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Published on: October 27, 2020
Transforming growth factor-beta1 inhibits tumor growth in a mouse melanoma model by down-regulating the plasminogen
Laurent Ramont1, Sylvie Pasco, William Hornebeck
1Laboratory of Medical Biochemistry and Molecular Biology, CNRS FRE 2534, IFR 53 Biomolecules, Faculty of Medicine, University of Reims Champagne-Ardenne, 51 Rue Cognacq Jay, F51095, REIMS Cedex, France.
Abstract:
The degradation of basement membranes by tumor cells involves secretion and activation of proteinases, such as matrix metalloproteinases (MMPs) and the plasminogen activation system (uPA, tPA, PAI-1), and results from an imbalance between their inhibitors and activators, controlled by various growth factors or cytokines. Among them, the TGF-beta family is one of the most intriguing because it has been reported either to decrease or promote cancer progression. In the present paper, we studied the effect of TGF-beta1 in a mouse melanoma model. In vivo, TGF-beta1 inhibited tumor growth after subcutaneous injection of B16F1 cells in syngenic mice. In vitro, TGF-beta1 did not alter B16F1 cell proliferation, but strongly decreased their migration through Matrigel-coated membranes. The protease production was analyzed by zymography, Western blot, or RT-PCR. MMP-2 and TIMP-2 expression were not altered by TGF-beta1. In contrast, TGF-beta1 triggered a large decrease of uPA and tPA, as well as a decrease of uPA and uPAR mRNAs. By Western blot and RT-PCR analyses, TGF-beta1 was shown to induce a strong increase of PAI-1 synthesis. Collectively, these results suggest that TGF-beta1 may inhibit melanoma tumor growth by specifically decreasing plasmin activity of tumor cells and play a protective role during the earliest stages of tumor progression.
Insights
Transforming growth factor-beta1 (TGF-beta1) inhibits melanoma growth by reducing tumor cell migration and plasmin activity. This suggests TGF-beta1 has a protective role in early cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor cell invasion involves basement membrane degradation by proteinases like MMPs and the plasminogen activation system.
- The TGF-beta family's role in cancer progression is complex, with reported roles in both inhibition and promotion.
- Understanding TGF-beta1's specific effects on melanoma is crucial for targeted therapies.
Purpose of the Study:
- To investigate the effect of TGF-beta1 on melanoma tumor growth and invasion.
- To elucidate the molecular mechanisms underlying TGF-beta1's action on melanoma cells, focusing on protease activity.
Main Methods:
- In vivo studies using a mouse melanoma model (B16F1 cells).
- In vitro assessment of cell proliferation and migration through Matrigel.
- Analysis of protease expression and activity using zymography, Western blot, and RT-PCR.
Main Results:
- TGF-beta1 inhibited subcutaneous B16F1 melanoma tumor growth in mice.
- TGF-beta1 reduced B16F1 cell migration in vitro but did not affect proliferation.
- TGF-beta1 decreased urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) levels and their mRNAs.
- TGF-beta1 significantly increased plasminogen activator inhibitor-1 (PAI-1) synthesis.
Conclusions:
- TGF-beta1 inhibits melanoma tumor growth, likely by reducing plasmin activity through modulation of the plasminogen activation system.
- TGF-beta1 may play a protective role in the early stages of melanoma progression by limiting tumor cell invasion.
