Cross-Species Functional Analysis of Cancer-Associated Fibroblasts Identifies a Critical Role for CLCF1 and IL-6 in Non–Small Cell Lung Cancer In Vivo

Abstract

Cancer-associated fibroblasts (CAFs) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLC, a cross-species functional characterization of mouse and human lung CAFs was performed. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts (NFs) and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in NSCLC patients. This secreted gene signature was upregulated in NFs after long-term exposure to tumor cells, demonstrating that NFs are “educated” by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1-CNTFR and IL6-IL6R signaling, in promoting growth of NSCLC cells. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLC and suggests new avenues for the development of therapeutic strategies.

Radiation-hormesis phenotypes, the related mechanisms and implications for disease prevention and therapy

“…The finding that low-dose gamma rays suppresses fibroblast-derived, IL-6-mediated transformation is supportive of complementary observations of Vicent et al (2012) discussed below. Vicent et al (2012) conducted gene expression analysis comparing normal mouse lung fibroblast and cancerassociated fibroblasts (CAF) from mice. The researchers identified a set of genes (called secreted genes [relates to their associated proteins]) that correlate with the CAF phenotype.…”

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

“…Studies with tumor xenografts, based on co-implantation into mice of either normal fibroblasts or CAFs together with cancer cells, have been performed independently by many groups. They consistently demonstrate significantly increased tumor growth-promoting potential of CAFs compared to normal fibroblasts [105][106][107][108][109][110][111]. CAFs are able to produce tumor-supportive ECM and secrete growth factors and chemokines that further alter the ECM and generate oncogenic signals [112].…”

Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders

“…Gene expression analysis of non-small cell lung carcinoma compared to normal lung revealed a gene signature that predicted patient survival; this signature included upregulation of mRNAs for CLCF1 and IL-6. [65]. Lung fibroblasts overexpressing CLCF1 or IL-6, when co-injected with tumour cells into mice provided greater support for tumour growth in a mouse model in vivo, a response that was decreased in CNTFR-deficient tumour cells, suggesting that cancer-associated fibroblasts expressing CLCF1/CRLF1 may provide a permissive environment for tumour progression.…”