PubMed/NCBI
34	Li A, Dubey S, Varney ML, Dave BJ and Singh RK: IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol. 170:3369–3376. 2003. View Article : Google Scholar : PubMed/NCBI
35	Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR, Otterson MF, Ota DM, Lugering N, Domschke W and Binion DG: Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem. 278:8508–8515. 2003. View Article : Google Scholar : PubMed/NCBI
36	Olson TS and Ley K: Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol. 283:R7–R28. 2002. View Article : Google Scholar : PubMed/NCBI
37	Hertzer KM, Donald GW and Hines OJ: CXCR2: A target for pancreatic cancer treatment? Expert Opin Ther Targets. 17:667–680. 2013. View Article : Google Scholar : PubMed/NCBI
38	Matsuo Y, Campbell PM, Brekken RA, Sung B, Ouellette MM, Fleming JB, Aggarwal BB, Der CJ and Guha S: K-Ras promotes angiogenesis mediated by immortalized human pancreatic epithelial cells through mitogen-activated protein kinase signaling pathways. Mol Cancer Res. 7:799–808. 2009. View Article : Google Scholar : PubMed/NCBI
39	Pan MR, Hsu MC, Luo CW, Chen LT, Shan YS and Hung WC: The histone methyltransferase G9a as a therapeutic target to override gemcitabine resistance in pancreatic cancer. Oncotarget. 7:61136–61151. 2016. View Article : Google Scholar : PubMed/NCBI
40	Matsuo Y, Sawai H, Ochi N, Yasuda A, Sakamoto M, Takahashi H, Funahashi H, Takeyama H and Guha S: Proteasome inhibitor MG132 inhibits angiogenesis in pancreatic cancer by blocking NF-kappaB activity. Dig Dis Sci. 55:1167–1176. 2010. View Article : Google Scholar : PubMed/NCBI
41	Qiao B, Luo W, Liu Y, Wang J, Liu C, Liu Z, Chen S, Gu J, Qi X and Wu T: The prognostic value of CXC chemokine receptor 2 (CXCR2) in cancers: A meta-analysis. Oncotarget. 9:15068–15076. 2017.PubMed/NCBI
42	Song Y, Baba T, Li YY, Furukawa K, Tanabe Y, Matsugo S, Sasaki S and Mukaida N: Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization. Biochem Biophys Res Commun. 458:341–346. 2015. View Article : Google Scholar : PubMed/NCBI
43	Khan MA, Srivastava SK, Bhardwaj A, Singh S, Arora S, Zubair H, Carter JE and Singh AP: Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications. Oncotarget. 6:39140–39150. 2015. View Article : Google Scholar : PubMed/NCBI
44	Maliandi MV, Mato-Berciano A, Sobrevals L, Roué G, José A and Fillat C: AduPARE1A and gemcitabine combined treatment trigger synergistic antitumor effects in pancreatic cancer through NF-κB mediated uPAR activation. Mol Cancer. 14:1462015. View Article : Google Scholar : PubMed/NCBI