Elsevier

Pharmacology & Therapeutics

Volume 147, March 2015, Pages 22-31
Pharmacology & Therapeutics

Associate editor: B. Teicher
Targeting the TGFβ pathway for cancer therapy

https://doi.org/10.1016/j.pharmthera.2014.11.001Get rights and content
Under a Creative Commons license
open access

Abstract

The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings.

Keywords

Angiogenesis
Fibrosis
Metastasis
Microenvironment
TGFβ inhibitors
Tumor-stroma interactions

Abbreviations

bFGF
basic fibroblast growth factor
bi-shRNAi
bi-functional short hairpin RNAi
CAF
cancer-associated fibroblasts
CR
complete response
CTGF
connective tissue growth factor
ECM
extracellular matrix
EMT
epithelial-to-mesenchymal transition
HCC
hepatocellular carcinoma
HGF
hepatocyte growth factor
HSC
hepatic stellate cell
I-SMAD
inhibitory SMAD
IFN
interferon
IL
interleukin
LOH
loss of heterozygosity
MCP-1
chemoattractant protein-1
MMP
matrix metalloproteinase
MSI
microsatellite instability
NK
natural killer
NOX
NADPH oxidase
NSCLC
non-small cell lung cancer
PBMC
peripheral blood mononuclear cell
PDAC
pancreatic ductal adenocarcinoma
PDGF
platelet-derived growth factor
PR
partial response
PSC
pancreatic stellate cell
OS
overall survival
ROS
reactive oxygen specie
SD
stable disease
TGFβ
transforming growth factor-β
TNFα
tumor necrosis factor-α
Th
T-helper
T-reg
T-regulatory cell
VEGF
vascular endothelial growth factor

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