Smoking-induced changes in cancer‑related factors in patients with upper tract urothelial cancer

Miyata,Yasuyoshi; Mitsunari,Kensuke; Akihiro,Asai; Watanabe,Shin‑Ichi; Mochizuki,Yasushi; Sakai,Hideki

doi:10.3892/mco.2014.471

Smoking-induced changes in cancer‑related factors in patients with upper tract urothelial cancer

Authors:
- Yasuyoshi Miyata
- Kensuke Mitsunari
- Asai Akihiro
- Shin‑Ichi Watanabe
- Yasushi Mochizuki
- Hideki Sakai
View Affiliations

Affiliations: Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852‑8501, Japan
Published online on: December 2, 2014 https://doi.org/10.3892/mco.2014.471
Pages: 287-294
Copyright: © Miyata 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

Cigarette smoking is a major risk factor for urothelial cancer (UC) development. However, the associations between smoking and changes in the pathological characteristics and molecular expression of cancer‑related molecules in upper tract (UT) UC have not been fully elucidated. We investigated the associations between smoking status and cancer‑related factors, including cancer cell proliferation, apoptosis, angiogenesis, lymphangiogenesis and expression of vascular endothelial growth factor‑A and ‑C, matrix metalloproteinase (MMP)‑2 and ‑9, cyclooxygenase (COX)‑2 and urokinase‑type plasminogen activator, in patients with UTUC. A total of 134 patients who underwent nephroureterectomy were retrospectively investigated. Proliferation index (PI), microvessel density and lymphatic vessel density (LVD) were measured using anti‑Ki‑67, anti‑CD105 and anti‑D2‑40 antibodies in formalin‑fixed specimens. The apoptotic index was evaluated using the terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling method. Other cancer‑related molecules were investigated by immunohistochemistry in similar specimens. The patients were divided into three groups; non‑smoker (n=54, 40.3%), former smoker (n=46, 34.3%) and current smoker (n=34, 25.4%). The PI and the apoptotic index were not found to be correlated with smoking status; however, the mean/standard deviation level of LVD in current smokers (40.9/12.9) was significantly higher (P=0.034) compared to that in patients who had never smoked (34.4/10.6). In addition, smoking status was positively correlated with the presence of intratumoral lymphatic vessels (iLV) (P=0.010) and the expression of COX‑2 and MMP‑9 (P=0.032). The multivariate analysis demonstrated that current smoking was independently associated with all the abovementioned smoking‑related factors. However, former smoking was correlated with LVD and the presence of iLV. In the survival analysis, LVD, the presence of iLV and the expression of COX‑2 and MMP‑9 were identified as predictive factors for metastasis following surgery. In conclusion, lymphangiogenesis and the expression levels of COX‑2 and MMP‑9 were found to be associated with the smoking status of UTUC patients. Our results may provide important insights into the pathological changes precipitated by smoking in these patients.

View Figures

View References

1	Strope SA and Montie JE: The causal role of cigarette smoking in bladder cancer initiation and progression, and the role of urologists in smoking cessation. J Urol. 180:31–37. 2008. View Article : Google Scholar : PubMed/NCBI
2	Huang RY and Chen GG: Cigarette smoking, cyclooxygenase-2 pathway and cancer. Biochim Biophys Acta. 1815:158–169. 2011.PubMed/NCBI
3	Mitra AP, Castelao JE, Hawes D, et al: Combination of molecular alternations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program. Cancer. 119:756–765. 2013. View Article : Google Scholar : PubMed/NCBI
4	Wang YH, Yeh SD, Wu MM, et al: Comparing the joint effect of arsenic exposure, cigarette smoking and risk genotypes of vascular endothelial growth factor on upper urinary tract urothelial carcinoma and bladder cancer. J Hazard Mater. 262:1139–1146. 2013. View Article : Google Scholar : PubMed/NCBI
5	Jensen OM, Knudsen JB, McLaughlin JK and Sørensen BL: The Copenhagen case-control study of renal pelvis and ureter cancer: role of smoking and occupational exposures. Int J Cancer. 41:557–561. 1988. View Article : Google Scholar : PubMed/NCBI
6	Ehdaie B, Furberg H, Zabor EC, et al: Impact of smoking status at diagnosis on disease recurrence and death in upper tract urothelial carcinoma. BJU Int. 111:589–595. 2013. View Article : Google Scholar : PubMed/NCBI
7	Hagiwara M, Kikuchi E, Tanaka N, et al: Impact of smoking status on bladder tumor recurrence after radical nephroureterectomy for upper tract urothelial carcinoma. J Urol. 189:2062–2068. 2013. View Article : Google Scholar : PubMed/NCBI
8	Rink M, Xylinas E, Margulis V, et al: Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Eur Urol. 63:1082–1090. 2013. View Article : Google Scholar : PubMed/NCBI
9	Crivelli JJ, Xylians E, Kluth LA, Rieken M, Rink M and Shariat SF: Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the literature. Eur Urol. 65:742–754. 2014. View Article : Google Scholar : PubMed/NCBI
10	Chen RJ, Chang LW, Lin P and Wang YJ: Epigenetic effects and molecular mechanisms of tumorigenesis induced by cigarette smoke: an overview. J Oncol. 2011:6549312011. View Article : Google Scholar : PubMed/NCBI
11	Miyata Y, Kanda S, Ohba K, et al: Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D. Clin Cancer Res. 12:800–806. 2006. View Article : Google Scholar : PubMed/NCBI
12	Bolenz C and Lotan Y: Translational research in bladder cancer: from molecular pathogenesis to useful tissue biomarkers. Cancer Biol Ther. 10:407–415. 2010. View Article : Google Scholar : PubMed/NCBI
13	Birrane G, Li H, Yang S, Tachado SD and Seng S: Cigarette smoke induces nuclear translocation of heme oxygenase 1 (HO-1) in prostate cancer cells: Nuclear HO-1 promotes vascular endothelial growth factor secretion. Int J Oncol. 42:1919–1928. 2013.PubMed/NCBI
14	Miyata Y, Kanda S, Nomata K, Hayashida Y and Kanetake H: Expression of metalloproteinase-2, metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in transitional cell carcinoma of the upper urinary tract: correlation with tumor stage and survival. Urology. 63:602–608. 2004. View Article : Google Scholar : PubMed/NCBI
15	Bhuvarahamurthy V, Schroeder J, Denkert C, et al: In situ gene expression of urokinase-type plasminogen activator and its receptor in transitional cell carcinoma of the human bladder. Oncol Rep. 12:909–913. 2004.PubMed/NCBI
16	AJCC, . Renal pelvis and ureter. In: American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th. New York, NY: Springer; pp. 329–334. 2002
17	Mostofi FK, Sobin LH and Torloni H: Histological typing of urinary bladder tumorsInternational Histological Classification of Tumors, No. 10. Geneva: World Health Organization; 1973
18	Miyata Y, Kanda S, Sakai H, Hakariya T and Kanetake H: Relationship between changes in prostate cancer cell proliferation, apoptotic index, and expression of apoptosis-related proteins by neoadjuvant hormonal therapy and duration of such treatment. Urology. 65:1238–1243. 2005. View Article : Google Scholar : PubMed/NCBI
19	Miyata Y, Sagara Y, Watanabe S, et al: CD105 is a more appropriate marker for evaluating angiogenesis in urothelial cancer of the upper urinary tract than CD31 or CD34. Virchows Arch. 463:673–679. 2013. View Article : Google Scholar : PubMed/NCBI
20	Miyata Y, Kanda S, Ohba K, et al: Tumor lymphangiogenesis in transitional cell carcinoma of the upper urinary tract: association with clinicopathological features and prognosis. J Urol. 176:348–353. 2006. View Article : Google Scholar : PubMed/NCBI
21	Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T and Kanetake H: Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. J Urol. 174:461–465. 2005. View Article : Google Scholar : PubMed/NCBI
22	Oku S, Higashi M, Imazono Y, et al: Overexpression of cyclooxygenase-2 in high-grade human transitional cell carcinoma of the upper urinary tract. BJU Int. 91:109–114. 2003. View Article : Google Scholar : PubMed/NCBI
23	Ishida M, Mikami S, Kikuchi E, et al: Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer. Carcinogenesis. 31:287–295. 2010. View Article : Google Scholar : PubMed/NCBI
24	von Hardenberg J, Martini T, Knauer A, et al: Expression and predictive value of lymph-specific markers in urothelial carcinoma of the bladder. Urol Oncol. 32:54.e9–17. 2014. View Article : Google Scholar
25	Kamat AM, Sethi G and Aggarwal BB: Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines though down-regulation of nuclear factor-kappa B and nuclear factor-kappa B-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells. Mol Cancer Ther. 6:1022–1030. 2007. View Article : Google Scholar : PubMed/NCBI
26	Badawi AF, Habib SL, Mohammed MA, Abadi AA and Michael MS: Influence of cigarette smoking on prostaglandin synthesis and cyclooxygenase-2 gene expression in human urinary bladder cancer. Cancer Invest. 20:651–656. 2002. View Article : Google Scholar : PubMed/NCBI
27	Srivastava P, Mandhani A, Kapoor R and Mittal RD: Role of MMP-3 and MMP-9 and their haplotypes in risk of bladder cancer in North Indian cohort. Ann Surg Oncol. 17:3068–3075. 2010. View Article : Google Scholar : PubMed/NCBI
28	Shishodia S, Potdar P, Gairola CG and Aggarwal BB: Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappa B activation through inhibition of Ikappa Balpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis. 24:1269–1279. 2003. View Article : Google Scholar : PubMed/NCBI
29	Ye YN, Wu WK, Shin VY and Cho CH: A mechanistic study of colon cancer growth promoted by cigarette smoke extract. Eur J Pharmacol. 519:52–57. 2005. View Article : Google Scholar : PubMed/NCBI
30	Dellalibera-Joviliano R, Jacob-Ferreira AL, Joviliano EE, Tanus-Santos JE and Evora PR: Imbalanced matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 activities in patients with thromboangiitis obliterans. Vasc Med. 17:73–78. 2012. View Article : Google Scholar : PubMed/NCBI
31	Sivaraman SK, Zachariah G and Annamala P: Effect of smoking on metalloproteinases (MMPs) activity in patients with acute myocardial infarction (AMI). J Clin Diagn Res. 8:27–30. 2014.PubMed/NCBI
32	Ku JH, Byun SS, Jeong H, Kwak C, Kim HH and Lee SE: Lymphovascular invasion as a prognostic factor in the upper urinary tract urothelial carcinoma: a systematic review and meta-analysis. Eur J Cancer. 49:2665–2680. 2013. View Article : Google Scholar : PubMed/NCBI
33	Chen X, Wan J, Liu J, et al: Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer. 69:348–354. 2010. View Article : Google Scholar : PubMed/NCBI
34	Yoo YA, Kang MH, Lee HJ, et al: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res. 71:7061–7070. 2011. View Article : Google Scholar : PubMed/NCBI
35	Morita Y, Hata K, Nakanishi M, Nishisho T, Yura Y and Yoneda T: Cyclooxygenase-2 promotes tumor lymphangiogenesis and lymph node metastasis in oral squamous cell carcinoma. Int J Oncol. 41:885–892. 2012.PubMed/NCBI
36	Lenz P, Pfeiffer R, Baris D, et al: Cell-cycle control in urothelial carcinoma: large-scale tissue array analysis of tumor tissue from Maine and Vermont. Cancer Epidemiol Biomarkers Prev. 21:1555–1564. 2012. View Article : Google Scholar : PubMed/NCBI
37	Rahmani A, Alzohairy M, Khadri H, Mandal AK and Rizvi MA: Expressional evaluation of vascular endothelial growth factor (VEGF) protein in urinary bladder carcinoma patients exposed to cigarette smoke. Int J Clin Exp Pathol. 5:195–202. 2012.PubMed/NCBI
38	Scheidt JH, Yurgel LS, Romanini J, Cherubini K, de Figueiredo MA and Salum FG: Oral squamous cell carcinoma from users and nonusers of tobacco and alcohol: clinicopathologic features and immunoreactivity of VEGF, caspase-3, and p 53. Appl Immunohistochem Mol Morphol. 21:148–153. 2013.PubMed/NCBI
39	Quentin T, Schlott T, Korabiowska M, et al: Alteration of the vascular endothelial growth factor and angiopoietins-1 and −2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression. Anticancer Res. 24:2745–2756. 2004.PubMed/NCBI
40	Mondul AM, Rager HC, Kopp W, Virtamo J and Albanes D: Supplementation with alpha-tocophenol or beta-carotene reduces serum concentrations of vascular endothelial growth factor-D, but not -A or -C, in male smokers. J Nutl. 141:2030–2034. 2011. View Article : Google Scholar
41	Lane D, Gray EA, Mathur RS and Mathur SP: Up-regulation of vascular endothelial growth factor-C by nicotine in cervical cancer cell lines. Am J Reprod Immunol. 53:153–158. 2005. View Article : Google Scholar : PubMed/NCBI
42	Inamine M, Nagai Y, Mitsuhashi A, et al: Cigarette smoke stimulates VEGF-C expression in cervical intraepithelial neoplasia (CIN) 1 and 2 lesions. Int J Clin Oncol. 17:498–504. 2012. View Article : Google Scholar : PubMed/NCBI