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Page 4 of 7 Mizejewski. J Cancer Metastasis Treat 2018;4:27 I http://dx.doi.org/10.20517/2394-4722.2018.20

AFP-DERIVED PEPTIDES, CTCS, AND METASTASIS
It is germane to the present commentary that full-length AFP mRNA detected in CTCs from hepatocellular
[26]
carcinoma patients has been reported to serve as a predictive marker for metastasis . Furthermore,
a computer bioinformatics study of multiple metastatic protein interactions with AFP (and its derived
[27]
peptides) has recently been reported . In that study, many of the “in silico” AFP interaction with metastatic
associated proteins were experimentally confirmed. Both in vitro and in vivo BC studies have been
performed using GIP which demonstrated both anti-growth and anti-metastatic activities. For example, in
a microarray study, GIP was found to down-regulate the mRNA (1.5 to 8 fold) of many proteins detected in
[10]
the “CTC signature” of the BC-derived circulating cells described by Boral et al. . Such proteins included
CD44, CD40, TNF, NFkB, IL-1 receptor, Serpin I-1, and p53 AIP1 among others. Many of these metastasis-
associated proteins were reported to interact with AFP in protein-to-protein interactions; such metastases-
related proteins included the laminin receptor, collagen-IV, Integrin B-1, IL-1B, and the neural cell adhesion
molecule (NCAM). It is of interest that, Serpin-I1 and plasminogen activator are known to promote cancer
[28]
cell survival in brain metastasis by means of brain plasmin inhibition . In the pro-inflammatory arena,
AFP itself was found to interact and block CCR5 and CXCR4 chemokine receptors which are required for
metastatic BC cell migration [29-31] .

BIOLOGICAL ACTIVITIES OF AFP-DERIVED PEPTIDES
Other sets of data involving AFP-derived peptides have been generated in vitro involving cancer cell
adhesion, cell-to-cell interactions, cell spreading, motility, migration, and growth [32,33] . Regarding cancer
cell proliferation, GIP was found to inhibit growth in multiple BC cell lines in vitro and to inhibit cell-to-
cell contact inhibition overgrowth in cultured MCF-7 cells [33-35] . In addition, both full length AFP and GIP
[36]
were both found capable of inhibiting platelet aggregation , a process necessary for CTC survival in the
bloodstream; this activity involved integrins α2β1, α5β1, and α2β3. CTCs are known to adhere to blood
vessel inner walls and to platelets, thereby cloaking themselves from circulating cytotoxic lymphocyte
destruction [13,35,36] . Furthermore, GIP was found to block both adhesion of extra-cellular matrix (ECM)
[35]
proteins to substrata as well as tumor cell adhesion to ECM-coated wells of microtiter plates . The ECM
proteins included laminin, fibrinogen, collagen-IV, fibronectin, thrombospondin, and vitronectin. In
addition, both collagen-IV and NCAM have been reported to bind to the third domain of AFP at amino acid
[34]
segments #433 to 545 . It has been further demonstrated in vitro that GIP notably interrupted the migration
[37]
and invasion of follicular thyroid cancer cells . It has also been reported that GIP could inhibit 60% of the
[34]
cell spreading and migration of MCF-7 tumor cells in culture assays . Because integrins and ECM proteins
are both involved in cell migration by modulating the fine balance between cell-to-contact, adhesion,
and cell detachment, it was noteworthy that GIP was found capable of disrupting the interaction between
receptors and binding proteins in such activities. The final involvement of GIP with cancer cell activities was
demonstrated using in vivo models of human BC xenografts in mice. GIP was reported to suppress cancer
growth/proliferation in both xenograft and homograft models of MCF-7, GI-101, MDA-MB-231, and 6WI-1
BC tumors in host mice [25,32] . In the human MDA-MB-231 BC in vivo mouse model, GIP injections resulted
in a 3-fold reduction in BC metastasis to the lungs as compared to controls. In the 6WI-1 in vivo mouse
homograft model, GIP suppressed BC cell migration, invasiveness, and adherence to surrounding cells and
tissues. Thus, GIP injections not only demonstrated BC growth suppression but also reduced metastatic-
associated events in BC cells such as cell adherence, invasiveness, and migration in addition to decreased
metastatic cell accumulation in distant organs. Finally, GIP administered in vitro produced an inhibition
of cell membrane-induced agglutination, and induced cell shape changes via enhanced microtubule
polymerization [24,34,35] .

CONCLUDING STATEMENTS
It can be concluded from the above discourse that peptide fragments derived from plasma, ECM, and
angiogenic-associated proteins are capable of tumor growth inhibition and suppression of metastatic spread.