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Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes
to Gemcitabine Resistance in Pancreatic Cancer
#MMPMID27792935
Lee J
; Yakubov B
; Ivan C
; Jones DR
; Caperell-Grant A
; Fishel M
; Cardenas H
; Matei D
Neoplasia
2016[Nov]; 18
(11
): 689-698
PMID27792935
show ga
Resistance to chemotherapy is a hallmark of pancreatic ductal adenocarcinoma
(PDA) and has been partly attributed to the dense desmoplastic stroma, which
forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a
Ca(2+)-dependent enzyme, is secreted by PDA cells and cross-links proteins in the
tumor microenvironment (TME) through acyl-transfer between glutamine and lysine
residues, promoting PDA growth. The objective of the current study was to
determine whether secreted TG2 by PDA cells alters the response of pancreatic
tumors to gemcitabine. Orthotopic pancreatic xenografts and co-culture of PDA and
stromal cells were employed to determine the mechanisms by which TG2 alters
tumor-stroma interactions and response to gemcitabine. Analysis of the pancreatic
The Cancer Genome Atlas (TCGA) database demonstrated that increased TG2
expression levels correlate with worse overall survival (hazard ratio=1.37).
Stable TG2 knockdown in PDA cells led to decreased size of pancreatic xenografts
and increased sensitivity to gemcitabine in vivo. However, TG2 downregulation did
not increase cytotoxicity of gemcitabine in vitro. Additionally, multivessel
density and gemcitabine uptake in pancreatic tumor tissue, as measured by mass
spectrometry (MS-HPLC), were not significantly different in tumors expressing TG2
versus tumors in which TG2 was knocked down. Fibroblasts, stimulated by TG2
secreted by PDA cells, secrete laminin A1, which protects cancer cells from
gemcitabine-induced cytotoxicity. In all, our results demonstrate that TG2
secreted in the pancreatic TME orchestrates the cross talk between cancer cells
and stroma, impacting tumor growth and response to chemotherapy. Our study
supports TG2 inhibition to increase the antitumor effects of gemcitabine in PDA.
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