Bladder cancer cells interact with vascular endothelial cells triggering EGFR signals to promote tumor progression

Huang,Zhixin; Zhang,Mengzhao; Chen,Guanqiu; Wang,Weiyi; Zhang,Pu; Yue,Yangyang; Guan,Zhenfeng; Wang,Xinyang; Fan,Jinhai

doi:10.3892/ijo.2019.4729

Bladder cancer cells interact with vascular endothelial cells triggering EGFR signals to promote tumor progression

Authors:
- Zhixin Huang
- Mengzhao Zhang
- Guanqiu Chen
- Weiyi Wang
- Pu Zhang
- Yangyang Yue
- Zhenfeng Guan
- Xinyang Wang
- Jinhai Fan
View Affiliations

Affiliations: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
Published online on: February 27, 2019 https://doi.org/10.3892/ijo.2019.4729
Pages: 1555-1566
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Although important progress has been made in elucidating the role of the tumor microenvironment in the development of bladder cancer, little is currently known regarding the interactions with vascular endothelial cells (ECs) that promote cancer progression. In the present study, it is reported that epidermal growth factor receptor ligands induced by the upregulation of vascular endothelial growth factor (VEGF)‑A and VEGF‑C via the VEGF receptor (R)2/nuclear factor‑κB signaling pathway in ECs, may trigger EGFR signaling in bladder cancer cells and promote bladder cancer progression. Furthermore, the interaction between bladder cancer cells and ECs enhanced EC recruitment though the CXCL1/CXCL5/CXCL8‑CXCR2 pathway. Western blotting was used to evaluate the presence of VEGFR, EGFR and nuclear factor‑κB, and reverse transcription‑quantitative polymerase chain reaction was used to evaluate the expression of VEGFR ligands and EGFR ligands. The present results indicate the mechanism by which the indirect interplay between bladder cancer cells and vascular ECs promotes cancer progression, through the VEGFR2 signaling pathway in vascular ECs and through the EGFR signaling pathway in bladder cancer cells.

View Figures

View References

1	Chavan S, Bray F, Lortet-Tieulent J, Goodman M and Jemal A: International variations in bladder cancer incidence and mortality. Eur Urol. 66:59–73. 2014. View Article : Google Scholar : PubMed/NCBI
2	Smith ZL and Guzzo TJ: Urinary markers for bladder cancer. F1000Prime Rep. 5:212013. View Article : Google Scholar : PubMed/NCBI
3	Calderaro J, Rebouissou S, de Koning L, Masmoudi A, Hérault A, Dubois T, Maille P, Soyeux P, Sibony M, de la Taille A, et al: PI3K/AKT pathway activation in bladder carcinogenesis. Int J Cancer. 134:1776–1784. 2014. View Article : Google Scholar
4	Ching CB and Hansel DE: Expanding therapeutic targets in bladder cancer: The PI3K/Akt/mTOR pathway. Lab Invest. 90:1406–1414. 2010. View Article : Google Scholar : PubMed/NCBI
5	López-Knowles E, Hernández S, Malats N, Kogevinas M, Lloreta J, Carrato A, Tardón A, Serra C and Real FX: PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 66:7401–7404. 2006. View Article : Google Scholar : PubMed/NCBI
6	Wu X, Obata T, Khan Q, Highshaw RA, De Vere White R and Sweeney C: The phosphatidylinositol-3 kinase pathway regulates bladder cancer cell invasion. BJU Int. 93:143–150. 2004. View Article : Google Scholar
7	Oka N, Tanimoto S, Taue R, Nakatsuji H, Kishimoto T, Izaki H, Fukumori T, Takahashi M, Nishitani M and Kanayama HO: Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci. 97:1093–1098. 2006. View Article : Google Scholar : PubMed/NCBI
8	Mukherjee N, Houston TJ, Cardenas E and Ghosh R: To be an ally or an adversary in bladder cancer: The NF-κB story has not unfolded. Carcinogenesis. 36:299–306. 2015. View Article : Google Scholar
9	Guan Z, Ding C, Du Y, Zhang K, Zhu JN, Zhang T, He D, Xu S, Wang X and Fan J: HAF drives the switch of HIF-1α to HIF-2α by activating the NF-κB pathway, leading to malignant behavior of T24 bladder cancer cells. Int J Oncol. 44:393–402. 2014. View Article : Google Scholar
10	Bennasroune A, Gardin A, Aunis D, Crémel G and Hubert P: Tyrosine kinase receptors as attractive targets of cancer therapy. Crit Rev Oncol Hematol. 50:23–38. 2004. View Article : Google Scholar : PubMed/NCBI
11	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29(Suppl 16): 15–18. 2002. View Article : Google Scholar
12	Sparmann A and Bar-Sagi D: Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. 6:447–458. 2004. View Article : Google Scholar : PubMed/NCBI
13	Warner KA, Miyazawa M, Cordeiro MMR, Love WJ, Pinsky MS, Neiva KG, Spalding AC and Nör JE: Endothelial cells enhance tumor cell invasion through a crosstalk mediated by CXC chemokine signaling. Neoplasia. 10:131–139. 2008. View Article : Google Scholar : PubMed/NCBI
14	Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J and Wang CY: Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 8:13–23. 2005. View Article : Google Scholar : PubMed/NCBI
15	Zhang Z, Dong Z, Lauxen IS, Filho MS and Nör JE: Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype. Cancer Res. 74:2869–2881. 2014. View Article : Google Scholar : PubMed/NCBI
16	Ferrara N, Hillan KJ, Gerber HP and Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 3:391–400. 2004. View Article : Google Scholar : PubMed/NCBI
17	Shaulian E and Karin M: AP-1 as a regulator of cell life and death. Nat Cell Biol. 4:E131–E136. 2002. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
19	Fus LP and Górnicka B: Role of angiogenesis in urothelial bladder carcinoma. Cent European J Urol. 69:258–263. 2016.PubMed/NCBI
20	Rajjayabun PH, Keegan PE, Lunec J and Mellon JK: erbB receptor expression patterns in human bladder cancer. Urology. 66:196–200. 2005. View Article : Google Scholar : PubMed/NCBI
21	Nicholson RI, Gee JM and Harper ME: EGFR and cancer prognosis. Eur J Cancer. 37(Suppl 4): pp. S9–S15. 2001, View Article : Google Scholar
22	Plate KH, Breier G, Millauer B, Ullrich A and Risau W: Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res. 53:5822–5827. 1993.PubMed/NCBI
23	Holmes K, Roberts OL, Thomas AM and Cross MJ: Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 19:2003–2012. 2007. View Article : Google Scholar : PubMed/NCBI
24	Kaneko T, Zhang Z, Mantellini MG, Karl E, Zeitlin B, Verhaegen M, Soengas MS, Lingen M, Strieter RM, Nunez G, et al: Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth. Cancer Res. 67:9685–9693. 2007. View Article : Google Scholar : PubMed/NCBI
25	Richmond A: Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol. 2:664–674. 2002. View Article : Google Scholar : PubMed/NCBI
26	Miyake M, Hori S, Morizawa Y, Tatsumi Y, Nakai Y, Anai S, Torimoto K, Aoki K, Tanaka N, Shimada K, et al: CXCL1-mediated interaction of cancer cells with tumor-associated macrophages and cancer-associated fibroblasts promotes tumor progression in human bladder cancer. Neoplasia. 18:636–646. 2016. View Article : Google Scholar : PubMed/NCBI
27	Tian YF, Tang K, Guan W, Yang T, Xu H, Zhuang QY and Ye ZQ: OK-432 suppresses proliferation and metastasis by tumor associated macrophages in bladder cancer. Asian Pac J Cancer Prev. 16:4537–4542. 2015. View Article : Google Scholar : PubMed/NCBI
28	Lin C, Lin W, Yeh S, Li L and Chang C: Infiltrating neutrophils increase bladder cancer cell invasion via modulation of androgen receptor (AR)/MMP13 signals. Oncotarget. 6:43081–43089. 2015. View Article : Google Scholar : PubMed/NCBI
29	Gunes S, Sullu Y, Yegin Z, Buyukalpelli R, Tomak L and Bagci H: ErbB receptor tyrosine kinase family expression levels in urothelial bladder carcinoma. Pathol Res Pract. 209:99–104. 2013. View Article : Google Scholar : PubMed/NCBI
30	Appert-Collin A, Hubert P, Crémel G and Bennasroune A: Role of ErbB receptors in cancer cell migration and invasion. Front Pharmacol. 6:2832015. View Article : Google Scholar : PubMed/NCBI
31	Gately K, Forde L, Cuffe S, Cummins R, Kay EW, Feuerhake F and O'Byrne KJ: High coexpression of both EGFR and IGF1R correlates with poor patient prognosis in resected non-small-cell lung cancer. Clin Lung Cancer. 15:58–66. 2014. View Article : Google Scholar
32	Lee HJ, Seo AN, Kim EJ, Jang MH, Kim YJ, Kim JH, Kim SW, Ryu HS, Park IA, Im SA, et al: Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer. Br J Cancer. 112:103–111. 2015. View Article : Google Scholar :
33	Day KC, Lorenzatti Hiles G, Kozminsky M, Dawsey SJ, Paul A, Broses LJ, Shah R, Kunja LP, Hall C, Palanisamy N, et al: HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone. Cancer Res. 77:74–85. 2017. View Article : Google Scholar :
34	Lipponen P and Eskelinen M: Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. Br J Cancer. 69:1120–1125. 1994. View Article : Google Scholar : PubMed/NCBI
35	Lo HW and Hung MC: Nuclear EGFR signalling network in cancers: Linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br J Cancer. 94:184–188. 2006. View Article : Google Scholar : PubMed/NCBI
36	Fine BA, Valente PT, Feinstein GI and Dey T: VEGF, flt-1, and KDR/flk-1 as prognostic indicators in endometrial carcinoma. Gynecol Oncol. 76:33–39. 2000. View Article : Google Scholar : PubMed/NCBI
37	Sato Y, Kanno S, Oda N, Abe M, Ito M, Shitara K and Shibuya M: Properties of two VEGF receptors, Flt-1 and KDR, in signal transduction. Ann NY Acad Sci. 902:201–205; discussion 205-207. 2000. View Article : Google Scholar : PubMed/NCBI
38	Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D, et al: The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 270:27348–27357. 1995. View Article : Google Scholar : PubMed/NCBI
39	Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A and Strieter RM: The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR⁺ CXC chemokine-induced angiogenic activity. J Immunol. 165:5269–5277. 2000. View Article : Google Scholar : PubMed/NCBI
40	Subauste MC and Proud D: Effects of tumor necrosis factor-alpha, epidermal growth factor and transforming growth factor-alpha on interleukin-8 production by, and human rhinovirus replication in, bronchial epithelial cells. Int Immunopharmacol. 1:1229–1234. 2001. View Article : Google Scholar : PubMed/NCBI
41	Richter A, O'Donnell RA, Powell RM, Sanders MW, Holgate ST, Djukanović R and Davies DE: Autocrine ligands for the epidermal growth factor receptor mediate interleukin-8 release from bronchial epithelial cells in response to cigarette smoke. Am J Respir Cell Mol Biol. 27:85–90. 2002. View Article : Google Scholar : PubMed/NCBI
42	Moscova M, Marsh DJ and Baxter RC: Protein chip discovery of secreted proteins regulated by the phosphatidylinositol 3-kinase pathway in ovarian cancer cell lines. Cancer Res. 66:1376–1383. 2006. View Article : Google Scholar : PubMed/NCBI
43	Yeudall WA, Vaughan CA, Miyazaki H, Ramamoorthy M, Choi MY, Chapman CG, Wang H, Black E, Bulysheva AA, Deb SP, et al: Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. Carcinogenesis. 33:442–451. 2012. View Article : Google Scholar