TGF-β: friend or foe? The role of TGF-β/SMAD signaling in epigenetic silencing of ovarian cancer and its implication in epigenetic therapy

Abstract

Disruption of TGF-β/SMAD signaling leads to epigenetic silencing of its target genes transiently through histone modifications but permanently by promoter hypermethylation. Targeting the TGF-β signaling pathway may be a novel therapeutic strategy in ovarian cancer.

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

“…The so-far reported interactions between TGF-b and NF-kB in tumor cells provide a confusing view, with TGF-b playing the role of either an inhibitor or activator of NF-kB signaling in different cell types. Besides, although TGF-b acts as a potent tumor suppressor in normal ovarian surface epithelial cells, the loss of growth-inhibitory responses is an early event in ovarian cancer and yet TGF-b acts as a tumor-promoting agent in advanced ovarian cancer (37). On the basis of these data, it has been suggested that in the context of ovarian cancer, mutations and/or alterations of the key nodes along canonical TGF-b pathway shift TGF-b to noncanonical pathways such as activation of NF-kB which describes the pro-oncogenic role of TGF-b in advanced ovarian cancer (38,39).…”

Dysregulated TGFB Signaling in Ovarian Cancer

“…There are in essence three major groups of TGF signaling therapeutics: (1) ligand traps including monoclonal TGF neutralizing antibodies and soluble TGFRI/RII; (2) antisense molecule mediated silencing strategies for targeting TGF ligands; and (3) small molecule inhibitors targeting TGFRI/RII and downstream mediators (Chou et al, 2010;Iyer et al, 2005;Korpal & Kang, 2010;Nagaraj & Datta, 2010). Neutralizing antibodies are designed to disrupt the interactions between TGF ligands and their cell-surface receptors (Chou et al, 2010). Some of these include 2G7 and 1D11 monoclonal antibodies which hinder the activity of all three TGF ligands to reduce tumor growth and metastasis (Chou et al, 2010).…”

“…Neutralizing antibodies are designed to disrupt the interactions between TGF ligands and their cell-surface receptors (Chou et al, 2010). Some of these include 2G7 and 1D11 monoclonal antibodies which hinder the activity of all three TGF ligands to reduce tumor growth and metastasis (Chou et al, 2010). GC1008 is yet another neutralizing antibody which entered a Phase I/II clinical trial for advanced malignant melanoma and renal cell carcinoma patients (Chou et al, 2010).…”

“…Some of these include 2G7 and 1D11 monoclonal antibodies which hinder the activity of all three TGF ligands to reduce tumor growth and metastasis (Chou et al, 2010). GC1008 is yet another neutralizing antibody which entered a Phase I/II clinical trial for advanced malignant melanoma and renal cell carcinoma patients (Chou et al, 2010). Soluble ligand traps include soluble TGFRII/III which hinder TGF interaction with its cognate cell surface receptors leading to inhibition of tumor growth and metastasis in athymic murine models (Chou et al, 2010).…”

“…GC1008 is yet another neutralizing antibody which entered a Phase I/II clinical trial for advanced malignant melanoma and renal cell carcinoma patients (Chou et al, 2010). Soluble ligand traps include soluble TGFRII/III which hinder TGF interaction with its cognate cell surface receptors leading to inhibition of tumor growth and metastasis in athymic murine models (Chou et al, 2010). Antisense oligonucleotides are yet another route to block TGF signaling, specifically against TGF1 gene expression which reduced tumor survival and metastasis in mouse models (Chou et al, 2010).…”