Prognostic relevance of Tiam1 protein expression in prostate carcinomas

Abstract

The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (P<0.001) and prostate carcinomas (P<0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. > or =3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P=0.016), the presence of lymph vessel invasion (P=0.031) and high Gleason scores (GS) (i.e. > or =7) (P=0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P=0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk= 3.75, 95% confidence interval=1.06-13.16; P=0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.

Figure 1

Immunohistochemical analysis of Tiam1 protein expression in human prostate cancer patients. Tiam1 expression was strongly increased in preneoplastic HG-PIN lesions (A) and prostate cancer (Ca) (B) as compared to adjacent benign secretory epithelium (Normal). Please note that fibromuscular stromal cells (FMS) were negative for Tiam1 expression. (C) Comparison of Tiam1 expression levels (mean±s.d.) in benign secretory epithelium (n=60), HG-PIN lesions (n=55), and prostate cancer (n=60) as determined by semiquantitative immunohistochemistry. Tiam1 expression levels were significantly higher in prostate cancer and HG-PIN lesions than in benign secretory epithelium (two-sided Wilcoxon test). (D) Tiam1 expression in inflammatory cells of prostate cancer patients. Tiam1 was strongly expressed in plasma cells (P) and weakly expressed in lymphocytes (L) and histiocytes (H). In contrast, neutrophilic granulocytes (N) proved to be negative. Moreover, Tiam1 was weakly expressed in adjacent benign epithelial cells (BE). (E) In addition to prostate cancer (Ca), strong Tiam1 expression was also seen in ganglion cells (G) adjacent to the prostate, whereas lymphocytes (L) exhibited only low Tiam1 expression levels. Original magnifications: (A) × 250; (B) × 100; (D) × 400; (E) × 200.

Figure 2

Kaplan–Meier analysis was performed after stratifying the data (A) as pT2 (organ-confined tumours)/pT3 (tumours with extraprostatic extension) and Tiam1 strong (s)/weak (w) and (B) as GS <7/⩾7 and Tiam1 strong (s)/weak (w). Statistical analysis was performed by means of the two-sided log-rank test.