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Published on: August 23, 2019
Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics
Frank K Reiher1, Olga V Volpert, Benilde Jimenez
1Department of Urology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL, USA.
Abstract:
Many normal human cells produce thrombospondin-1 (TSP-1), a potent antiangiogenic protein that promotes vascular quiescence. In various organ systems, including the brain, breast and bladder and in fibroblasts, TSP-1 secretion is reduced during tumorigenesis, thereby allowing induction of the vigorous neovascularization required for tumor growth and metastasis. Full-length and short TSP-1-derived peptides inhibit angiogenesis by inducing endothelial cell apoptosis and thus disrupting the vasculature of the growing tumor. CD36 expressed on the surface of endothelial cells functions as the primary antiangiogenic receptor for TSP-1. A D-isoleucyl enantiomer of a TSP-1 heptapeptide specifically inhibits the proliferation and migration of capillary endothelial cells. DI-TSP, an approximately 1 kDa capped version of this peptide, is also antiangiogenic in vitro, with a specific activity approaching that of the 450 kDa parental molecule. Here, we show that DI-TSP delivered systemically dose-dependently inhibits the growth of murine melanoma metastases in syngeneic animals and that its more soluble isomer, DI-TSPa, similarly blocks the progression of primary human bladder tumors in an orthotopic model in immune-deficient mice. Like intact TSP-1, these peptide mimetics had no effect on cancer cells growing in vitro but markedly suppressed the growth of endothelial cells by inducing receptor-dependent apoptosis. Antibodies raised against CD36 blocked the ability of peptides to induce apoptosis in endothelial cells but had no effect on tumor necrosis factor-alpha-induced apoptosis. In vivo, the peptide mimetics were associated with a significantly reduced microvessel density and increased apoptotic indices in both the endothelial and tumor cell compartments. Such short peptides targeted to a specific antiangiogenic receptor, potent and easy to synthesize, show great promise as lead compounds in clinical antiangiogenic strategies.
Insights
Short peptide mimetics of thrombospondin-1 (TSP-1) effectively inhibit tumor growth by inducing endothelial cell apoptosis via the CD36 receptor. These potent compounds show promise for anti-angiogenic cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Thrombospondin-1 (TSP-1) is a natural anti-angiogenic protein that inhibits tumor growth.
- Reduced TSP-1 levels during tumorigenesis promote neovascularization, supporting tumor growth and metastasis.
- TSP-1 exerts its anti-angiogenic effects by inducing apoptosis in endothelial cells, primarily through the CD36 receptor.
Purpose of the Study:
- To evaluate the anti-angiogenic and anti-tumor efficacy of short TSP-1-derived peptide mimetics, specifically DI-TSP and DI-TSPa.
- To investigate the mechanism of action of these peptides, focusing on their interaction with the CD36 receptor and their effect on endothelial cells.
- To assess the therapeutic potential of these peptides in preclinical models of cancer metastasis and primary tumor growth.
Main Methods:
- Systemic administration of DI-TSP in murine melanoma metastasis models.
- Orthotopic implantation of human bladder tumors in immune-deficient mice treated with DI-TSPa.
- In vitro studies assessing peptide effects on endothelial cell proliferation, migration, and apoptosis.
- In vivo assessment of microvessel density and apoptotic indices in tumor tissues.
- Use of CD36 blocking antibodies to elucidate the receptor-dependent mechanism.
Main Results:
- Systemic DI-TSP dose-dependently inhibited the growth of murine melanoma metastases.
- DI-TSPa effectively blocked the progression of primary human bladder tumors in an orthotopic model.
- Peptide mimetics induced apoptosis in endothelial cells in a CD36-dependent manner, without affecting cancer cells directly.
- In vivo studies showed reduced microvessel density and increased apoptosis in both endothelial and tumor cells.
Conclusions:
- Short peptide mimetics of TSP-1, such as DI-TSP and DI-TSPa, are potent anti-angiogenic agents.
- These peptides target the CD36 receptor on endothelial cells, leading to apoptosis and inhibition of tumor growth and metastasis.
- The peptides demonstrate significant therapeutic promise as lead compounds for clinical anti-angiogenic strategies.
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