Skip to main content

Advertisement

SpringerLink
Log in

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

  • Nonthematic Review
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ingham KC, Brew SA, Erickson HP: Localization of a cryptic binding site for tenascin on fibronectin. J Biol Chem 279: 28132–28135, 2004

    Article  PubMed  Google Scholar 

  2. Podolnikova NP, Yakubenko VP, Volkov GL, Plow EF, Ugarova TP: Identification of a novel binding site for platelet integrins alpha IIb beta 3 (GPIIbIIIa) and alpha 5 beta 1 in the gamma C-domain of fibrinogen. J Biol Chem 278: 32251–32258, 2003

    Article  PubMed  Google Scholar 

  3. Mizejewski G. New insights into AFP structure and function: Potential biomedical applications. Alpha-fetoprotein and Congenital Disorders, ed. Mizejewski G, Porter IH, Orlando, Academic Press, 1985, pp. 5–34.

    Google Scholar 

  4. Mizejewski GJ: Alpha-fetoprotein as a biologic response modifier: Relevance to domain and subdomain structure. Proc Soc Exp Biol Med 215: 333–362, 1997

    PubMed  Google Scholar 

  5. Mizejewski GJ: Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Exp Biol Med (Maywood) 226: 377–408, 2001

    Google Scholar 

  6. Mizejewski GJ, Dias JA, Hauer CR, Henrikson KP, Gierthy J: Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment. Mol Cell Endocrinol 118: 15–23, 1996

    Article  PubMed  Google Scholar 

  7. Gershwin ME, Castles JJ, Makishima R: Accelerated plasmacytoma formation in mice treated with alpha-fetoprotein. J Natl Cancer Inst 64: 145–149, 1980

    PubMed  Google Scholar 

  8. Uriel J: The physiological role of alpha-fetoprotein in cell growth and differentiation. J Nucl Med Allied Sci 33: 12–17, 1989

    PubMed  Google Scholar 

  9. Wang XW, Xu B: Stimulation of tumor-cell growth by alpha-fetoprotein. Int J Cancer 75: 596–599, 1998

    Article  PubMed  Google Scholar 

  10. Li MS, Li PF, Yang FY, He SP, Du GG, Li G: The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells. Cell Res 12: 151–156, 2002

    PubMed  Google Scholar 

  11. Liang OD, Korff T, Eckhardt J, Rifaat J, Baal N, Herr F, Preissner KT, Zygmunt M: Oncodevelopmental alpha-fetoprotein acts as a selective proangiogenic factor on endothelial cell from the fetomaternal unit. J Clin Endocrinol Metab 89: 1415–1422, 2004

    Article  PubMed  Google Scholar 

  12. Takahashi Y, Ohta T, Mai M: Angiogenesis of AFP producing gastric carcinoma: correlation with frequent liver metastasis and its inhibition by anti-AFP antibody. Oncol Rep 11: 809–813, 2004

    PubMed  Google Scholar 

  13. Li MS, Li PF, Chen Q, Du GG, Li G: Alpha-fetoprotein stimulated the expression of some oncogenes in human hepatocellular carcinoma Bel 7402 cells. World J Gastroenterol 10: 819–824, 2004

    PubMed  Google Scholar 

  14. Um SH, Mulhall C, Alisa A, Ives AR, Karani J, Williams R, Bertoletti A, Behboudi S: Alpha-fetoprotein impairs APC function and induces their apoptosis. J Immunol 173: 1772–1778, 2004

    PubMed  Google Scholar 

  15. Vakharia D, Mizejewski GJ: Human alpha-fetoprotein peptides bind estrogen receptor and estradiol, and suppress breast cancer. Breast Cancer Res Treat 63: 41–52, 2000

    Article  PubMed  Google Scholar 

  16. Sinenko SA, Belyaev NN, Mizejewski G: Analysis of functional activities of human alpha-fetoprotein with new monoclonal antibodies and a synthetic peptide. Tumor Biol 21: 112, 2000

    Google Scholar 

  17. Kuznetsova IM, Turoverov KK, Uversky VN: Use of the phase diagram method to analyze the protein unfolding-refolding reactions: Fishing out the “invisible” intermediates. J Proteome Res 3: 485–494, 2004

    Article  PubMed  Google Scholar 

  18. Mizejewski GJ, MacColl R: Alpha-fetoprotein growth inhibitory peptides: Potential leads for cancer therapeutics. Mol Cancer Ther 2: 1243–1255, 2003

    PubMed  Google Scholar 

  19. Mizejewski G, Smith G, Butterstein G: Review and Proposed Action of alpha-fetoprotein growth inhibiting peptides as estrogen and cytoskeletal-associated factors. Intl Journal Cell Biology 28: 913–933, 2004.

    Article  Google Scholar 

  20. Czokalo M, Tomasiak M: Alpha fetoprotein inhibits aggregation of human platelets. Haematologia (Budap) 22: 11–18, 1989

    Google Scholar 

  21. Mizejewski GJ: Levels of alpha-fetoprotein during pregnancy and early infancy in normal and disease states. Obstet Gynecol Surv 58: 804–826, 2003

    Article  PubMed  Google Scholar 

  22. Brenner T, Stupp-Da-Costa Y, Sicsic C, Abramsky O: Inhibition by alpha-fetoprotein fractions of hemagglutination reactions between A and B antigens of human red blood cells and specific antisera. Clin Immunol Immunopathol 34: 20–26, 1985

    Article  PubMed  Google Scholar 

  23. Dauphinee MJ, Mizejewski GJ: Human alpha-fetoprotein contains potential heterodimerization motifs capable of interaction with nuclear receptors and transcription/growth factors. Med Hypotheses 58: 453–461, 2002

    Article  PubMed  Google Scholar 

  24. Eisele LE, Mesfin FB, Bennett JA, Andersen TT, Jacobson HI, Soldwedel H, MacColl R, Mizejewski GJ: Studies on a growth-inhibitory peptide derived from alpha-fetoprotein and some analogs. J Pept Res 57: 29–38, 2001

    Article  PubMed  Google Scholar 

  25. Eisele LE, Mesfin FB, Bennett JA, Andersen TT, Jacobson HI, Vakharia DD, MacColl R, Mizejewski GJ: Studies on analogs of a peptide derived from alpha-fetoprotein having antigrowth properties. J Pept Res 57: 539–546, 2001.

    Article  PubMed  Google Scholar 

  26. MacColl R, Eisele LE, Stack RF, Hauer C, Vakharia DD, Benno A, Kelly WC, Mizejewski GJ: Interrelationships among biological activity, disulfide bonds, secondary structure, and metal ion binding for a chemically synthesized 34-amino-acid peptide derived from alpha-fetoprotein. Biochim Biophys Acta 2 1528: 127–134, 2001

    Google Scholar 

  27. Butterstein G, MacColl R, Mizejewski GJ, Eisele LE, Meservey M: Biophysical studies and anti-growth activities of a peptide, a certain analog and a fragment peptide derived from alpha-fetoprotein. J Pept Res 61: 213–218, 2003

    Article  PubMed  Google Scholar 

  28. Butterstein G, Morrison J, Mizejewski GJ: Effect of alpha-fetoprotein and derived peptides on insulin- and estrogen-induced fetotoxicity. Fetal Diagn Ther 18: 360–369, 2003

    Article  PubMed  Google Scholar 

  29. Mizejewski GJ: An apparent dimerization motif in the third domain of alpha-fetoprotein: Molecular mimicry of the steroid/thyroid nuclear receptor superfamily. Bioessays 15: 427–432, 1993

    Article  PubMed  Google Scholar 

  30. Mizejewski GJ: Role of integrins in cancer: Survey of expression patterns. Proc Soc Exp Biol Med 222: 124–138, 1999

    Article  PubMed  Google Scholar 

  31. Murawaki Y, Yamamoto H, Kawasaki H, Shima H: Serum tissue inhibitor of metalloproteinases in patients with chronic liver disease and with hepatocellular carcinoma. Clin Chim Acta 218: 47–58, 1993

    Article  PubMed  Google Scholar 

  32. Parsons DF, Foley J, Marko M, Wansor K: Immediate ascites conversion of mammary tumors induced in NYLR/Nya mice by 7,12-dimethylbenz-[a] anthracene and urethane feeding and by forced breeding. Cancer Invest 4: 109–126, 1986

    PubMed  Google Scholar 

  33. Hurst J, Maniar N, Tombarkiewicz J, Lucas F, Roberson C, Steplewski Z, James W, Perras J: A novel model of a metastatic human breast tumour xenograft line. Br J Cancer 68: 274–276, 1993

    PubMed  Google Scholar 

  34. Morrissey JJ, Raney S: A metastatic breast tumor cell line, GI-101A, is estrogen receptorpositive and responsive to estrogen but resistant to tamoxifen. Cell Biol Int 22: 413–419, 1998

    Article  PubMed  Google Scholar 

  35. Garewal HS, Ahmann FR, Schifman RB, Celniker A: ATP assay: Ability to distinguish cytostatic from cytocidal anticancer drug effects. J Natl Cancer Inst 77: 1039–1045, 1986

    PubMed  Google Scholar 

  36. Kuzmits R, Rumpold H, Muller MM, Schopf G: The use of bioluminescence to evaluate the influence of chemotherapeutic drugs on ATP-levels of malignant cell lines. J Clin Chem Clin Biochem 24: 293–298, 1986

    PubMed  Google Scholar 

  37. Kurbacher CM, Cree IA, Bruckner HW, Brenne U, Kurbacher JA, Muller K, Ackermann T, Gilster TJ, Wilhelm LM, Engel H, Mallmann PK, Andreotti PE: Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 9: 51–57, 1998

    PubMed  Google Scholar 

  38. Ginsberg MH, Loftus JC, D'Souza S, Plow EF: Ligand binding to integrins: common and ligand specific recognition mechanisms. Cell Differ Dev 32: 203–213, 1990

    Article  PubMed  Google Scholar 

  39. Hynes RO: Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25, 1992

    Article  PubMed  Google Scholar 

  40. Ruoslahti E: Control of cell motility and tumor invasion by extracellular matrix interactions. Br J Cancer 66: 239–242, 1992

    PubMed  Google Scholar 

  41. Gui GP, Puddefoot JR, Vinson GP, Wells CA, Carpenter R: In vitro regulation of human breast cancer cell adhesion and invasion via integrin receptors to the extracellular matrix. Br J Surg 82: 1192–1196, 1995

    PubMed  Google Scholar 

  42. Juliano RL: The role of beta 1 integrins in tumors. Semin Cancer Biol 4: 277–283, 1993.

    PubMed  Google Scholar 

  43. Ruoslahti E: Stretching is good for a cell. Science 276: 1345–1346, 1997

    Article  PubMed  Google Scholar 

  44. Dedhar S: Integrin mediated signal transduction in oncogenesis: an overview. Cancer Metastasis Rev 14: 165–172, 1995

    Article  PubMed  Google Scholar 

  45. Liu Z, Brattain MG, Appert H: Differential display of reticulocalbin in the highly invasive cell line, MDA-MB-435, versus the poorly invasive cell line, MCF-7. Biochem Biophys Res Commun 231: 283–289, 1997

    Article  PubMed  Google Scholar 

  46. Burridge K, Chrzanowska-Wodnicka M: Focal adhesions, contractility, and signaling. Annu Rev Cell Dev Biol 12: 463–518, 1996

    Article  PubMed  Google Scholar 

  47. Virtanen I, Korhonen M, Kariniemi AL, Gould VE, Laitinen L, Ylanne J: Integrins in human cells and tumors. Cell Differ Dev 32: 215–227, 1990.

    Article  PubMed  Google Scholar 

  48. Edwards JG, Hameed H, Campbell G: Induction of fibroblast spreading by Mn2+: A possible role for unusual binding sites for divalent cations in receptors for proteins containing Arg-Gly-Asp. J Cell Sci 89: 507–513, 1988

    PubMed  Google Scholar 

  49. Kinlough-Rathbone RL, Packham MA, Mustard JF, Platelet Aggregation in Measurements of Platelet Function, ed. Harker LA,Zimmerman TS., Churchill Livingstone, London, 1983, pp. 64–87

    Google Scholar 

  50. Whittle BJR, Hamid S, Lidbury P, Rosam AC, Specificity between the anti-aggregatory actions of prostacyclin, prostaglandin E1 and D2 on platelets in. Mechanisms of stimulus-response coupling in platelets, ed. V.V. K, MacIntyre DE, Scully MF. New York and London, Plenum Press 1985, pp. 109–115

    Google Scholar 

  51. Hamberg M, Svensson J, Samuelsson B: Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 72: 2994–2998, 1975

    PubMed  Google Scholar 

  52. Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE: Geometric control of cell life and death. Science 276: 1425–1428, 1997

    Article  PubMed  Google Scholar 

  53. Fox JE, Reynolds CC, Boyles JK: Studying the platelet cytoskeleton in Triton X-100 lysates. Methods Enzymol 215: 42–58, 1992

    PubMed  Google Scholar 

  54. Ellis EF, Oelz O, Roberts LJ, 2nd, Payne NA, Sweetman BJ, Nies AS, Oates JA: Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2. Science 193: 1135–1137, 1976

    PubMed  Google Scholar 

  55. Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S: Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer 11: 704–718, 1973

    PubMed  Google Scholar 

  56. Gould RJ, Polokoff MA, Friedman PA, Huang TF, Holt JC, Cook JJ, Niewiarowski S: Disintegrins: A family of integrin inhibitory proteins from viper venoms. Proc Soc Exp Biol Med 195: 168–171, 1990

    PubMed  Google Scholar 

  57. Sheu JR, Lin CH, Peng HC, Huang TF: Triflavin, an Arg-Gly-Asp-containing peptide, inhibits the adhesion of tumor cells to matrix proteins via binding to multiple integrin receptors expressed on human hepatoma cells. Proc Soc Exp Biol Med 213: 71–79, 1996

    PubMed  Google Scholar 

  58. Sheu JB, Ko WC, Hung WC, Peng HC, Huang TF: Interaction of thrombin-activated platelets with extracellular matrices (fibronectin and vitronectin): comparison of the activity of Arg-Gly-Asp-containing venom peptides and monoclonal antibodies against glycoprotein IIb/IIIa complex. J Pharm Pharmacol 49: 78–84, 1997

    PubMed  Google Scholar 

  59. Scarborough RM, Rose JW, Hsu MA, Phillips DR, Fried VA, Campbell AM, Nannizzi L, Charo IF: Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. J Biol Chem 266: 9359–9362, 1991

    PubMed  Google Scholar 

  60. Chiang HS, Swaim MW, Huang TF: Characterization of platelet aggregation induced by human colon adenocarcinoma cells and its inhibition by snake venom peptides, trigramin and rhodostomin. Br J Haematol 87: 325–331, 1994

    PubMed  Google Scholar 

  61. Nierodzik ML, Klepfish A, Karpatkin S: Role of platelet integrin GPIIb-GPIIIa, fibronectin, von Willebrand factor, and thrombin in platelet-tumor interaction in vitro and metastasis in vivo. Semin Hematol 31: 278–288, 1994.

    PubMed  Google Scholar 

  62. Wolfsberg TG, Primakoff P, Myles DG, White JM: ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol 131: 275–278, 1995

    Article  PubMed  Google Scholar 

  63. Chiang HS, Swaim MW, Huang TF: Characterization of platelet aggregation induced by human breast carcinoma and its inhibition by snake venom peptides, trigramin and rhodostomin. Breast Cancer Res Treat 33: 225–235, 1995

    Article  PubMed  Google Scholar 

  64. Coller BS, Anderson KM, Weisman HF: The anti-GPIIb-IIIa agents: fundamental and clinical aspects. Haemostasis 26: 285–293, 1996

    PubMed  Google Scholar 

  65. Nurden AT: New thoughts on strategies for modulating platelet function through the inhibition of surface receptors. Haemostasis 26: 78–88, 1996

    PubMed  Google Scholar 

  66. Ruiz-Espejo F, Cabezas-Herrera J, Illana J, Campoy FJ, Vidal CJ: Cholinesterase activity and acetylcholinesterase glycosylation are altered in human breast cancer. Breast Cancer Res Treat 72: 11–22, 2002

    Article  PubMed  Google Scholar 

  67. Sastry BV: Human placental cholinergic system. Biochem Pharmacol 53: 1577–1586, 1997

    Article  PubMed  Google Scholar 

  68. Greenfield SA, Jack JJ, Last AT, French M: An electrophysiological action of acetylcholinesterase independent of its catalytic site. Exp Brain Res 70: 441–444, 1988

    Article  PubMed  Google Scholar 

  69. Greenfield SA: A noncholinergic action of acetylcholinesterase (AChE) in the brain: from neuronal secretion to the generation of movement. Cell Mol Neurobiol 11: 55–77, 1991

    Article  PubMed  Google Scholar 

  70. Nitsch RM, Rossner S, Albrecht C, Mayhaus M, Enderich J, Schliebs R, Wegner M, Arendt T, von der Kammer H: Muscarinic acetylcholine receptors activate the acetylcholinesterase gene promoter. J Physiol Paris 92: 257–264, 1998

    Article  PubMed  Google Scholar 

  71. Fernandez HL, Moreno RD, Inestrosa NC: Tetrameric (G4) acetylcholinesterase: structure, localization, and physiological regulation. J Neurochem 66: 1335–1346, 1996

    PubMed  Google Scholar 

  72. Grisaru D, Sternfeld M, Eldor A, Glick D, Soreq H: Structural roles of acetylcholinesterase variants in biology and pathology. Eur J Biochem 264: 672–686, 1999

    Article  PubMed  Google Scholar 

  73. Massoulie J: The origin of the molecular diversity and functional anchoring of cholinesterases. Neurosignals 11: 130–143, 2002

    Article  PubMed  Google Scholar 

  74. Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, Griffin WS: Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci 20: 149–155, 2000

    PubMed  Google Scholar 

  75. Speirs V, Kerin MJ, Newton CJ, Walton DS, Green AR, Desai SB, Atkin SL: Evidence for transcriptional activation of ERalpha by IL-1beta in breast cancer cells. Int J Oncol 15: 1251–1254, 1999

    PubMed  Google Scholar 

  76. Layer PG, Willbold E: Novel functions of cholinesterases in development, physiology and disease. Prog Histochem Cytochem 29: 1–94, 1995

    Google Scholar 

  77. Lampert IA, Van Noorden S: Acetyl cholinesterase is expressed in the follicular dendritic cells of germinal centres: Differences between normal and neoplastic follicles. J Pathol 180: 169–174, 1996

    Article  PubMed  Google Scholar 

  78. Ruiz-Espejo F, Cabezas-Herrera J, Illana J, Campoy FJ, Munoz-Delgado E, Vidal CJ: Breast cancer metastasis alters acetylcholinesterase activity and the composition of enzyme forms in axillary lymph nodes. Breast Cancer Res Treat 80: 105–114, 2003

    Article  PubMed  Google Scholar 

  79. Wang Y, Chen CH: Acetylcholine receptor-enriched membrane vesicles in response to ethanol: Activity and microcalorimetric studies. Biophys Chem 43: 51–59, 1992

    Article  PubMed  Google Scholar 

  80. Lasner M, Roth LG, Chen CH: Structure-functional effects of a series of alcohols on acetylcholinesterase-associated membrane vesicles: Elucidation of factors contributing to the alcohol action. Arch Biochem Biophys 317: 391–396, 1995

    Article  PubMed  Google Scholar 

  81. Butterstein GM, Mizejewski GJ: Alpha-fetoprotein inhibits frog metamorphosis: Implications for protein motif conservation. Comp Biochem Physiol A Mol Integr Physiol 124: 39–45, 1999

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Serometrix Biotechnology, Syracuse, New York

    M. Muehlemann

  2. Platelet Laboratory, University of Miami, Miami, Florida

    K. D. Miller

  3. Rumbaugh-Goodwin Cancer Research Institute, Plantation, Florida

    M. Dauphinee

  4. Wadsworth Ctr., Albany, N.Y., 12201

    G. J. Mizejewski (Non-compensated scientific adviser)

Authors
  1. M. Muehlemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. D. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Dauphinee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. J. Mizejewski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Muehlemann.

Additional information

Portions of the peptide data contained in this manuscript has been designated “Patent Pending”.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muehlemann, M., Miller, K.D., Dauphinee, M. et al. Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis. Cancer Metastasis Rev 24, 441–467 (2005). https://doi.org/10.1007/s10555-005-5135-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-005-5135-2

Keywords

Search

Navigation