Format

Send to

Choose Destination
Elife. 2019 Feb 5;8. pii: e40033. doi: 10.7554/eLife.40033.

FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells.

Author information

1
Knight Cancer Institute, Oregon Health & Science University, Portland, United States.
2
Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, United States.
3
Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, United States.
4
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, United States.
5
Howard Hughes Medical Institute, Chevy Chase, United States.
#
Contributed equally

Abstract

Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion. FGFR inhibition (or gene silencing) interrupts stromal autocrine growth and significantly decreases secretion of FGF2-containing exosomes, resulting in less stromal protection of leukemia cells. Likewise, Fgf2 -/- mice transplanted with retroviral BCR-ABL leukemia survive significantly longer than their +/+ counterparts when treated with TKI. Thus, inhibition of FGFR can modulate stromal function, reduce exosome secretion, and may be a therapeutic option to overcome resistance to TKIs.

Editorial note:

This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

KEYWORDS:

FGF2; FGFR1; bone marrow stroma; cancer biology; drug resistance; exosomes; human; human biology; medicine; microenvironment; mouse

Conflict of interest statement

NJ, JM, IE, SJ, RS, DE, AA, CL, DJ, JT, ET No competing interests declared, BD Is currently principal investigator or co-investigator on Novartis clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead. He does not derive salary, nor does his lab receive funds from these contracts.

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center