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

Thyer, Lynda; Ward, Emma; Smith, Rodney; Fiore, Maria Giulia; Magherini, Stefano; Branca, Jacopo Junio Valerio; Morucci, Gabriele; Gulisano, Massimo; Ruggiero, Marco; Pacini, Stefania

doi:10.3390/nu5072577

Cited by 48 publications

(44 citation statements)

References 17 publications

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“…Thus, we recently hypothesized that the effects of GcMAF are mediated by cross-talk with the Vitamin D Receptor (VDR) and we elucidated the molecular type of interaction occurring between these two vitamin D binding proteins that belong to the vitamin D axis and exert a multiplicity of effects at the cellular and molecular level Thyer et al, 2013). Since the VDR is expressed in a variety of tissues including the central nervous system (Harms et al, 2011) it can be hypothesized that GcMAF may exert a direct effect on neurons as well as an indirect effect of rebalancing the immune system that is often dysfunctional in autism and ME/CFS.…”

Section: Ajimentioning

confidence: 99%

Therapeutic Effects of Highly Purified De-Glycosylated Gcmaf in the Immunotherapy of Patients With Chronic Diseases

Thyer¹,

Ward²,

Smith³

et al. 2013

American Journal of Immunology

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The de-Glycosylated vitamin D binding protein is a powerful Macrophage Activating Factor (GcMAF) that shows multiple biological effects that could be exploited in the immunotherapy of tumours, viral infections and autism. Here we report the observation of a series of clinical cases describing the results obtained administering highly purified GcMAF to patients with diverse types of chronic diseases. These are heterogeneous and refer to patients with different types of diseases at different stages. In some cases, patients underwent other complementary treatments such as stem cell infusion or administration of supplements. In patients harbouring tumours, GcMAF treatment was initiated at late stages of tumour progression. Therefore, since this is an open-label, non-controlled, retrospective analysis, caution must be employed when ascribing cause and effect to any treatment outcome. However, the response to GcMAF was robust and certain trends emerge evident. In all cases (n = 7), GcMAF subcutaneous injections were associated with improvement of clinical conditions. No adverse side effects were reported. The observation reported here confirm and extend the results previously presented by several Authors and open the way to further trials aimed at assessing the precise role and indications for GcMAF in the immunotherapy of chronic diseases.

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Section: Ajimentioning

confidence: 99%

Therapeutic Effects of Highly Purified De-Glycosylated Gcmaf in the Immunotherapy of Patients With Chronic Diseases

Thyer¹,

Ward²,

Smith³

et al. 2013

American Journal of Immunology

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“…55 MAFs are lymphokines involved in cytotoxicity of macrophages to tumors. 56,57 GcMAF directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. 58 However, the enzyme a-N-acetylgalactosaminidase which is produced by cancer cells deactivates this factor and facilitates spread of tumors.…”

Section: Secretory Phenotype Of Sclc Ctc-induced Macrophagesmentioning

confidence: 99%

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

et al. 2015

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Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 C , CD163 weak and CD68 C macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

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“…Among these, the results presented at the biennial meeting of the International Association for CFS and ME, held in Ottawa, Ontario, in 2011(CFS, 2011 and those presented by researchers and patients at the GcMAF Immunology Conference, 2013 in Frankfurt, Germany. Consistent with these congress presentations, a very recent peer-reviewed paper reported the therapeutic effects of GcMAF on a variety of neurological diseases, including ME/CFS (Thyer et al, 2013a).…”

Section: Discussionmentioning

confidence: 73%

“…Macrophage activation by GcMAF induces a significant variation of surface receptors that in turn recognize abnormality in malignant cell surface and induce the apoptosis of cancerous cells as well as virus-infected cells (Yamamoto et al, 2009;Thyer et al, 2013a).…”

Section: Myalgicmentioning

confidence: 99%

“…At the end of the production process, GcMAF was checked for sterility in-house and externally by independent laboratories. Its safety and biological activity were tested in monocytes, human breast cancer cells and chick embryos (Pacini et al, 2011;2012a;Thyer et al, 2013a). When not indicated otherwise, common reagents were from Sigma Aldrich, Milano, Italy.…”

Section: Reagentsmentioning

confidence: 99%

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Effects of Gc-Macrophage Activating Factor in Human Neurons; Implications for Treatment of Chronic Fatigue Syndrome

Smith¹,

Thyer²,

Ward³

et al. 2013

American Journal of Immunology

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of multifactorial aetiology characterized by immune system dysfunction, widespread inflammation, multisystemic neuropathology and persistent pain. Given the central role of the immune system in the pathogenesis of the syndrome, we studied the effects of a potent modulator of the immune system in in vitro and in vivo models that could help clarifying its role and indications in ME/CFS treatment. To this end, we studied the effects of vitamin D-binding protein-derived macrophage activating factor (also designated as GcMacrophage Activating Factor or (GcMAF)) on human neuronal cells (SH-SY5Y) and on the persistent pain induced by osteoarticular damage in rats. GcMAF at pM concentration increased neuronal cell viability and metabolism through increased mitochondrial enzyme activity. These effects were accompanied by cAMP formation and by morphological changes that were representative of neuronal differentiation. We hypothesize that these effects are to be ascribed to the interconnection between the GcMAF and Vitamin D Receptor (VDR) signalling pathways. The results presented here confirm at the experimental level the therapeutic effects of GcMAF in ME/CFS and elucidate the mechanisms of action through which GcMAF might be responsible for such therapeutic effects.

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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

Cited by 48 publications

References 17 publications

Therapeutic Effects of Highly Purified De-Glycosylated Gcmaf in the Immunotherapy of Patients With Chronic Diseases

Therapeutic Effects of Highly Purified De-Glycosylated Gcmaf in the Immunotherapy of Patients With Chronic Diseases

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

Effects of Gc-Macrophage Activating Factor in Human Neurons; Implications for Treatment of Chronic Fatigue Syndrome

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