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.

Expression of angiogenin, TGF-beta, VEGF, APEX and TNF-alpha in oral squamous cell carcinoma

PURPOSE: The purpose of this study was to verify that the expressions of angiogenin, transforming growth factor-beta(TGF-beta), vascular endothelial growth factor(VEGF), human apurinic/apyrimidinic endonuclease(APEX) and tumor necrosis factoralpha(TNF-alpha) were associated with the tumorigenesis of the oral squamous cell carcinoma(OSCC). MATERIALS AND METHODS: Fifty-one samples of OSCC and fifteen normal oral mucosae were obtained to analyze the expression levels of above five factors. mRNA expressions were quantified by the quantitative competitive PCR(QC-PCR) method. After 2% agarose gel electrophoresis stained with ethidium bromide, the concentration of mRNA was calculated by a digital image analysis system. The expression levels of angiogenin, TGF-beta, VEGF, APEX and TNF-alpha were compared by unpaired Student's ttests between cancer and normal tissues. We analyzed statistically to find the cut-off values that would be useful as diagnostic markers, and the linear regression analysis between every two factors of these five factors by SAS system. RESULTS: All of these five factors (angiogenin: P<0.0037, TGF-beta: P<0.0001, VEGF: P<0.0102, APEX: P<0.0023, TNF-alpha: P<0.0074) were significantly correlated with OSCC. In the analysis to find the cut-off values for the diagnosis, we could not find any value that had a reasonable sensitivity and specificity. In the linear regression analysis, there were correlations between angiogenin and TNF-alpha, TGF-beta and VEGF, TGF-beta and APEX, TGF-beta and TNF-alpha, VEGF and APEX, VEGF and TNF-alpha, APEX and TNF-alpha. CONCLUSION: Our results suggest that not only angiogenin, TGF-beta, VEGF, APEX and TNF-alpha are significantly associated with the tumorigenesis, but also the close relationship between these factors might enhance the tumorigenesis of OSCC. We can not find clinical availability for diagnosis.

Increased Expression of the TGF-beta Isoform and Changed Contents of Collagen in Tendon of Cerebral Palsy Patients / 대한정형외과학회잡지

PURPOSE: This study measured the expression level of the transforming growth factor-beta (TGF-beta ) isoform expression and the collagen composition within the Achilles tendon from cerebral palsy (CP) patients. MATERIALS AND METHODS: The Achilles tendons were obtained from 15 CP patients with spastic equinovarus. The presence of the TGF-beta isoform and the composition of the collagen were examined histologically, performing by immunohistochemical staining (IHS) and determining the mRNA expression level using a reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: IHS revealed the presence of TGF-beta 1 and TGF-beta 2 expression in 2/15 cases and 4/15 cases respectively, and weak TGF-beta 3 expression in 7/15 cases. The TGF-beta 1 and TGF-beta 2 expression levels were uniform in all 15 cases according to RT-PCR, while TGF-beta 3 expression was observed in 8 out of 15 cases. IHS and RT-PCR showed strong TGF-beta 3 expression in 6/7 non-ambulatory patients. An immature form of collagen, type III collagen, was observed more abundantly in the non-ambulatory patients. CONCLUSION: These results suggest that contracture in CP may induce changes in the type of collagen via growth factors such as TGF-beta .

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.