The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma?

Abstract

Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.

Interleukin-6 Induced Proliferation Is Attenuated by Transforming Growth Factor-β-Induced Signaling in Human Hepatocellular Carcinoma Cells

“…While IL-6 was found to have a growth stimulatory effect, we were interested in analyzing the impact of TGF-β, a cytokine abundantly produced in the HCC microenvironment ( 24 ). It is well known that TGF-β induces epithelial to mesenchymal transition (EMT), facilitating tumor cell invasion ( 59 ).…”

“…For example, during the early stages of cancer, it primarily acts as a tumor suppressor, typically by inducing cytostasis and apoptosis, while at later stages, TGF-β is known to promote multiple pro-tumorigenic features like epithelial to mesenchymal transition (EMT), invasion, metastasis, and angiogenesis. TGF-β plays this dichotomous role in hepatocarcinogenesis as well ( 24 ). Comparative functional genomic studies reveal that there might be two distinct groups of TGF-β-responsive genes, early and late, that can be triggered at different stages of liver cancer development, driving the conflicting effects ( 25 ).…”

Inhibition of RFX6 Suppresses the Invasive Ability of Tumor Cells Through the Notch Pathway and Affects Tumor Immunity in Hepatocellular Carcinoma

“…The pathogenesis study of HCC involves the genome, transcriptome, proteome and metabolism. A variety of key signaling pathways contribute to HCC tumorigenesis including the MEK/ERK (2), mitogen-activated protein kinases (MAPK) (3), mammalian target of rapamycin (mTOR) (4), JAK/STAT (5), Hedgehog (6), and TGF-b signaling pathways (7). Studies have sought to target key components in molecular and cellular pathways that are known to have aberrant signaling in HCC.…”

The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications

“…Table 3 compiles the complete information on molecules targeting TGF-β signaling components, including those mentioned above and others. Despite having a favorable tolerability profile in metastatic patients, translating these pharmacological interventions from bench to bedside has proven challenging, given the apparent heterogeneity of HCC tumors [ 321 , 322 , 323 ]. Besides, the clinical implications of the dual and opposing activities of TGF-β signaling are only beginning to be revealed.…”