Beyond angiogenesis: the paradoxical emerging pro-tumorigenic role of Thrombospondin-2

The tumor microenvironment is a complex ecosystem where the extracellular matrix serves as a dynamic signaling hub and regulates tumorigenesis. Thrombospondin-2 (THBS2), a matricellular extracellular matrix protein, has traditionally been regarded as an inhibitor of angiogenesis. However, emerging evidence reveals a pleiotropic and paradoxical pro-tumorigenic role of THBS2 in several malignancies. THBS2 has been identified as a multifaceted regulator of critical mechanisms driving cancer progression including angiogenesis induction, vasculogenic mimicry, sustained proliferation, invasion, metastasis, phenotypic plasticity, and immune suppression in aggressive cancers. By modulating diverse signaling pathways, especially the PI3K/AKT/mTOR axis, remodeling the collagenous architecture of the extracellular matrix, and formation of non-endothelial vascular channels, THBS2 supports tumor progression and metastasis. This minireview encompasses current research regarding the emerging molecular mechanisms by which THBS2 regulates pro-tumorigenic functions and discusses its role in resistance to therapy. The diagnostic and prognostic value of THBS2, particularly in aggressive cancers, underscores the need for the development of novel therapeutics specifically targeting this deregulated protein.