Transforming growth factor-beta1 inhibits tumor growth in a mouse melanoma model by down-regulating the plasminogen activation system

Exp Cell Res. 2003 Nov 15;291(1):1-10. doi: 10.1016/s0014-4827(03)00336-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Female
  • Fibrinolysin / drug effects
  • Fibrinolysin / metabolism
  • Matrix Metalloproteinases / drug effects
  • Matrix Metalloproteinases / metabolism
  • Melanoma / drug therapy
  • Melanoma / metabolism*
  • Melanoma / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / physiopathology*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Activators / antagonists & inhibitors*
  • Plasminogen Activators / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Urokinase Plasminogen Activator
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / physiopathology
  • Tissue Plasminogen Activator / antagonists & inhibitors
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / therapeutic use
  • Transforming Growth Factor beta1
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Plasminogen Activator Inhibitor 1
  • Plaur protein, mouse
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Plasminogen Activators
  • Tissue Plasminogen Activator
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinases