Page 56 - Read Online

Page 6 of 14 Stenina-Adognravi et al. Vessel Plus 2018;2:30 I http://dx.doi.org/10.20517/2574-1209.2018.40

take advantage of its interactions with ligands in ECM and on the cell surface.

Multiple attempts to use TSP-1 fragments to inhibit cancer growth have been described in the literature.
Adenovirus-mediated gene therapy containing an antiangiogenic fragment of TSP-1 inhibited the growth
[128]
of the human leukemia xenograft in mice . Gene therapy with a fragment of TSP-1 inhibited the growth
[129]
of human breast carcinoma, MDA-MB-435, in vivo in mice . The delivery of the fragment together with
p53 resulted in a synergistic effect and decreased the cancer growth more than the TSP-1 fragment or p53
administered separately. Linear and cyclic peptide TSP-1 mimetics have been tested in anti-angiogenesis
therapies [130-135] .

[136]
The interaction of TSP-1 with CD47 was shown to mediate multiple effects of TSP-1 . Targeting this
interaction, with the goal of increasing angiogenesis, led to an unexpected outcome - angiogenesis
[137]
inhibition . The peptide, designed to block the interaction of TSP-1 with CD47, named TAX2, increased
the binding of TSP-1 to CD36 and disrupted vascular endothelial growth factor receptor 2 activation and
subsequent downstream NO signaling. This peptide was also tested in experimental animal cancer models
[137]
[137]
[138]
and inhibited angiogenesis and growth of melanoma , pancreatic carcinoma and neuroblastoma .
[139]
It was also effective in preventing the spread of melanoma . The 4N1 peptide, based on the sequence of
[140]
TSP-1 domain that binds CD47, was successfully used in a mouse model as an anti-leukemia agent . The
interaction of TSP-1 with CD47 was found to be important in multiple processes related to tumor growth.
For example, blocking the signaling through CD47 conferred protection of normal tissue to irradiation
through activation of autophagy pathways [141,142] . Modulation of the anti-tumor immunity by CD47 in T
[143]
cells by this pathway has been described . Thus, this TSP-1-CD47 interaction appears to be a valuable
therapeutic target.
One of the cell-specific effects of TSP-1, mediated by its interaction with CD47, limits cell survival
in response to radiation [144] , suggesting that antagonizing this interaction would provide a selective
radioprotection for normal cells and tissues. Another tissue- and cell-specific approach targeted a miRNA
regulating TSP-1 production: miR-467 increases in a cell- and tissue-specific manner in response to
hyperglycemia and silences the production of TSP-1 [124] . Thus, antagonizing this miRNA slows down
the growth of certain cancers without affecting TSP-1 production in response to high glucose in other
[125]
tissues .

Some unexpected outcomes from using anti-TSP-1 strategies highlight the complexity of TSP-1 interactions
and its functions. The domains involved in regulating angiogenesis, TGF-β activation, and MMP inhibition
are localized in N-terminal part of TSP-1, while interaction with CD47 depends on the C-terminal domain
of the protein. However, based on the results of peptide studies, the domains are functionally associated,
such that blocking the interaction with one receptor also changes the interactions of distant domains with
other receptors and ligands [64,145] . Due to the multiple cell-specific functions, the effects of TSPs on various
cells types that are involved in tumor progression should be also taken in the account when considering
pharmacological interventions that target the expressions of TSPs or block their interactions with their
ligands.

ECM proteins appear to be good targets for therapy because of their extracellular localization and relatively
easy availability for drugs. However, very few ECM proteins have become successful therapeutic targets.
Most ECM proteins, including TSPs, have a complex multi-domain structure with a number of ligands on
the ECM and cell surface. The combined effect of TSP interactions with other ligands and receptors may
not only depend on their protein levels in tissues but also on the availability of ligands and receptors on
the cell surface. Ultimately, the systemic effects caused by inhibiting TSPs or regulating their production
should be considered. Successful strategies need to be based on tissue- and cell-specific evidence such that