Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer

We analyzed Rac1 activity and Pak1 protein expression in matched sets of tumor tissue, non-tumor tissue, and metastatic lymph node tissue obtained from the surgical specimens of 108 Japanese patients with UC-UUT.Rac1 activity and Pak1 protein levels were higher in tumor tissue and metastatic lymph node tissue than in non-tumor tissue (both P < 0.0001). A high level of Rac1 activity and Pak1 protein expression in the primary tumor was related to poor differentiation (P < 0.05), muscle invasion (P < 0.01), LVI (P < 0.0001), and lymph node metastasis (P < 0.0001). Kaplan-Meier survival analysis showed that an increase of Rac1 activity and Pak1 protein was associated with a shorter disease-free survival time (P < 0.01) and shorter overall survival (P < 0.001). Cox proportional hazards analysis revealed that high Rac1 activity, Pak1 protein expression and LVI were independent prognostic factors for shorter overall and disease-free survival times (P < 0.01) on univariate analysis, although only Pak1 and LVI had an influence (P < 0.05) according to multivariate analysis.These findings suggest that Rac1 activity and Pak1 are involved in LVI and lymph node metastasis of UC-UUT, and may be prognostic markers for this disease.Urothelial carcinoma of the upper urinary tract (UC-UUT) is relatively uncommon, accounting for <10% of all urothelial malignancies, but its incidence is increasing [1]. Many patients who undergo curative resection develop systemic metastases within a few years, so the prognosis of this cancer is poor [2], presumably due to occult micrometastasis at the time of surgery because of the thin walls and rich lymphatic drainage of the ureter.Metastasis involves the spread of tumor cells from the primary tumor to a distant site [3], and is the major cause of human cancer death. Various pathological studies have shown that poorly differentiated cancer, muscle invasion, lymph node metastasis, and lymphovascular invasion (LVI) are associated with recurrence and are