Page 53 - Read Online

Stenina-Adognravi et al. Vessel Plus 2018;2:30 I http://dx.doi.org/10.20517/2574-1209.2018.40 Page 3 of 14

with the structural elements of the ECM. One of the influential groups of proteins that regulates the inter-
actions between structural proteins and cells are TSPs. This family of proteins consists of five members in
humans (TSP-1 - TSP-5). The five members of the family share a high level of homology and a number of
[15]
properties . However, they have unique domains and protein sequences that render each of the five TSPs
distinct in their interactions with the ligands in ECM and with cell surface receptors. As a result, TSPs
[16]
have distinct functions in tissue remodeling and regulation of cancer growth . Furthermore, a strong and
repeated association of TSP expression or suppression in various cancers highlights their role in cancer
[17]
regulation .

TSP-3, TSP-4, AND TSP-5
TSPs of group B (TSP-3, TSP-4, and TSP-5) are evolutionarily older proteins with fewer domains than in
[18]
the group A TSP proteins . Group B TSPs are important in embryonic development [16,19] and participate in
[20]
the activation of embryonic tissue remodeling programs . TSP-3 and TSP-5 are involved in the regulation
[21]
of growth plate organization and limb length . Complete deletion of TSP-3 and TSP-5 leads to reduced
[21]
limb length, which signifies their prominent role in skeletal growth . Not surprisingly, TSP-3 is also
linked to cancer angiogenesis, metastasis and invasion in osteosarcoma patients .
[22]
TSP-4 is one of the highly upregulated genes (in the top 1%) in several types of cancer, e.g., gastric
cancer [23-25] and breast cancer [26-28] . Its expression is upregulated in stromal tissue of invasive breast and
gastric adenoma cancers [20,29] . A recent study suggests that the loss of miR-142, resulting in high expression
of TSP-4, enhances hepatocellular carcinoma (HCC) invasion and progression. Therefore, targeting TSP-4
[30]
may be an important strategy to treat HCC . Increased expression of TSP-4 in ECM promotes invasion of
[20]
the breast cancer cells . Another study stated that TSP-4 mRNA expression in fibroblasts was stimulated
by cancer cells, suggesting that TSP-4 is an important novel marker in the detection of diffuse-type gastric
[29]
adenocarcinomas . Flexible heteroarotinoid compounds coordinate growth, apoptosis and differentiation
of cancer cells. One of the compounds of this group, SHetA2, inhibits angiogenic effects by decreasing
the secretion of TSP-4, along with vascular endothelial growth factor A and fibroblast growth factor, in
[31]
ovarian and renal cancers .

[32]
TSP-4 promotes cancer angiogenesis and growth in mouse models of breast cancer . Knocking out TSP-
4 in mice resulted in smaller tumors with decreased numbers of endothelial cells and lower levels of
angiogenesis markers. Conversely, a P387 variant of TSP-4 that is a more active variant of TSP-4 in cellular
[32]
[32]
effects and interactions with ligands , had increased cancer angiogenesis and tumor growth . Although
the vascular cells appear to be the main source of TSP-4 in breast cancers [32,33] , in vivo, the cancer cells
themselves also produce small amounts of TSP-4 that appear to be sufficient to support angiogenesis and
cancer growth even in TSP-4 deficient animals [32,33] . Complete deletion of TSP-4, in both the host and the
[33]
cancer cells, is required in order to document effects on tumor growth . In addition to these effects in
[32]
[34]
tumors, TSP-4 promotes adhesion and migration of leukocytes . Thus, TSP-4 is a pro-angiogenic and a
[35]
pro-inflammatory protein that supports tumor growth by activating multiple complementary pathways.
TSP-4 mediates the effects of transforming growth factor beta (TGF-β), a master regulator of ECM and
[33]
inflammation, on angiogenesis . The direct roles of TSP-4 in ECM regulation remain poorly understood.
[36]
However, it is clear that TSP-4 regulates collagen production and can prevent fibrosis in tissues .
On the other hand, TSP-4 serves as a tumor suppressor in colorectal cancer and suppresses in vitro tumor
[37]
colony formation . Epigenetic profiling studies revealed that hypermethylation of the TSP-4 promoter
[38]
leads to its inactivation and loss of TSP-4 tumor suppressor function in cutaneous T cell lymphoma .
The opposite effects of TSPs on cancer cells and on the cancer microenvironment are a recurrent theme
when studying the roles of TSPs in cancer regulation, leading to controversial findings that are difficult to