Thrombospondin-1 in drug activity and tumor response to therapies.

Thrombospondins (TSPs) have numerous different roles in cancer, regulating the behavior of cancer cells and non-neoplastic cells, and defining the responses of tumor cells to environmental changes, thorough their ability to orchestrate cellular and molecular interactions in the tumor microenvironment (TME). As a result of these activities, TSPs can also control drug delivery and activity, tumor response and resistance to therapies, with different outcomes depending on the nature of TSP-interacting cell types, receptors, and ligands, in a highly context-dependent manner. This review, focusing primarily on TSP-1, discusses the effects of TSPs on tumor response to chemotherapy, antiangiogenic, low-dose metronomic chemotherapy, immunotherapy, and radiotherapy, by analyzing TSP activity on different cell compartments - tumor cells, vascular endothelial cells and immune cells. We review evidence of the value of TSPs, specifically TSP-1 and TSP-2, as biomarkers of prognosis and tumor response to therapy. Finally, we examine possible approaches to develop TSP-based compounds as therapeutic tools to potentiate the efficacy of anticancer therapy.

Controlled extracellular proteolysis of thrombospondins.

Limited proteolysis of thrombospondins is a powerful mechanism to ensure dynamic tuning of their activities in the extracellular space. Thrombospondins are multifunctional matricellular proteins composed of multiple domains, each with a specific pattern of interactions with cell receptors, matrix components and soluble factors (growth factors, cytokines and proteases), thus with different effects on cell behavior and responses to changes in the microenvironment. Therefore, the proteolytic degradation of thrombospondins has multiple functional consequences, reflecting the local release of active fragments and isolated domains, exposure or disruption of active sequences, altered protein location, and changes in the composition and function of TSP-based pericellular interaction networks. In this review current data from the literature and databases is employed to provide an overview of cleavage of mammalian thrombospondins by different proteases. The roles of the fragments generated in specific pathological settings, with particular focus on cancer and the tumor microenvironment, are discussed.

Tumor vascular remodeling by thrombospondin-1 enhances drug delivery and antineoplastic activity.

The disorganized and inefficient tumor vasculature is a major obstacle to the delivery and efficacy of antineoplastic treatments. Antiangiogenic agents can normalize the tumor vessels, improving vessel function and boosting the distribution and activity of chemotherapy. The type III repeats (T3R) domain of thrombospondin-1 contains different potential antiangiogenic sequences. We therefore hypothesized that it might affect the tumor vasculature. Ectopic expression of the T3R domain by the tumor cells or by the host, or administration of recombinant T3R, delayed the in vivo growth of experimental tumors. Tumors presented marked reorganization of the vasculature, with abundant but smaller vessels, associated with substantially less necrosis. Mechanistically, the use of truncated forms of the domain, containing different active sequences, pointed to the FGF2/FGFR/ERK axis as a target for T3R activity. Along with reduced necrosis, the expression of T3R promoted tumor distribution of chemotherapy (paclitaxel), with a higher drug concentration and more homogeneous distribution, as assessed by HPLC and MALDI imaging mass spectrometry. T3R-expressing tumors were more responsive to paclitaxel and cisplatin. This study shows that together with its known role as a canonical inhibitor of angiogenesis, thrombospondin-1 can also remodel tumor blood vessels, affecting the morphological and functional properties of the tumor vasculature. The ability of T3R to reduce tumor growth and improve the response to chemotherapy opens new perspectives for therapeutic strategies based on T3R to be used in combination therapies.