BIOREGULATORY MEDICINE

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GcMAF

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GcMAF is a vitamin D-binding protein and is scientifically known as Gc protein-derived macrophage activating factor. It is a protein found in different body fluids (serum, urine, breast milk, ascitic fluid, cerebrospinal fluid, saliva and seminal fluid) and organs (brain, heart, lungs, kidneys, placenta, spleen, testes 
and uterus).

 

Although its major function is binding, solubilization and transport of vitamin D and its metabolites, this glycoprotein exhibits numerous other important biological functions in the body.

 

GcMAF activates macrophage cells, or the cells responsible for fighting off infection, such as viruses and diseases such as cancer. Cancer cells and tumors release a protein called nagalase. When released, it prevents immune system cells from functioning properly by blocking GcMAF protein. 

 

The articles herein (none of which have been retracted) describe current GcMAF research and discuss its multifunctional capacity - particularly, its ability to enhance cellular immunity in cultures and animal models.

Bellone M, Rigamonti N. Vitamin D-binding protein-derived
macrophage-activating factor, GcMAF, and prostate cancer. Cancer Immunol Immunother. 2012 Dec;61(12):2377-8. doi: 10.1007/s00262-012-1310-9. Epub 2012 Jun 28. PubMed PMID: 22740161.

 

Branca JJ, Morucci G, Malentacchi F, Gelmini S, Ruggiero M, Pacini S. Effects of oxaliplatin and oleic acid Gc-protein-derived macrophage-activating factor on murine and human microglia. J Neurosci Res. 2015 Sep;93(9):1364-77. doi:
10.1002/jnr.23588. Epub 2015 Mar 18. PubMed PMID: 25782915.

 

Delanghe JR, Speeckaert R, Speeckaert MM. Behind the scenes of vitamin D binding protein: more than vitamin D binding. Best Pract Res Clin Endocrinol
Metab. 2015 Oct;29(5):773-86. doi: 10.1016/j.beem.2015.06.006. Epub 2015 Jul 2.
Review. PubMed PMID: 26522461. (Abstract)

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Gregory KJ, Zhao B, Bielenberg DR, Dridi S, Wu J, Jiang W, et al. (2010) Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, Migration, and uPAR Expression of Prostate Cancer Cells. PLoS ONE 5(10): e13428. doi:10.1371/journal.pone.0013428

 

Hamilton G, Rath B, Klameth L, Hochmair MJ. Small cell lung cancer: Recruitment of macrophages by circulating tumor cells. Oncoimmunology. 2015 Oct 29;5(3):e1093277. eCollection 2016 Mar. PubMed PMID: 27141354; PubMed Central PMCID: PMC4839345.

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Hirota K, Nakagawa Y, Takeuchi R, Uto Y, Hori H, Onizuka S, Terada H. Antitumor effect of degalactosylated gc-globulin on orthotopic grafted lung cancer in mice. Anticancer Res. 2013 Jul;33(7):2911-5. PubMed PMID: 23780979.

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Ikeda T, Kasai M, Tatsukawa E, Kamitakahara M, Shibata Y, Yokoi T, Nemoto TK, Ioku K. A bone substitute with high affinity for vitamin D-binding protein–relationship with niche of osteoclasts. J Cell Mol Med. 2014 Jan;18(1):170-80. doi: 10.1111/jcmm.12180. Epub 2013 Nov 28. PubMed PMID:
24286277; PubMed Central PMCID: PMC3916128.

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Inui T, Kubo K, Kuchiike D, Uto Y, Nishikata T, Sakamoto N, Mette M. Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports. Anticancer Res. 2015 Aug;35(8):4545-9. PubMed PMID:26168499.

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Inui T, Makita K, Miura H, Matsuda A, Kuchiike D, Kubo K, Mette M, Uto Y, Nishikata T, Hori H, Sakamoto N. Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy. Anticancer Res. 2014
Aug;34(8):4589-93. Erratum in: Anticancer Res. 2015 Apr;35(4):2477. PubMed PMID: 25075104.

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Ishikawa M, Inoue T, Inui T, Kuchiike D, Kubo K, Uto Y, Nishikata T. A novel assay system for macrophage-activating factor activity using a human U937 cell line. Anticancer Res. 2014 Aug;34(8):4577-81. PubMed PMID: 25075102.

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Kanda S, Mochizuki Y, Miyata Y, Kanetake H, Yamamoto N. Effects of vitamin D(3)-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis. J Natl Cancer Inst. 2002 Sep 4;94(17):1311-9. PubMed PMID: 12208896.

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Kalkunte S, Brard L, Granai CO, Swamy N. Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf. Angiogenesis. 2005;8(4):349-60. Epub 2006 Jan 7. PubMed PMID: 16400520. (Abstract)

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Kisker O, Onizuka S, Becker CM, Fannon M, Flynn E, D’Amato R, Zetter B, Folkman J, Ray R, Swamy N, Pirie-Shepherd S. Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice.
Neoplasia. 2003 Jan-Feb;5(1):32-40. PubMed PMID: 12659668; PubMed Central PMCID:PMC1502120.

 

Koga Y, Naraparaju VR, Yamamoto N. Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice. Proc Soc Exp Biol Med. 1999 Jan;220(1):20-6. PubMed PMID: 9893164. (Abstract)

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Korbelik M, Naraparaju VR, Yamamoto N. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998 Mar; 77(6):1009-14.

 

Korbelik, M., V. R. Naraparaju, and N. Yamamoto. 
Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer. British journal of cancer 75, no. 2 (1997): 202.

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Kuchiike D, Uto Y, Mukai H, Ishiyama N, Abe C, Tanaka D, Kawai T, Kubo K, Mette M, Inui T, Endo Y, Hori H. Degalactosylated/desialylated human serum
containing GcMAF induces macrophage phagocytic activity and in vivo antitumor activity. Anticancer Res. 2013 Jul;33(7):2881-5. PubMed PMID: 23780974.

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Matsuura T, Uematsu T, Yamaoka M, Furusawa K. Effect of salivary gland adenocarcinoma cell-derived alpha-N-acetylgalactosaminidase on the bioactivity of macrophage activating factor. Int J Oncol. 2004 Mar;24(3):521-8. PubMed PMID: 14767536. (Abstract)

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Meier, Ursula, Olav Gressner, Frank Lammert, and Axel M. Gressner. Gc-globulin: roles in response to injury. Clinical chemistry 52, no. 7 (2006): 1247-1253.

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Morucci G, Branca JJ, Gulisano M, Ruggiero M, Paternostro F, Pacini A, Di Cesare Mannelli L, Pacini S. Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin. Anticancer Drugs. 2015 Feb;26(2):197-209. doi: 10.1097/CAD.0000000000000177. PubMed PMID: 25304987.

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Mohamad SB, Nagasawa H, Uto Y, Hori H. Preparation of Gc protein-derived macrophage activating factor (GcMAF) and its structural characterization and biological activities. Anticancer Res. 2002 Nov-Dec;22(6C):4297-300. PubMed PMID:12553073.

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Mohamad SB, Nagasawa H, Sasaki H, Uto Y, Nakagawa Y, Kawashima K, Hori H. Gc protein-derived macrophage activating factor (GcMAF): isoelectric focusing pattern and tumoricidal activity. Anticancer Res. 2003 Nov-Dec;23(6a):4451-7. PubMed PMID: 14666733.

 

Naraparaju VR, Yamamoto N. 1994. Roles of b-galactosidase of B lymphocytes and sialidase of T lymphocytes in inflammation primed activation of macrophages. Immunol Lett 43:143–148. (Abstract)

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Nonaka K, Onizuka S, Ishibashi H, Uto Y, Hori H, Nakayama T, Matsuura N, Kanematsu T, Fujioka H. Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice. J Surg Res. 2012 Jan;172(1):116-22. doi:
10.1016/j.jss.2010.07.057. Epub 2010 Sep 17. PubMed PMID: 20855083.

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Odell, James Paul Maffitt. GcMAF (Globulin Component Macrophage Activating Factor), BRMI E-Journal #1 2018.

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Onizuka S, Kawakami S, Taniguchi K, Fujioka H, Miyashita K. Pancreatic carcinogenesis: apoptosis and angiogenesis. Pancreas. 2004 Apr;28(3):317-9. PubMed PMID: 15084979. (Abstract)

 

Pacini S, Punzi T, Morucci G, Gulisano M, Ruggiero M. Effects of vitamin D-binding protein-derived macrophage-activating factor on human breast cancer cells. Anticancer Res. 2012 Jan;32(1):45-52. PubMed PMID: 22213287.

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Pacini S, Morucci G, Punzi T, Gulisano M, Ruggiero M, Amato M, Aterini S. Effect of paricalcitol and GcMAF on angiogenesis and human peripheral blood mononuclear cell proliferation and signaling. J Nephrol. 2012 Jul-Aug;25(4):577-81. doi: 10.5301/jn.5000035. PubMed PMID: 21956771.

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Pacini S, Morucci G, Punzi T, Gulisano M, Ruggiero M. Gc protein-derived macrophage-activating factor (GcMAF) stimulates cAMP formation in human mononuclear cells and inhibits angiogenesis in chick embryo chorionallantoic 
membrane assay. Cancer Immunol Immunother. 2011 Apr;60(4):479-85. doi: 10.1007/s00262-010-0953-7. Epub 2010 Dec 14. PubMed PMID: 21170647.

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Rehder DS, Nelson RW, Borges CR. Glycosylation status of vitamin D binding protein in cancer patients. Protein Sci. 2009 Oct;18(10):2036-42. doi: 10.1002/pro.214. PubMed PMID: 19642159; PubMed Central PMCID: PMC2786967.

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Ruggiero M, Ward E, Smith R, Branca JJ, Noakes D, Morucci G, Taubmann M, Thyer L, Pacini S. Oleic Acid, deglycosylated vitamin D-binding protein, nitric oxide: a molecular triad made lethal to cancer. Anticancer Res. 2014 Jul;34(7):3569-78. PubMed PMID: 24982371.

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Siniscalco D, Bradstreet JJ, Cirillo A, Antonucci N. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. J Neuroinflammation. 2014 Apr
17;11:78. doi: 10.1186/1742-2094-11-78. PubMed PMID: 24739187; PubMed Central
PMCID: PMC3996516.

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Thyer L, Ward E, Smith R, Branca JJ, Morucci G, Gulisano M, Noakes D, Eslinger R, Pacini S. GC protein-derived macrophage-activating factor decreases
α-N-acetylgalactosaminidase levels in advanced cancer patients. Oncoimmunology. 2013 Aug 1;2(8):e25769. Epub 2013 Jul 29. PubMed PMID: 24179708; PubMed Central PMCID: PMC3812199.

 

Thyer L, Ward E, Smith R, Fiore MG, Magherini S, Branca JJ, Morucci G, Gulisano M, Ruggiero M, Pacini S. A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages. Nutrients. 2013 Jul 8;5(7):2577-89. doi: 10.3390/nu5072577. PubMed PMID:23857228; PubMed Central PMCID: PMC3738989.

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Toyohara Y, Hashitani S, Kishimoto H, Noguchi K, Yamamoto N, Urade M. Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line. Oncol Lett. 2011 Jul;2(4):685-691. Epub 2011 May 13. PubMed PMID: 22848250; PubMed Central PMCID: PMC3406437. 

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Uto Y, Kawai T, Sasaki T, Hamada K, Yamada H, Kuchiike D, Kubo K, Inui T, Mette M, Tokunaga K, Hayakawa A, Go A, Oosaki T. Degalactosylated/Desialylated Bovine Colostrum Induces Macrophage Phagocytic Activity Independently of Inflammatory Cytokine Production. Anticancer Res. 2015 Aug;35(8):4487-92. PubMed PMID: 26168491.

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Uto Y, Yamamoto S, Mukai H, Ishiyama N, Takeuchi R, Nakagawa Y, Hirota K, Terada H, Onizuka S, Hori H. β-Galactosidase treatment is a common first-stage
modification of the three major subtypes of Gc protein to GcMAF. Anticancer Res. 2012 Jun;32(6):2359-64. PubMed PMID: 22641675.

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Uto Y, Yamamoto S, Takeuchi R, Nakagawa Y, Hirota K, Terada H, Onizuka S, Nakata E, Hori H. Effect of the Gc-derived macrophage-activating factor precursor (preGcMAF) on phagocytic activation of mouse peritoneal macrophages. Anticancer Res. 2011 Jul;31(7):2489-92. PubMed PMID: 21873164.

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Yamamoto N, Homma S, Haddad JG, Kowalski MA. Vitamin D3 binding protein required for in vitro activation of macrophages after alkylglycerol treatment of mouse peritoneal cells. Immunology. 74 420–424 (1991).

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Yamamoto N, Homma S, Millman I. 1991. Identification of the serum factor required for in vitro activation of macrophages: Role of vitamin D3 binding protein (Group specific component, Gc) in lysophospholipid activation of mouse peritoneal macrophages. J Immunol 147:273–280. (Abstract)


Yamamoto N, and Homma S. Vitamin D3 binding protein (group specific component) is a precursor for the macrophage-activating signal. Proc.Natl. Acad. Sci. USA 88 8539–8543 (1991). 

 

Yamamoto, N., and Homma, S. Vitamin D3 binding protein (group-specific component, Gc) is a precursor for the macrophage activating signal factor from lysophosphatidylcholine-treated lymphocytes. Proc. NatI. Acad. Sci. USA, 88: 8539-8543, 1991.

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Yamamoto N, and Kumashiro R. Conversion of vitamin D3 binding protein (group specific component) to a macrophage activating factor by the stepwise action of ß-galactosidase of B cells and sialidase of T cells. J. lmmunol. 151 2794–2802 (1993). (Abstract)

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Yamamoto N, Kumashiro R. Conversion of vitamin D3 binding protein (Group specific component) to a macrophage activating factor by the stepwise action of b-galactosidase of B cells and sialidase of T cells. J Immunol 151:2794–2802, 1993. (Abstract)

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Yamamoto N, Naraparaju VR, Srinivasula SM. Structural modification of serum vitamin D3-binding protein and immunosuppression in AIDS patients. AIDS Res Hum Retroviruses. 1995 Nov;11(11):1373-8. PubMed PMID: 8573395. (Abstract)

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Yamamoto N. Structural definition of a potent macrophage activating factor derived from vitamin D3-binding protein with adjuvant activity for antibody production. Mol Immunol. 1996 Oct;33(15):1157-64. PubMed PMID: 9070663. (Abstract)

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Yamamoto N, Naraparaju VR, Asbell SO. Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in cancer patients. Cancer Res. 1996 Jun 15;56(12):2827-31. PubMed PMID: 8665521.

 

Yamamoto N, Naraparaju VR. Vitamin D3-binding protein as a precursor for macrophage activating factor in the inflammation-primed macrophage activation cascade in rats. Cell Immunol. 1996 Jun 15;170(2):161-7. PubMed PMID: 8660814. (Abstract)

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Yamamoto N, Naraparaju VR. A defect in beta-galactosidase of B lymphocytes in the osteopetrotic (op/op) mouse. Immunol Lett. 1996 Apr;50(1-2):35-40. PubMed
PMID: 8793557.

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Yamamoto N, Naraparaju VR. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res. 1997 Jun 1;57(11):2187-92. PubMed PMID: 9187119.

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Yamamoto N, Naraparaju VR, Urade M. Prognostic utility of serum alpha-N-acetylgalactosaminidase and immunosuppression resulted from deglycosylation of serum Gc protein in oral cancer patients. Cancer Res. 1997 Jan 15;57(2):295-9. PubMed PMID: 9000571.

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Yamamoto N, Naraparaju VR. Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization. Immunol Cell Biol. 1998 Jun;76(3):237-44. PubMed PMID: 9682967.

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Yamamoto N, Urade M. Pathogenic significance of alpha-N-acetyl-galacto-saminidase activity found in the hemagglutinin of influenza virus. Microbes Infect. 2005 Apr;7(4):674-81. Epub 2005 Mar 22. PubMed PMID:
15848273. (Abstract)

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Yamamoto N, Suyama H and Yamamoto N. Immunotherapy for prostate cancer with Gc protein-derived macrophage-activating factor, GcMAF. Transl Oncol 1: 65-72, 2008.

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