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Targeting of cancer?associated fibroblasts enhances the efficacy of cancer
chemotherapy by regulating the tumor microenvironment
#MMPMID26846566
Li M
; Li M
; Yin T
; Shi H
; Wen Y
; Zhang B
; Chen M
; Xu G
; Ren K
; Wei Y
Mol Med Rep
2016[Mar]; 13
(3
): 2476-84
PMID26846566
show ga
Cancer?associated fibroblasts (CAFs), key components of the tumor stroma, can
regulate tumorigenesis by altering the tumor microenvironment in variety of ways
to promote angiogenesis, recruit inflammatory immune cells and remodel the
extracellular matrix. Using a murine xenograft model of colon carcinoma, the
present study observed that oxaliplatin increased the accumulation of CAFs and
stimulated the production of cytokines associated with CAFs. When oxaliplatin was
combined with the small?molecule dipeptidyl peptidase inhibitor PT?100, which
inhibits CAFs by targeting fibroblast activation protein (FAP), the accumulation
of CAFs was markedly reduced, xenograft tumor growth was significantly suppressed
and the survival of the mice increased, compared to those of mice treated with
oxaliplatin or PT?100 alone. Furthermore, the xenograft tumor tissues of mice
treated with oxaliplatin and PT?100 contained lower numbers of tumor?associated
macrophages and dendritic cells, expressed lower levels of cytokines associated
with CAFs and had a lower density of CD31+ endothelial cells. The present study
demonstrated that pharmacological inhibition of CAFs improved the response to
chemotherapy, reduced the recruitment of immune tumor?promoting cells and
inhibited angiogenesis. Combining chemotherapy with agents which target CAFs may
represent a novel strategy for improving the efficacy of chemotherapy and
reducing chemoresistance.
|Animals
[MESH]
|Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use
[MESH]
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