Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis

M Streit1, L Riccardi, P Velasco

  • 1Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

Insights

Thrombospondin-2 (TSP-2) significantly inhibits tumor growth and angiogenesis. Overexpression of TSP-2 in cancer cells reduced tumor size and blood vessel formation, offering potential therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Thrombospondin-2 (TSP-2) is a matricellular glycoprotein implicated in regulating primary angiogenesis.
  • Understanding TSP-2's role in tumor development is crucial for developing novel cancer therapies.

Purpose of the Study:

  • To investigate the direct biological effects of TSP-2 expression on tumor growth and angiogenesis.
  • To compare the anti-tumorigenic effects of TSP-2 with TSP-1.

Main Methods:

  • Human A431 squamous cell carcinoma cells, lacking TSP-2, were stably transfected with TSP-2 or control vectors.
  • Tumorigenicity and angiogenesis were assessed following subcutaneous injection into nude mice.
  • In vitro assays evaluated cell growth, colony formation, and apoptosis susceptibility.

Main Results:

  • TSP-2 expression did not alter in vitro cancer cell growth, colony formation, or apoptosis.
  • Subcutaneous tumors formed by TSP-2-expressing cells showed significantly inhibited growth compared to controls.
  • TSP-2 demonstrated stronger inhibition of tumor growth and angiogenesis than TSP-1.
  • Combined TSP-1 and TSP-2 overexpression completely prevented tumor formation.
  • TSP-2-expressing tumors exhibited extensive necrosis and reduced vascularization, despite maintained vascular endothelial growth factor levels.

Conclusions:

  • TSP-2 acts as a potent endogenous inhibitor of tumor growth and angiogenesis.
  • TSP-2's anti-angiogenic properties are significant and potentially synergistic with TSP-1.
  • Targeting TSP-2 may represent a viable therapeutic strategy for inhibiting tumor progression.

Related Concept Videos

The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
Mechanism of Angiogenesis01:10

Mechanism of Angiogenesis

Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...