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Figure 2. Interaction of hyperglycemia-regulated thrombospondin (TSP) pathways. TSP-4 increases recruitment of macrophages, while
TSP-1 is needed for the resolution of inflammation. In response to hyperglycemia, TSP-1 levels are downregulated by increased levels of
miR-467. TSP-4 is upregulated as a result of upregulation of TGF-β and activation of SMAD3. Upregulation of TSP-4 result in increased
recruitment of macrophages into the tumor. In the absence of TSP-1 and resolution of inflammation, the accumulation of macrophages
increases. In a feedback loop, TSP-4 increases the levels of an inhibitory TGF-β receptor beta-glycan. TGF-β further decreases the
production of TSP-1. In a feedback loop, TSP-1 is an activator of TGF-β. Green arrow and text = upregulation in response to hyperglycemia;
red arrow and text = downregulation in response to hyperglycemia. TGF-β: transforming growth factor beta

While multiple targets may potentiate the effects of modulation of TSP expression and functions, the
complexity of TSP interactions requires an unbiased testing of the effects of potential anti-cancer therapies
in in vivo models. When the interactions and mechanisms are dissected and understood, TSPs may become
desirable targets for the integrative anti-cancer approaches.

DECLARATIONS
Authors’ contributions
Analyzed the literature, collected the references: Muppala S, Gajeton J, Stenina-Adognravi O
Prepared a draft of the manuscript: Muppala S, Gajeton J
Prepared the final version of the manuscript: Stenina-Adognravi O

Availability of data and materials
Not applicable.

Financial support and sponsorship
The work on this review has been supported by funds from NIH to Olga Stenina-Adognravi (RO1 HL117216
and RO1 CA177771) and from the American Heart Association to Jasmine Gajeton/Olga Stenina-Adognravi
(17PRE33660475).

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.