Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis

Abstract

This review surveys the biological activities of an alpha-fetoprotein (AFP) derived peptide termed the Growth Inhibitory Peptide (GIP), which is a synthetic 34 amino acid segment produced from the full length 590 amino acid AFP molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult terminally-differentiated cells. The mechanism of action of this peptide has not been fully elucidated; however, GIP is highly interactive at the plasma membrane surface in cellular events such as endocytosis, cell contact inhibition and cytoskeleton-induced cell shape changes. The GIP was shown to be growth-suppressive in nine human tumor types and to suppress the spread of tumor infiltrates and metastases in human and mouse mammary cancers. The AFP-derived peptide and its subfragments were also shown to inhibit tumor cell adhesion to extracellular matrix (ECM) proteins and to block platelet aggregation; thus it was expected that the GIP would inhibit cell spreading/migration and metastatic infiltration into host tissues such as lung and pancreas. It was further found that the cyclic versus linear configuration of GIP determined its biological and anti-cancer efficacy. Genbank amino acid sequence identities with a variety of integrin alpha/beta chain proteins supported the GIP's linkage to inhibition of tumor cell adhesion and platelet aggregation. The combined properties of tumor growth suppression, prevention of tumor cell-to-ECM adhesion, and inhibition of platelet aggregation indicate that tumor-to-platelet interactions present promising targets for GIP as an anti-metastatic agent. Finally, based on cholinergic studies, it was proposed that GIP could influence the enzymatic activity of membrane acetylcholinesterases during tumor growth and metastasis. It was concluded that the GIP derived from full-length AFP represents a growth inhibitory motif possessing instrinsic properties that allow it to interfere in cell surface events such as adhesion, migration, metastasis, and aggregation of tumor cells.

Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

“…It has been further demonstrated in vitro that GIP notably interrupted the migration and invasion of follicular thyroid cancer cells [37] . It has also been reported that GIP could inhibit 60% of the cell spreading and migration of MCF-7 tumor cells in culture assays [34] . 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.…”

“…Regarding cancer cell proliferation, GIP was found to inhibit growth in multiple BC cell lines in vitro and to inhibit cell-tocell contact inhibition overgrowth in cultured MCF-7 cells [33][34][35] . In addition, both full length AFP and GIP were both found capable of inhibiting platelet aggregation [36] , a process necessary for CTC survival in the bloodstream; this activity involved integrins α2β1, α5β1, and α2β3.…”

“…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 segments #433 to 545 [34] . It has been further demonstrated in vitro that GIP notably interrupted the migration and invasion of follicular thyroid cancer cells [37] .…”

Inhibition by Tyroserleutide (YSL) on the Invasion and Adhesion of the Mouse Melanoma Cell

“…Zhi Yao, 1,2 Academy of Military Medical Sciences (Beijing, China). The animals were maintained at our university under specific pathogen-free (SPF) conditions according to the guidelines of the Chinese Association for Laboratory Animal Care, using a laminar air-flow rack, and had continuous access to sterilized pelleted food and autoclaved water with a controlled light/dark cycle, temperature at 20 to 25°C, and 50% to 60% relative humidity with 15 fresh air changes per hour.…”

“…It is crucial to control the invasion and metastasis of tumors in the treatment for cancer. GIP (growth inhibitory peptide) has been reported to inhibit the growth, adhesion, and metastasis of some tumors (2). RGD (Arg-Gly-Asp) and YIGSR (Tyr-Ile-GlySer-Arg) also showed the same effects on mouse melanoma (3,4).…”