Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells

Overview

Journal Cancer Res

Specialty Oncology

Date 2017 Jul 9

PMID 28687621

Citations 112

Authors

Lucia Borriello

Rie Nakata

Michael A Sheard

G Esteban Fernandez

Richard Sposto

Jemily Malvar

Laurence Blavier

Hiroyuki Shimada

Shahab Asgharzadeh

Robert C Seeger

Yves A DeClerck

Affiliations

Soon will be listed here.

Abstract

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1-expressing CAFs that share phenotypic and functional characteristics with bone marrow-derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. .

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