Targeting the TGFβ pathway for cancer therapy

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.

Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis

“…Enhanced stiffness is thought to promote tumor cell β 1 integrin activation, leading to more invasive tumor phenotypes and metastasis, consistent with the strong correlation of TGF-β1 signaling with poor cancer prognosis (9,13,14). For these and other reasons there has been much interest in TGF-β1 signaling as a therapeutic target (15)(16)(17).…”

“…Eight-week-old C57BL/6 mice were intratracheally instilled with saline or 1.9 units/kg of bleomycin (Sigma-Aldrich). Mice were implanted with Alzet osmotic pumps (1007D, DURECT Corp.) loaded with EA salt (24 mg/kg/d, days [10][11][12][13][14][15][16][17], fed with red raspberry diet (EA chow, days 0-21), or gavaged with corilagin (100 mg/kg, days 10-21). Controls were treated with control pump, control diet, or vehicle in the same formulation.…”

The Importance of Controlling the TGF-β Signaling Pathway in the Gastric Cancer Microenvironment

“…Numerous excellent reviews extensively cover TGF-β signal transduction [14][15][16][17]. Briefly, the TGF-β superfamily comprises more than 30 different members, including the TGF-βs (comprising the three highly homologous isoforms TGF-β1, TGF-β2, and TGF-β), activins, NODAL, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), and anti-Mullerian hormone (AMH) [18].…”

“…Furthermore, the outcomes of several Phase I and Phase II clinical trials show that therapeutics targeted to TGF-β are safe and efficacious for patients with colorectal, hepatocellular, and non-small cell lung cancer as well as patients with pancreatic ductal carcinoma and other cancers. Many of these trials are in progress [16]. In contrast, clinical trials of TGF-β inhibitors targeting gastric cancer have not been implemented.…”

Untitled

“…Inhibition of TGFβ signaling pathway is an emerging strategy for cancer therapy where prevention can be taken at early stage of tumor formation 5 .…”