CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation

Wei Wu,Esther A Zaal,Celia R Berkers,Simone Lemeer,Albert J.R Heck

doi:10.1074/mcp.ra118.000708

Abstract

Fibroblast activation is associated with tumor progression and implicated in metastasis, but the initial triggering signals required to kick-start this process remain largely unknown. Because small cancerous lesions share limited physical contact with neighboring fibroblasts, we reasoned the first tumor-derived signal for fibroblast activation should be secreted and diffusible. By pulsed metabolic labeling and click-chemistry based affinity enrichment, we sieved through the ductal carcinoma secretome for potential fibroblast activators. Using immuno-depletion/supplementation assays on various secreted factors, we pinpointed that tumor-secreted CTGF/VEGFA alone is sufficient to activate paired mammary fibroblasts from the same patient via ROCK1 and JunB signaling. Fibroblasts activated in this manner are distinct in morphology, growth, and adopt a highly tumor-like secretion profile, which in turn promotes tumor migration by counteracting oxidative and lactate stress. These findings reveal a profound division-of-labor between normal and cancer cells under the directive of the latter, and allude to potential metastatic prevention through inhibiting local fibroblast activation.

Highlights

Cancer is a disease of immortal cells in the comfort of their tissue microenvironment
Because tumors begin as small lesions that contact only a few neighboring fibroblasts, physical interactions between the tumor and fibroblast cells can most likely not account for fibroblast activation and recruitment to tumor site at disease onset
From a panel of secreted factors selected in this manner, we show that tumor-derived connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGFA) together are already sufficient to induce mammary fibroblast (Hs578Bst) activation

Summary

Introduction

Cancer is a disease of immortal cells in the comfort of their tissue microenvironment. Tumors that are more tightly encapsulated by ECM are associated with better prognostic outcome [10], whereas the inhibitory role of micro-environmental oxidative stress on tumor migration has been described recently [11]. In view of these findings, targeting fibroblasts in the tumor environment should be of therapeutic interest to limit metastatic spread, because these cells that deposit ECM during normal wound healing are activated in cancer and amplified in number with disease progression (Fig. 1). Fibroblast Activation by Tumor-derived CTGF/VEGFA naling events between tumor and fibroblast cells, as mediated through secreted molecular entities

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