Abstract 1421: Inhibition of melanoma growth by activation of Notch pathway in stromal fibroblasts

Abstract

Abstract Background. Tumor microenvironment influences tumor initiation and progression. Fibroblasts are major components of tumor stroma and critically involved in regulating tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell-cell interaction. The Notch pathway regulates a variety of cellular activities. However, it is unknown whether and how manipulation of Notch signaling in stromal fibroblasts affects melanoma growth. Objectives. This study aimed to investigate the effects of Notch-activated stromal fibroblasts on melanoma growth and elucidate the underlying mechanism. Methods. Enforced activation of Notch pathway was achieved by transducing fibroblasts with lentiviral vector encoding activated Notch1 (NIC). The effect of Notch1-activated stromal fibroblasts on melanoma growth was tested by in vitro co-culture and in vivo co-injection approaches. The soluble factor which produced by Notch1-activated fibroblasts was identified by PCR Array and validated by Western blot analysis. Function of the candidate factor in mediating the inhibitory effect of Notch1-activated stromal fibroblasts on melanoma growth was examined through siRNA-mediated blockade approach and tested by in vitro cell co-culture and in vivo tumor xenografting animal models. Results. Notch1-activated fibroblasts significantly inhibited melanoma growth by inducing tumor cell apoptosis and suppressing tumor angiogenesis. The inhibitory effect of NIC-engineered fibroblasts was mediated by up-regulating WISP-1 expression. Elevated WISP-1 suppressed melanoma growth while blockade of WISP-1 liberated the inhibitory effect. Conclusions. Activation of Notch pathway in stromal fibroblasts can suppress melanoma growth, partially through WISP-1. Our study provides a novel approach to target tumor microenvironment through modulating stromal fibroblasts by manipulation of Notch signaling, and highlights WISP-1 as a potential therapeutic target in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1421.