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, 7 (2), 6-16

Mechanisms of Oncolysis by Paramyxovirus Sendai

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Mechanisms of Oncolysis by Paramyxovirus Sendai

O V Matveeva et al. Acta Naturae.

Abstract

Some viral strains of the Paramyxoviridae family may be used as anti-tumor agents. Oncolytic paramyxoviruses include attenuated strains of the measles virus, Newcastle disease virus, and Sendai virus. These viral strains, and the Sendai virus in particular, can preferentially induce the death of malignant, rather than normal, cells. The death of cancer cells results from both direct killing by the virus and through virus-induced activation of anticancer immunity. Sialic-acid-containing glycoproteins that are overexpressed in cancer cells serve as receptors for some oncolytic paramyxoviruses and ensure preferential interaction of paramyxoviruses with malignant cells. Frequent genetic defects in interferon and apoptotic response systems that are common to cancer cells ensure better susceptibility of malignant cells to viruses. The Sendai virus as a Paramyxovirus is capable of inducing the formation of syncytia, multinuclear cell structures which promote viral infection spread within a tumor without virus exposure to host neutralizing antibodies. As a result, the Sendai virus can cause mass killing of malignant cells and tumor destruction. Oncolytic paramyxoviruses can also promote the immune-mediated elimination of malignant cells. In particular, they are powerful inducers of interferon and other cytokynes promoting antitumor activity of various cell components of the immune response, such as dendritic and natural killer cells, as well as cytotoxic T lymphocytes. Taken together these mechanisms explain the impressive oncolytic activity of paramyxoviruses that hold promise as future, efficient anticancer therapeutics.

Keywords: Newcastle disease virus; Sendai virus; attenuated measles virus strains; cancer therapy; oncolytic paramyxoviruses; viral anti-tumor mechanism; viral anticancer immune stimulation.

Figures

Fig. 1
Fig. 1
Paramyxoviridae phylogenetic tree along with a virion composition and genomic organization scheme of the Sendai virus. A) The phylogenetic tree based on the alignment of the amino-acid sequences of the HN genes of selected Paramyxoviridae subfamily members. The family members with proven oncolytic properties are circled. The tree was generated by Clustal W multiple alignments using the Neighbor-Joining method. Viruses are grouped according to genus and abbreviated as follows. Morbillivirus genus: MV (measles virus), CDV (canine distemper virus); Henipavirus genus: HeV (Hendra virus), NiV (Nipah virus); Respirovirus genus: SeV (Sendai virus), hPIV3 (human parainfluenza virus 3); Avulavirus genus: NDV (Newcastle Disease Virus); Rubulavirus genus: hPIV2 (human parainfluenza virus 2), hPIV-4a (human parainfluenza virus 4a), hPIV-4b (human parainfluenza virus 4b), MuV (mumps virus), PoRV (porcine rubulavirus), SV5 (simian parainfluenza virus 5), SV41 (simian parainfluenza virus 41); TiV (tioman virus); MenV (menangle virus); Unclassified: TPMV (Tupaia paramyxovirus), B) Structure and composition of virion, C) Genomic organization of the Sendai virus
Fig. 2
Fig. 2
Sendai virus infection and spread in malignant but not in normal cells. First level of virus specificity for cancer cells is related to overexpression of specific receptors for paramyxoviruses. Sialic acids residues in the form of sialoglycoproteins serve as receptors for the Sendai virus. These sialoglycoproteins are frequently overexpressed in malignant cells. Another level of oncoselectivity is related to frequent genetic defects of cancer cells that help viral replication. During the malignant progression cancer cells accumulate many genetic changes. Along with mutations that promote accelerated proliferation and invasion, many cancerous cells lose the abilities to produce interferon and to respond to interferon by induction of the antiviral state. Such abnormalities make these cells highly susceptible to viral infection. Therefore, because cancer cells are overexpressing surface receptors and are commonly defective in antiviral immunity the Sendai virus could easily replicate in malignant cells, but not in normal cells
Fig. 3
Fig. 3
Sendai virus infection may spread through syncytium formation to achieve an accelerated elimination of cancer cells. In natural hosts virus infected cells start expressing the viral fusion protein (F) on the cell surface that forces fusion of infected and surrounding non-infected cells into large polykaryonic structures known as syncytia. The syncytia support viral replication through continuous fusion with neighboring cells, even in the presence of high titers of neutralizing antibodies. Eventually, the syncytia die, which assists in viral oncolysis. The fusion protein of the Sendai virus is synthesized as an inactive precursor (F0), and proteolytic cleavage is needed to convert it to active F1 that can promote syncytia formation. A tumor-resident host protease is needed for the efficient formation of syncytia
Fig. 4
Fig. 4
Death of cancer cells through activation of the immune response against cancer cells triggered by the removal of syalic acid residues from the cancer cell’s surface by viral sialidase. Metastatic cancer cells often overexpress sialic acid-rich cell-surface glycoproteins that render a negative charge and electrostatic repulsion between cells that facilitates cancer cells entry into the blood stream, thereby promoting metastasis. One of the possible mechanisms linking increased sialylation with a malignant phenotype is the creation of a thick “coat” on the cell surface that may mask cancer-antigens-protect malignant cells from immunosurveillance. Removing some sialic acid residues by sialidase can unmask cancer-specific antigens and make cells visible to the immune system. The removal of sialic acids from tumor cells is associated with a reduced growth potential, activation of NK cells, and secretion of IFN-gamma. The hemagglutinin- neuraminidase proteins present in the Sendai virus and some other paramyxoviruses possess neuraminidase (sialidase) activity, and, therefore, its action on the surface of cancer cells may dramatically increase the induction of the cytotoxic T-cell response
Fig. 5
Fig. 5
Sendai virus indices both direct and immune-mediated death of cancer cells. Cancer cells are more accessible to viruses and susceptible to viral replication. Ordered architecture of normal tissues (blood vessels, basal membranes, tight cell-to-cell contacts etc.) protects against viral invasion from the bloodstream. Chaotic organization of a tumor, loose cell-to-cell contacts, and leakiness of immature tumor vasculature provide better access to viruses. Normal cells exposed to viruses provide antiviral protection to surrounding normal cells by secreting IFNs. Tumor cells are generally defective for IFNs induction and, therefore, support viral replication even in the present of IFNs produced by the surrounding normal cells. The Sendai virus is capable of accelerated spread inside a tumor through the formation of syncytia. Exposure of viral antigens on the surface of infected cells induces massive immunogenic death of tumor cells. Virus-specific proteins represent danger signals triggering activation of innate and adaptive anticancer immune responses. Activated cytotoxic T lymphocytes (CTLs), natural killer (NKs), and antigen-presenting dendritic cells (DCs) migrate into the tumor and provide accelerated immune-mediated destruction of malignant cells

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