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.
Keywords: cyclooxygenase-2; lymphangiogenesis; matrix metalloproteinases; prognosis; smoking; upper tract urothelial cancer.