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Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth

W M Miao1, W L Seng, M Duquette

  • 1The Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Cancer Research
|November 3, 2001
PubMed

Insights

Thrombospondin-1 type 1 repeats (TSRs) inhibit tumor growth by reducing angiogenesis and regulating tumor cell apoptosis. This regulation is transforming growth factor-beta (TGF-β) dependent, while angiogenesis inhibition is not.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Thrombospondin-1 (TSP-1) is a known inhibitor of tumor growth and angiogenesis.
  • The anti-angiogenic activity of TSP-1 is localized to its procollagen homology region and type 1 repeats (TSRs).

Purpose of the Study:

  • To investigate the molecular mechanisms by which TSRs inhibit tumor growth.
  • To assess the efficacy of recombinant TSR proteins in inhibiting experimental tumor growth.

Main Methods:

  • Expression of recombinant TSP-1 TSR proteins in Drosophila S2 cells.
  • Assay of recombinant TSRs' ability to inhibit endothelial cell migration.
  • Evaluation of tumor growth inhibition in B16F10 melanoma and Lewis lung carcinoma models.
  • Analysis of tumor cell apoptosis and proliferation, and tumor vessel density.

Main Results:

  • Recombinant proteins containing TSRs, particularly 3TSR/hTSP-1 and TSR2+RFK, significantly inhibited B16F10 tumor growth.
  • TSR2+RFK demonstrated a greater effect on tumor cell apoptosis and proliferation compared to TSR2.
  • TGF-β activation was observed with 3TSR/hTSP-1 and TSR2+RFK.
  • Inhibition of B16F10 tumor growth by TSR2+RFK was reduced when combined with TGF-β pathway inhibitors.

Conclusions:

  • TSRs inhibit tumor growth through combined mechanisms of angiogenesis inhibition and TGF-β-dependent regulation of tumor cell apoptosis and proliferation.
  • The TGF-β activating sequence (RFK) within TSR2 is crucial for its effects on tumor cell apoptosis and proliferation.
  • Angiogenesis inhibition by TSRs is independent of TGF-β activation.

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