A Paradoxical Correlation of Cancer-Associated Fibroblasts With Survival Outcomes in B-Cell Lymphomas and Carcinomas.

Marcela Haro,Sandra Orsulic

doi:10.3389/fcell.2018.00098

Marcela Haro, Sandra Orsulic

Open Access

https://doi.org/10.3389/fcell.2018.00098

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Abstract

The tumor microenvironment is increasingly recognized as an active participant in tumor progression. A recent pan-cancer genomic profile analysis has revealed that gene signatures representing components of the tumor microenvironment are robust predictors of survival. A stromal gene signature representing fibroblasts and extracellular matrix components has been associated with good survival in diffuse large B-cell lymphoma (DLBCL). Paradoxically, a closely related gene signature has been shown to correlate with poor survival in carcinomas, including breast, ovarian, pancreatic, and colorectal cancer. To date, there has been no explanation for this paradoxical inverse correlation with survival outcomes in DLBCL and carcinomas. Using public gene data sets, we confirm that the DLBCL stromal gene signature is associated with good survival in DLBCL and several other B-cell lymphomas while it is associated with poor survival in ovarian cancer and several other solid tumors. We show that the DLBCL stromal gene signature is enriched in lymphoid fibroblasts in normal lymph nodes and in cancer-associated fibroblasts (CAFs) in ovarian cancer. Based on these findings, we propose several possible mechanisms by which CAFs may contribute to opposite survival outcomes in B-cell lymphomas and carcinomas.

Highlights

During the past decade, gene expression profile analyses of frozen tumor pieces have been widely used to quantify various biological characteristics of malignant tumor cells and the microenvironment in which they reside
Using the diffuse large B-cell lymphoma (DLBCL) stromal-1 gene signature represented by 50 genes (Lenz et al, 2008), we confirmed that the signature is associated with poor survival in carcinomas and brain tumors and good survival in DLBCL and several other B-cell lymphomas (Table 1)
To identify immune cell types that express the DLBCL stromal1 and stromal-2 signature genes, we looked for enrichment of these genes in the transcriptomes of 249 normal immunological cell types that had been isolated from mice and characterized by the Immunological Genome Project (ImmGen) (Heng and Painter, 2008; Shay and Kang, 2013)

Summary

Introduction

Gene expression profile analyses of frozen tumor pieces have been widely used to quantify various biological characteristics of malignant tumor cells and the microenvironment in which they reside. Similar to lymphoid fibroblasts in normal lymph nodes, cancer-associated fibroblasts (CAFs) are stromal cells that produce ECM, provide scaffolding, and exert regulatory functions through growth factors, cytokines, and chemokines that can promote tumor growth, angiogenesis, invasion, and metastasis (Kalluri and Zeisberg, 2006; Levental et al, 2009; Lu et al, 2012; Spano and Zollo, 2012; Harper and Sainson, 2014).

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Conclusion