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Page 4 of 14 Stenina-Adognravi et al. Vessel Plus 2018;2:30 I http://dx.doi.org/10.20517/2574-1209.2018.40

explain. Ultimately, the results from in vivo studies, where TSPs levels have been manipulated, should be
considered to help define physiological roles for individual TSPs in cancer regulation.

TSP-1 AND TSP-2
The more recently developed group of TSPs, which includes TSP-1 and TSP-2 and is termed “group A”, ap-
peared in evolution along with the development of the cardiovascular system [19,39] . These two proteins have
several C-terminal domains homologous to group B proteins but differ from group B TSPs in their N-terminal
[40]
protein parts . The newly acquired in evolution domains of TSP have important roles in regulating vascu-
lar tissue remodeling: they harbor sequences associated with the anti-angiogenic action of these two pro-
teins [41,42] and with the inhibition of metalloproteinases (MMP) [43,44] . One of the N-terminal domains in TSP-
1 contains a sequence that binds TGF-β: TSP-1 is a major activator of latent TGF-β [45-47] .

[48]
The anti-angiogenic properties of TSP-1 and TSP-2 have been studied for over 30 years . TSP-1 and TSP-2
inhibit endothelial cell proliferation, migration, and apoptosis [49-52] . The decreased expression of TSP-1 and
TSP-2 in tumors and surrounding tissues has been reported [53-55] , and animal studies confirmed their anti-
[56]
angiogenic and tumor-preventing action . Furthermore, TSP-1 expression has been associated with cancer
dormancy [57,58] ; merely suppressing or overexpressing TSP-1 is enough to reverse the patterns of tumor
growth in specific anatomical areas with differential expression of TSP-1 [59-63] .

In addition to the direct effects of TSP-1 and TSP-2 on endothelial cells, the regulation of angiogenesis may
[44]
be an indirect consequence of regulation of MMP activity , binding of growth factors and regulation of
[64]
their availability and activity , and regulation of functions of the immune and inflammatory cells [65,66] .
The effects of TSP-1 on cancer cells are sometimes inconsistent with its anti-angiogenic and anti-cancer
effects observed in in vivo studies. TSP-1 has adhesive properties that support cancer cell growth [67-69] ,
[70]
promote metastatic properties of breast cancer cells , facilitate the invasion of squamous cell carcinoma ,
[71]
[72]
[73]
[74]
breast cancer cells and melanoma , may increase proliferation of cancer cells , and decrease cancer
[75]
cell apoptosis .
INTEGRATIVE APPROACH TO UNDERSTANDING TSP ROLES IN CANCER
These contradictory effects of TSPs on cultured cancer cells and on the fate of a tumor in vivo have not
been explained. To better understand their significance, these contradictory effects should be considered
in a context of complex relationships between the cancer cells and the entire organism: prevention of a
tumor growth not only relies on the cancer cell properties alone but also requires a concerted response of
the body that involves the activation of immune responses, the recognition of cancer cells, and clearance of
these cells. Tumor development occurs only when multiple body systems fail to eliminate cancer cells from
[76]
the system. Cancer cells are constantly forming in different tissues and also circulate in blood but fail to
attach and initiate a tumor growth when the microenvironment (including ECM of tissues), regulation of
angiogenesis, and responses of the immune system are normal [77,78] . Dysregulation of metabolic, immune,
and tissue remodeling processes is what leads a single cancer cell to progress to a tumor rather than being
recognized, killed and eliminated. The physiological balance of cancer cell attachment, proliferation and
mobility versus their recognition, apoptosis, and elimination define the fate of each cancer cell that forms
in the body.

The in vivo effects of TSP-1 and TSP-2, suggest that these proteins activate a whole-organism anti-
angiogenic and anti-cancer program that ultimately leads to a decrease in cancer growth or to cancer cell
[58]
dormancy . Thus, the positive effects of TSP-1 and TSP-2 on cancer cell proliferation could be considered