Role of transforming growth factor beta in cancer

Pasche, Boris

doi:10.1002/1097-4652(200002)186:2<153::aid-jcp1016>3.0.co;2-j

Cited by 207 publications

(123 citation statements)

References 177 publications

(105 reference statements)

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“…However, it is generally accepted that TGF-b1 has a key role in inducing myofibroblast differentiation, and high levels of the cytokine are usually associated with MF-containing lesions (Tuan and Nichter, 1998). TGF-b1 is frequently detectable in SCC, particularly in the more advanced stages of tumour progression, and relatively high concentrations of TGF-b1 are usually found in tumour stroma (Pasche, 2001). Recently, Bauer et al (2002) showed that keratinocytes genetically modified to produce activated TGF-b1 induced collagen type I gene expression in dermal fibroblasts in a coculture system.…”

Section: Discussionmentioning

confidence: 99%

Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

et al. 2004

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The development of an altered stromal microenvironment is a common feature of many tumours including squamous cell carcinoma (SCC), and there is increasing evidence that these changes in the stroma, which include increased expression of proteases and cytokines, may actually promote tumour progression. A common finding is that stromal fibroblasts become 'activated' myofibroblasts, expressing smooth muscle actin and secreting cytokines, proteases and matrix proteins. We show that myofibroblasts are commonly found in the stroma of oral SCC and are often concentrated at the invasive margin of the tumour. Using oral SCC cells and primary oral fibroblasts, we demonstrate that tumour cells directly induce a myofibroblastic phenotype, and that this transdifferentiation is dependent on SCC-derived TGF-b1. In turn, myofibroblasts secrete significantly higher levels of hepatocyte growth factor/scatter factor compared with fibroblast controls, and this cytokine promotes SCC invasion through Matrigel, a mixture of basement membrane proteins. This is the first time that this double paracrine mechanism has been demonstrated between squamous carcinoma cells and fibroblasts, and emphasises that cancer invasion can be promoted indirectly by the release of tumour-induced host factors from stroma.

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Section: Discussionmentioning

confidence: 99%

Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

et al. 2004

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“…1). Loss of growth responsiveness to TGF-␤ is extremely common in tumor cells (49). Interestingly, this failure of TGF-␤ to inhibit cell growth was not due to a loss of TGF-␤ receptors or defects in the early portions of TGF-␤ signaling.…”

Section: Discussionmentioning

confidence: 99%

Soluble Type II Transforming Growth Factor-β Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity

Suzuki

Kapoor

Cheung

et al. 2004

Clinical Cancer Research

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Purpose: Transforming growth factor (TGF)-␤ blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-␤. The purpose of this study was to explore the possible therapeutic utility of TGF-␤ blockade on MM.Experimental Design: To evaluate this hypothesis, we tested the effects of a soluble TGF-␤ type II receptor (sTGF-␤R) that specifically inhibits TGF-␤1 and TGF-␤3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-␤) and AB1 (which does not produce TGF-␤).Results: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-␤R. In contrast, AB1 tumors showed little response to sTGF-␤R. The mechanism of these antitumor effects was evaluated and determined to be primarily dependent on immune-mediated responses because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice or mice depleted of CD8 ؉ T cells and (b) CD8 ؉ T cells isolated from spleens of mice treated with sTGF-␤R showed strong antitumor cytolytic effects, whereas CD8 ؉ T cells isolated from spleens of tumor-bearing mice treated with of control IgG2a showed no antitumor cytolytic effects.Conclusions: Our data suggest that TGF-␤ blockade of established TGF-␤-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-␤.

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“…This inhibition was noted because of an accumulation of the pro form of TGF-␤1 in PDX-transfected cells, a fact that could not be observed in the vector alone-transfected cells. TGF-␤1 is known for its role in activating MMP-2 in normal and cancer cells (29,30) and for enhancing invasion and metastasis in several human and experimental cancer models (31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells

Bassi

Cicco

Mahloogi

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

147

130

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Pro-protein convertases such as furin are expressed in many human tumor lines and primary tumors. Furin processes stromelysin-3, membrane type 1 matrix metalloproteinase (MMPs) involved in tumor cell invasiveness, as well as growth factors such as transforming growth factor ␤1. Evaluation of furin expression in head and neck squamous cell carcinoma (HNSCC) cells exhibiting different invasive ability showed that furin overexpression correlated with their respective invasiveness. The use of a selective furin inhibitor, alpha 1-PDX (PDX) was studied in three furin-expressing invasive HNSCC cell lines. The effects of PDX transfection were evaluated in vivo and in vitro to determine changes in the malignant phenotype. Transfection of HNSCC cell lines with PDX resulted in significant decrease or absence of tumorigenicity after s.c. inoculation into severe combined immunodeficient mice. Likewise, in vitro invasiveness was reduced Ϸ50%. The in vivo invasion assay using tracheal xenotransplants showed even more drastic reductions of the invasive ability of PDX-transfected cells (up to an 80% decrease). PDX-transfected cells did not invade or penetrated less into the tracheal wall tissues than their vector alone-transfected counterparts. In addition, the former cells showed a remarkable decrease in MMP-2 processing and activity. After PDX transfection the cells were less efficient in processing the tumor progressionassociated furin substrates transforming growth factor ␤1 and pro-membrane type 1-MMP. These findings indicate that furin inhibition is a feasible approach to attenuate and even abolish certain critical attributes of the advanced malignant phenotype. Thus, furin should be considered as a promising target for cancer therapy.alpha1-PDX ͉ squamous cell carcinoma ͉ invasion ͉ tumor progression

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Role of transforming growth factor beta in cancer

Cited by 207 publications

References 177 publications

Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

Soluble Type II Transforming Growth Factor-β Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity

Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells

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