Targeting the Transforming Growth Factor-beta Signaling in Cancer Therapy

TGF-beta pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-beta (TGF-beta) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-beta related functional contexts. This review discusses the molecular mechanism of the TGF-beta pathway and describes the different ways of tumor suppression and promotion by TGF-beta. In the last part of the review, the data on targeting TGF-beta pathway for cancer treatment is assessed. The TGF-beta inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.

Regulation of Tumor Immune Surveillance and Tumor Immune Subversion by TGF-beta

Transforming growth factor-beta (TGF-beta) is a highly pleiotropic cytokine playing pivotal roles in immune regulation. TGF-beta facilitates tumor cell survival and metastasis by targeting multiple cellular components. Focusing on its immunosuppressive functions, TGF-beta antagonists have been employed for cancer treatment to enhance tumor immunity. TGF-beta antagonists exert anti-tumor effects through #1 activating effector cells such as NK cells and cytotoxic CD8+ T cells (CTLs), #2 inhibiting regulatory/suppressor cell populations, #3 making tumor cells visible to immune cells, #4 inhibiting the production of tumor growth factors. This review focuses on the effect of TGF-beta on T cells, which are differentiated into effector T cells or newly identified tumor-supporting T cells.

Differential Expression of TGF-beta Isoforms in Human Kerationocytes by Narrow Band UVB

BACKGROUND: Transforming growth factor-beta (TGF-beta), a multifunctional growth factor, has three isoforms: TGF-beta1, TGF-beta2, and TGF-beta3. Different isoforms of TGF-beta are associated with different proliferation and differentiation states of the epidermis. Narrow band ultraviolet B (NBUVB) emits a concentrated UVB source of 311 nm. NBUVB 1,000 mJ/cm2 induces apoptosis in approximately 50% of keratinocytes. OBJECTIVE: The purpose of this study was to evaluate whether irradiation with NBUVB would alter the expression and production of TGF-beta1, 2, and 3. METHODS: We measured TGF-beta1, 2, and 3 mRNA and TGF-beta1 and 2 protein levels at 800, 1,000, and 1,200 mJ/cm2 for 24 hours and 48 hours. RESULTS: TGF-beta1 mRNA levels were increased at both 24 hr and 48 hr, TGF-beta2 mRNA levels were decreased at both 24 hr and 48 hr, and TGF-beta3 mRNA levels were increased at 24 hr and similar to control at 48 hr. TGF-beta1 protein levels were increased at 48 hr but decreased at 24 hr. TGF-beta2 protein levels were decreased at both 24 hr and 48 hr. CONCLUSION: The results suggest a possible role for TGF-beta1 after NBUVB irradiation and opposing roles for TGF-beta1 and TGF-beta2 isoforms in NBUVB irradiation.

The Clinical Significance of VEGF and TGF-beta Expression in Osteosarcoma / 대한정형외과학회잡지

INTRODUCTION: The transforming growth factor-beta (TGF-beta ) is a multipotent glycoprotein that has been implicated in tumor development. The vascular endothelial growth factor (VEGF), which is an endothelial-specific mitogen that is overexpressed in various malignancies, is believed to be a potent regulator of angiogenesis. Osteosarcoma was examined to determine firstly, if VEGF and the TGF-beta isoform were overexpressed in this sarcoma, and secondly, if the degree of expression might represent a significant biologic predictor for disease-specific survival. MATERIALS AND METHODS: Selected paraffin-embedded tissues of surgical specimens from 25 patients of prechemotherapy case with osteosarcoma, who were treated between 1995 and 2001 were stained with rabbit polyclonal anti-VEGF and TGF-beta isoform antibodies. RESULTS: The majority of high-grade osteosarcomas in this study had a high intensity TGF-beta 2, - 3 and VEGF expression levels. The three in 5 patients who died of the disease had a high VEGF expression level. However VEGF expression was only independent predictor of overall survival. CONCLUSION: Further studies about TGF-beta and VEGF may provide useful information for understanding of pathophysiology of osteosarcoma.