Anti-cancer properties of gastropodan hemocyanins in murine model of colon carcinoma

Gesheva, Vera; Chausheva, Stela; Mihaylova, Nikolina; Manoylov, Iliyan; Doumanova, Lyuba; Idakieva, Krassimira; Tchorbanov, Andrey

doi:10.1186/s12865-014-0034-3

Cited by 41 publications

(51 citation statements)

References 32 publications

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“…Interestingly, the three hemocyanins induced significant elevations in the mRNA levels of CD40L (Cd40lg) in macrophages, which might support the observed nonspecific antitumor activity of hemocyanins in several cancers (6,71). CD40-CD40L interactions promote the activation of NK cells by murine macrophages (72).…”

Section: Discussionmentioning

confidence: 88%

Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages

Zhong

Arancibia

Born

et al. 2016

The Journal of Immunology

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Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5. Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages.

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Section: Discussionmentioning

confidence: 88%

Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages

Zhong

Arancibia

Born

et al. 2016

The Journal of Immunology

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“…In addition, Tchorbanov et al have achieved enhanced antigen immunogenicity for the epitope of influence A virus hemagglutinin bound to RtH or its subunits and they have suggested that Hcs can be successfully used in many immunization protocols as adjuvants or protein carriers [23]. Gesheva et al have demonstrated the potential of RtH as cancer preventive vaccine, which was tested "in vivo" experiments with murine model of colon carcinoma [24].…”

Section: Introductionmentioning

confidence: 98%

Rapana thomasiana hemocyanin modified with ionic liquids with enhanced anti breast cancer activity

Guncheva

Paunova

Ossowicz

et al. 2016

International Journal of Biological Macromolecules

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“…They most likely reflect the snail‐intrinsic, reversible O ‐GalNAc glycosylations , initiating protein glycosylations even in mollusks . While the agglutinins are engaged in self‐defense, the agglutinin‐free hemocyanin from H. pomatia (HPH) exerted strong anti‐proliferative effects in murine models of colon carcinoma . In addition, Concholepas hemocyanin inhibits the growth of bladder tumors , and the Gal( β 1‐3)GalNAc‐bearing hemocyanin of Megathura crenulata (keyhole limpet hemocyanin, KLH) shows cross‐reactivity with T antigen , inducing a potent Th1‐dominant immune response and was used as an effective immunogenic carrier in dendritic cell vaccination developed for immunotherapy of human B cell lymphoma .…”

Section: Cross‐specificity Between Mammalian Anti‐a/anti‐tn/t‐reactivmentioning

confidence: 99%

Early ovariectomy reveals the germline encoding of natural anti‐A‐ and Tn‐cross‐reactive immunoglobulin M (IgM) arising from developmental O‐GalNAc glycosylations. (Germline‐encoded natural anti‐A/Tn cross‐reactive IgM)

Arend

2017

Cancer Medicine

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While native blood group A‐like glycans have not been demonstrated in prokaryotic microorganisms as a source of human “natural” anti‐A isoagglutinin production, and metazoan eukaryotic N‐acetylgalactosamine O‐glycosylation of serine or threonine residues (O‐GalNAc‐Ser/Thr‐R) does not occur in bacteria, the O‐GalNAc glycan‐bearing ovarian glycolipids, discovered in C57BL/10 mice, are complementary to the syngeneic anti‐A‐reactive immunoglobulin M (IgM), which is not present in animals that have undergone ovariectomy prior to the onset of puberty. These mammalian ovarian glycolipids are complementary also to the anti‐A/Tn cross‐reactive Helix pomatia agglutinin (HPA), a molluscan defense protein, emerging from the coat proteins of fertilized eggs and reflecting the snail‐intrinsic, reversible O‐GalNAc glycosylations. The hexameric structure of this primitive invertebrate defense protein gives rise to speculation regarding an evolutionary relationship to the mammalian nonimmune, anti‐A‐reactive immunoglobulin M (IgM) molecule. Hypothetically, this molecule obtains its complementarity from the first step of protein glycosylations, initiated by GalNAc via reversible O‐linkages to peptides displaying Ser/Thr motifs, whereas the subsequent transferase depletion completes germ cell maturation and cell renewal, associated with loss of glycosidic bonds and release of O‐glycan‐depleted proteins, such as complementary IgM revealing the structure of the volatilely expressed “lost” glycan carrier through germline Ser residues. Consequently, the evolutionary/developmental first glycosylations of proteins appear metabolically related or identical to that of the mucin‐type, potentially “aberrant” monosaccharide GalNAcα1‐O‐Ser/Thr‐R, also referred to as the Tn (T “nouvelle”) antigen, and explain the anti‐Tn cross‐reactivity of human innate or “natural” anti‐A‐specific isoagglutinin and the pronounced occurrence of cross‐reactive anti‐Tn antibody in plasma from humans with histo‐blood group O. In fact, A‐allelic, phenotype‐specific GalNAc glycosylation of plasma proteins does not occur in human blood group O, affecting anti‐Tn antibody levels, which may function as a growth regulator that contributes to a potential survival advantage of this group in the overall risk of developing cancer when compared with non‐O blood groups.

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Anti-cancer properties of gastropodan hemocyanins in murine model of colon carcinoma

Cited by 41 publications

References 32 publications

Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages

Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages

Rapana thomasiana hemocyanin modified with ionic liquids with enhanced anti breast cancer activity

Early ovariectomy reveals the germline encoding of natural anti‐A‐ and Tn‐cross‐reactive immunoglobulin M (IgM) arising from developmental O‐GalNAc glycosylations. (Germline‐encoded natural anti‐A/Tn cross‐reactive IgM)

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