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Stenina-Adognravi et al. Vessel Plus 2018;2:30 I http://dx.doi.org/10.20517/2574-1209.2018.40 Page 7 of 14

Figure 1. Hyperglycemia promotes cancer growth by regulating thrombospondin (TSP)-1- and TSP-4-dependent pathways. Upregulation
of TGF-β in response to hyperglycemia leads to upregulation of TSP-4. TSP-4 is a pro-angiogenic protein that also promotes recruitment
of macrophages and other leukocytes into tissues and increases local inflammation. Upregulation of miR-467 in a tissue-specific manner
blocks TSP-1 production. In the absence of the anti-angiogenic pressure of TSP-1, cancer angiogenesis is increased. In the absence of TSP-
1, the resolution of inflammation is impaired. Increased inflammation and angiogenesis promote cancer growth in the absence of TSP-1.
TSP-1 and TSP-4 pathways converge and complement each other to promote the tumor growth

interactions do not alter the functions or expression of TSPs elsewhere.

Interactions between TSP pathways further complicate the final outcomes. For example, studies of the
effects of hyperglycemia on breast cancer suggest that TSP-1-dependent pathways may synergize with
TSP-4-dependent pathways. Higher expression of miR-467 in response to high glucose was associated
with inhibition of TSP-1 production [123,124,146] [Figure 1]. In addition to its anti-angiogenic effects, TSP-1 is a
[147]
regulator of inflammation and functions of macrophages . TSP-1 is known to regulate the production of
[152]
[151]
cytokines by macrophages [148-150] , to stimulate micropinocytosis , motility , to activate toll-like receptor
4 pathway in macrophages [153] , and to promote the resolution of inflammation [150,154] . Hyperglycemia
changes the levels of multiple ECM proteins, including the master ECM regulator TGF-β [155,156] . Higher
levels of TGF-β have been detected in the cancers of diabetic patients [157,158] , and blocking TGF-β signaling
leads to better outcomes in animal models [159-161] . It was reported recently that increased levels of TGF-β led
to increased production of TSP-4. Unlike TSP-1, TSP-4 is pro-angiogenic [162,163] and increases accumulation
of macrophages and other leukocytes in tissues via increased recruitment into tissues [34,35] . Increased levels
of TSP-4 combined with decreased levels of TSP-1 would promote a pro-angiogenic and inflammatory
microenvironment leading to tumor growth [Figure 1].

In addition to functional interaction, TSP pathways interact at the mechanistic level. For example, TSP-1
[163]
[163]
activates TGF-β [45,47,164] and is downregulated by TGF-β but TSP-4 is a mediator of the TGF-β effects
and, in turn, modulates the expression of one of the TGF-β receptors, beta-glycan [165] , thus, controlling
TGF-β signaling [Figure 2].

CONCLUSION
TSPs become available to many cell types after they are secreted and incorporated into ECM. They have
multiple interactions and functions, which depend on the availability of specific cell surface receptors
on each cell type at any given moment. The final outcome of modulating TSP levels is determined by a
combined effect from their actions in multiple cell types and organs, from the tumor itself to the immune
system and vasculature.