Phospho-Akt pathway activation and inhibition depends on N-cadherin or phospho-EGFR expression in invasive human bladder cancer cell lines.

OBJECTIVES: A particular interest in epithelial-mesenchymal transition (EMT), which takes place during embryonic development, provided potential mechanisms involved in the progression of many epithelial tumors, including bladder cancer (BC). The phospho-Akt signaling pathway is supposed to be involved in invasion and progression of human tumors, including BC. Moreover, it has been demonstrated in bladder cancer cell lines that N-cadherin or phospho-epithelial growth factor receptor (EGFR) expression are correlated to tumor progression. Our objectives were to evaluate the potential phospho-Akt pathway involvement in N-cadherin and/or phospho-EGFR positive BC cell lines and to evaluate the prognostic value of E- and N-cadherin expression in patients undergoing cystectomy for invasive BC. MATERIALS AND METHODS: We screened a panel of invasive and noninvasive BC cell lines for E- and N-cadherin, phospho-EGFR, and phospho-Akt expression using the Western blot technique (WB). The potential role of N-cadherin in invasion was assessed by Matrigel assays with and without the N-cadherin blocking monoclonal antibody GC-4. Then we used the Affymetrix microarray technique to evaluate the prognostic value of E- and N-cadherin expression in 30 patients undergoing a cystectomy for invasive BC. RESULTS: N-cadherin and phospho-EGFR expression are associated with Akt activation and with invasive behavior modulation. Even if Akt activation is sufficient in promoting invasion, its inactivation by LY294002 (PI-3 kinase inhibitor) is less efficient on invasion than inhibition of N-cadherin and phospho-EGFR by GC-4 (monoclonal antibody) and gefitinib (anti-tyrosine kinase), respectively. N-cadherin and phospho-EGFR inhibition decreased phospho-Akt activation but also caused restoration and reinforcing of E-cadherin expression, respectively, while phospho-Akt inhibition did not have any impact on E-cadherin expression. In a group of high-risk bladder tumors (T(1)G(3)), N- and E-cadherin expression could be considered as a prognostic marker. In a group of patients with invasive BC (pT(2)-T(4)) undergoing cystectomy, we showed a shorter overall survival when BC expressed N-cadherin (P = 0.0064) and when E-cadherin expression was down-regulated (P = 0.00165). The N (positive) /E (negative) profile has the worst prognosis (P = 0.00153). CONCLUSIONS: We confirmed the partial responsibility of p-Akt activation in invasion of some BC cell lines expressing N-cadherin or p-EGFR and also the potential role of N-cadherin and p-EGFR as target in cancer therapy. N/E- cadherin expression profile has a significant prognostic value in invasive BC.

Molecular targeting in the treatment of either advanced or metastatic bladder cancer or both according to the signalling pathways.

PURPOSE OF REVIEW: An estimated 300,000 new cases of bladder cancer worldwide are diagnosed annually. Although new cytotoxic chemotherapeutic agents for either advanced or metastatic bladder cancer or both are used, no improvement in survival has been observed. Indeed, the 5-year survival rate of metastatic bladder cancer is very low (6%). The target-directed approach is an attractive challenge for treating specific genetic alterations involved in progression and metastasis development. This article aims to describe the new targeted therapies available to cure advanced cancer or metastatic bladder cancer or both according to the signalling pathways potentially involved. RECENT FINDINGS: The rapidly expanding understanding of the pathogenesis of bladder cancer at the molecular level has led to the identification of signalling pathways involved in this disease and provided molecular targets for new biological agents directed against tumorigenesis and progression. The recent results of clinical trials have not only highlighted the need to select patients who could benefit from such a therapy but also the fact that oncology has completely entered into a new era. SUMMARY: Toxic chemotherapeutic agents are slowly being supplemented by a new generation of drugs that recognize specific targets in or on cancer cells. Recent technological advances in pharmacogenomics and proteomics have led to an improvement in identifying biomarkers predictive of response and thereby to identify patients who would be more likely to respond to such a therapy. There is a real hope to improve both the efficiency and the tolerability of bladder cancer treatment.