Work

Targeting N-cadherin Increases Vascular Permeability and Differentially Activates AKT in Melanoma

Year: 2014

Type: article

Abstract: In Brief Objective: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. Background: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Methods: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Results: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. Conclusions: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin–targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy. Targeting N-cadherin, an adhesion molecule known to be overexpressed in many melanoma cells, is a promising strategy to augment tumor responses to alkylating therapy. However, the underlying mechanism through which N-cadherin antagonism may alter the efficacy of chemotherapy remains unclear. Here, we report that targeting N-cadherin can increase tumor vascular permeability without altering interstitial fluid pressure, leading to more efficient delivery of protein-bound agents. We also demonstrate that blocking N-cadherin can differentially modulate the PI3K-AKT signaling axis, which can both inhibit and promote tumor growth. These results may explain the variable responses since seen in clinical trials studying the effects of N-cadherin antagonism on regional chemotherapeutics and provide further insight on the role of N-cadherin in melanoma tumor biology.

Source: Annals of Surgery

DOI: 10.1097/sla.0000000000000635