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Page 8 of 11 Mizejewski. J Cancer Metastasis Treat 2019;5:35 I http://dx.doi.org/10.20517/2394-4722.2018.70

In the AFP derived GIP fragment example, a normal growth enhancing AFP molecule is converted to
a growth inhibitory full-length protein capable of blocking normal and cancer growth and metastasis.
Aside from GIP, other protein-derived peptide sites on the AFP third domain have since been identified
and mapped; some such peptide segments have been found to bind and/or interact with other proteins
such as metastasis-associated family members of the ECM, interstitial, and stromal proteins of tumor
[16]
microenvironments .
Third-domain derived AFP peptide-interactions with ECM proteins
As displayed in Table 2, the third domain of AFP provides an example of naturally occurring protein-
derived peptides segments with biological activities of significance. The AFP third domain houses multiple
peptide segments (8-10 or more amino acids) that have been identified by “in silico” prediction tools and
molecular modeling; these were verified by in vitro cell-based assays and the AFP-derived peptides were
found to bind various proteins [16,41,42] . Recent examples of confirmed protein-to-peptide binding interactions
between AFP peptides and natural proteins include the scavenger receptor proteins, immune dendritic
cells, mucin proteins, retinoic acid receptors, and metastasis-associated proteins in both cancer and non-
[42]
malignant models . Logic would dictate that disruption and/or interference of cross-talk and signaling
pathways between tumor cells and their surrounding proteins (both free and cell bound) located in the
microenvironment might serve to hamper or obstruct this crucial linkage. As discussed above, the tumor
microenvironment contains 4 or more protein families of metastasis-associated proteins relate to tumor
cell detachment, adhesion, contact, and migration via the ECM. By use of the AFP receptor and protein
binding third domain peptides as displayed in Table 3, it can be noted that such peptides might be capable
of disabling and/or disrupting communication lines between the tumor primary mass and/or metastasis
nesting sites. The identities of these potential protein-to-AFP peptide interaction sites with the metastasis-
associated proteins from tumor micro-environments are addressed below.

Interaction of metastasis-associated proteins with AFP-derived peptides
It has previously reported that metastasis-associated proteins are capable of binding and/or interacting
with AFP-derived peptides of the third domain [16,42] . In that report, members of the cell adhesion/contact
protein family, such as cadherins, contactins and connexins were identified “in silico” to interact with AFP
derived peptide sites on the amino-terminal half of domain-3, AA#401-500. The same was true for the ECM-
associated proteins of the MMP and ADAM family proteins being clustered from AA# 409-480; moreover,
these results showed interaction sites with AFP AA# 504-558 in the carboxy end of domain-3. The third
group of interacting proteins, the growth factor receptors, demonstrated two cluster interaction sites on
AFP-3D; the first group at AA#s 433-477 and the second grouping at AA# 512-550. Finally, the last class of
AFP interacting proteins, the growth factors and regulators, consisted of two distinct interaction regions;
the first extending from AA# 413-487, while the second encompassed sites at AFP AA#s 508-522. It can be
concluded from these data that metastasis-related proteins are potentially capable of interaction with various
[16]
AFP peptide segments on both the 1st and 2nd halves of the AFP domain-3 .

CONCLUSION
It can be concluded from the above discourse that both naturally occurring protein-derived and
synthetic peptides, ranging from 8-50 AA or larger, might be candidates capable of disabling tumor-to-
microenvironment communications. Such network connections are essential for supplying blood vascular
and nutrient supplies from the ECM to the tumor, critical locations required for tumor survival and
subsequent metastasis. The microenvironmental compartments surrounding tumors are required for
successful cell detachment from the primary mass and taking advantage of migration and adhesion factors
already present in the extracellular and stromal cell areas.

The present study further highlighted the many natural protein-derived peptides in human beings, whose
activities involved cell adhesion, mobility, contact, angiogenesis, blood clotting, and tumorigenesis. In