Therapy-Educated Mesenchymal Stem Cells Enrich for Tumor-Initiating Cells.
Cancer Res
; 78(5): 1253-1265, 2018 03 01.
Article
in En
| MEDLINE
| ID: mdl-29301792
ABSTRACT
Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10-CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.Significance:
These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253-65. ©2018 AACR.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Neoplastic Stem Cells
/
Biomarkers, Tumor
/
Cell Transformation, Neoplastic
/
Deoxycytidine
/
Mesenchymal Stem Cells
/
Lung Neoplasms
Language:
En
Journal:
Cancer Res
Year:
2018
Document type:
Article
Affiliation country:
Israel