Herpes simplex virus‐induced, death receptor‐dependent apoptosis and regression of transplanted human cancers

Abstract

he use of replication-competent viral vectors, in particular herpes simplex virus (HSV) type 1 vectors, is a promising strategy for cancer therapy because the virus can replicate and spread in situ, exhibiting oncolytic activity through a direct cytopathic effect.1) A number of oncolytic HSV vectors have been developed by introduction of mutations that disrupt genes associated with neurovirulence and/or viral DNA synthesis in order to restrict viral replication in transformed cells and to diminish the infectious disease.2-11) Restriction of viral growth by introduction of a tissue-specific calponin promoter into the HSV genome resulted in efficient oncolysis of malignant soft tissue and bone tumors.12) Evidence to date following administration of such vectors into the brain attests to their safety, an important observation in light of the neuropathogenicity of the virus. Phase 1 clinical trials of these vectors are either ongoing or completed, without any severe adverse events.13-16) These variants have been demonstrated to be effective in the treatment of a wide variety of malignancies including brain, breast, colorectal, prostate, head and neck cancers, disseminated peritoneal, and soft tissue and bone tumors in animal models. 12,[17][18][19][20][21][22] On the basis of early studies using immunocompromised athymic or severe combined immunodeficiency mice, one mechanism of antitumor activity of oncolytic HSV is thought to be tumor cell destruction due to virus infection and intracellular replication.Recent studies in immunocompetent syngeneic models have suggested that the host defense mechanisms provoked by HSV play important roles in oncolysis. Oncolytic HSV growing within a tumor elicits an immune response to HSV and tumorspecific antigens.23) Colon cancer tumors were transplanted on the bilateral flanks of syngeneic immunocompetent mice, and HSV was inoculated into one of the established tumors. The tumors in the syngeneic immunocompetent mice showed greater and prompter regression than those in athymic animals. Further, the inoculation into a tumor on one side induced regression of the tumor on the other side. In addition, a CD8 + T cell-mediated response is generated to a tumor-specific antigen on the cells. The recognition that conditionally replicating HSV vectors induce antitumor immune responses has led to engineering of HSV to carry genes for cytokines that potentiate the antitumor immune response. 11,[24][25][26] We examined the antitumor effect of an attenuated HSV expressing β-galactosidase, βH1, using immunocompromised athymic models to analyze the direct effect of HSV on oncolysis in the absence of an antitumor immune response. We found that tumor regression due to HSV was mediated by apoptosis that occurred during HSV growth and subsequent expression of CD30, CD30 ligand (CD30L), tumor necrosis factor (TNF)-α, TNF-receptor 1 (TNF-R1), FAS, and FAS-L in transplanted human cancer cells. These observations suggest that expression of these ligands and receptors might enhance the susceptibility of ...

Phylogenetically Distant Viruses Use the Same BH3-Only Protein Puma to Trigger Bax/Bak-Dependent Apoptosis of Infected Mouse and Human Cells

“…Another controversial issue has been to what extent death receptor signalling contributes to HSV-1- and SFV-induced apoptosis. While in one case inhibition of FasL by soluble Fas did not prevent apoptosis caused by HSV [ 46 ], another report found that HSV-induced apoptosis was suppressed by antibodies directed towards Fas or FasL [ 47 , 48 ]. Moreover, gD and gJ of HSV-1 were shown to protect against FasL-induced apoptosis [ 17 , 18 ] and dendritic cells seem to die after HSV-1 infection due to the downregulation of the caspase-8 inhibitor c-FLIP [ 28 ].…”

Proteomic Analysis of Serum in Lung Cancer Induced by 3‐Methylcholanthrene

“…So it promoted the transmission of intracellular information. Because that information could be positive or negative signal, consequently, it resulted in cellular growth was inhibited or cellular apoptosis [44], cellular hyperplasia or differentiation, secretion of cytokine, and so on. Wright et al [45] further confirmed that in ALCL cells, the stimulation of CD30 elicits p21 (waf1)-mediated arrest through the canonical but not the alternative NF-kappaB pathway.…”

Auto-antibodies against apolipoprotein A-1 block cancer cells proliferation and induce apoptosis

“…First, several members of the death receptor family were induced by anti-apoA-1 antibodies. Among them, TNF receptor super family 8 (TNFRSF8 or CD30) and TNFRSF10D (TRAIL Receptor), together with two TNFRSF ligands TNFSF9 (CD137Ligand) and TNFSF4 (Ox40 Ligand) were notably up-regulated and some link to caspase 3-dependent tumor apoptosis have been described for TNFRSF8 (CD30) [56][57][58] and for TNFSF9 [59,60], the lastest being also involved in promoting neuronal cell death [61]. TLR6, TLR1, TLR10 and CD14, co-receptors of TLR2 and TLR4 previously identified as anti-apoA-1 antibodies receptors [9,13], and TLR4 have been transcriptionnaly up-regulated.…”