Hemocyanins in the Immunotherapy of Superficial Bladder Cancer

Arancibia, Sergio; Salazar, Fabián; Becker, María

doi:10.5772/28281

Cited by 17 publications

(29 citation statements)

References 95 publications

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“…The aim of this study was to determine how mollusk hemocyanins, in the absence of additional adjuvants, trigger an innate immune response that leads to the maturation of a Th1-specific adaptive immune response together with powerful nonspecific immunomodulatory effects, including an antitumor capacity in certain cancers (3,5,6). The immune response is triggered by a proinflammatory signal that arises from various components of the innate immune system that sense invading pathogens (52) or danger/alarm signals from injured cells (53), phenomena in which phagocytic cells and APCs are fundamental.…”

Section: Discussionmentioning

confidence: 99%

“…Hemocyanins alone are capable of potently activating the immune system of mammals. Therefore, hemocyanins have been used as a biotechnological tool in the development of Abs and vaccines, and also as immunomodulators such as nonspecific immunostimulants in superficial bladder cancer (3). The hemocyanin purified from the giant keyhole limpet gastropod Megathura crenulata, commonly known as keyhole limpet hemocyanin (KLH), has traditionally been used for those purposes (4)(5)(6).…”

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confidence: 99%

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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: 99%

mentioning

confidence: 99%

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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“…They have large molecular weights (from 4 up to 9 MDa) [4] and, due to their xenogenic nature, are strongly immunogenic. Activating the immune system of mammals [9][10][11][12][13], they stimulate innate immunity by inducing macrophage activation [9].…”

Section: Introductionmentioning

confidence: 99%

Antitumour activity of Helix hemocyanin against bladder carcinoma permanent cell lines

Dolashki

Dolashka

Stenzl

et al. 2019

Biotechnology & Biotechnological Equipment

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Hemocyanins are oxygen-transporting glycoproteins in molluscs and arthropods. In this study, we assayed the biomacromolecules from the molluscs Helix lucorum (HlH), Rapana venosa (RvH) and Megatura crenulata (KLH) including their functional units (FUs), for therapy of bladder cancer permanent cells. In vitro studies antitumour activities of these proteins were performed with bladder cancer permanent cell line CAL-29 and the normal urothelial cell line HL 10/29 in comparison to doxorubicin. The obtained results showed that the human tumour CAL-29 cell line is sensitive to the action of the tested hemocyanins and their isoforms. We observed a dose-and time-dependent inhibition of tumour cell growth after incubation with native HlH and two FUs (b c-HlH-a and FU b c-HlH-h); and of particular significance, FU b c-HlH-h showed a surprisingly stronger effect than that the doxorubicin-treated cells. Cells treated with b c-HlH-h, showed both, apoptotic and necrotic cells. In addition, two-dimensional polyacrylamide gel electrophoresis (PAGE) found for differential up-regulation of several proteins after hemocyanin treatment. Eight different down-regulated and two up-regulated proteins were identified, which may be associated with the apoptosis pathway. No inhibition of the normal urothelial cell line HL 10/29 was observed after treatment with HlH and its isoforms. The most effective inhibition of CAL-29 tumour cells was observed after treatment with b c-HlH-h, probably caused by a specific oligosaccharide structure of HlH with methylated hexoses. These results suggest that hemocyanin glycosylation plays an important role in its anticancer activity.

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“…Mollusk hemocyanins are enormous glycoproteins (4)(5)(6)(7)(8) formed by an intricate arrangement of 10 subunits, approximately 350-450 kDa each, that are self-assembled into hollow cylinders 35 nm in diameter and are referred to as decamers. This structure is easily observed by negative staining using transmission electron microscopy, as shown in Figure 1.…”

Section: Structure Of the Mollusk Hemocyaninsmentioning

confidence: 99%

“…Other therapeutic strategies using hemocyanins include their use as adjuvants to disrupt self-tolerance to tumor antigens in the generation of ex vivo autologous tumor cell lysate-loaded dendritic cells (DCs) to induce T-cell responses in cancer patients (Del Campo et al, 2011). Furthermore, hemocyanins can be used as non-specific immunostimulants during therapy for recurrent superficial bladder cancer after transurethral surgical resection with negligible toxic side effects, thus making them ideal for longterm on going treatments (Arancibia et al, 2012b).…”

Section: Introductionmentioning

confidence: 99%