Intratumoral Injection of Lipopolysaccharide Causes Regression of Subcutaneously Implanted Mouse Glioblastoma Multiforme

Chicoine, Michael R.; Won, Eun Kyung; Zahner, Michael C.

doi:10.1097/00006123-200103000-00032

Cited by 66 publications

(43 citation statements)

References 31 publications

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“…In some tumor types, Th1 cells are tumoricidal via a FasL-Fas interaction, while Th2 cells promote tumor growth [22], underscoring the ability of the two helper T cell types to exert opposite effects on tumors. The observations that glioblastoma patients who experience postoperative cranial wound infections exhibit longer survival [23,24] and that postoperative empyema prolongs survival in bronchogenic carcinoma patients [25,26] have been attributed to bacterial lipopolysaccharide (LPS) eliciting a nonspecific immune response a portion of which targets the tumor [27,28] or to these infections causing an immune cell infiltrate at the tumor resection site which promotes a specific cross-reactive immunological attack against the tumor. However, our findings also raise the possibility that tumor mutations might stratify patients into two groups with different circulating helper T cell profiles-those with more potent antitumor Th1-mediated cellular immunity capable of limiting tumor growth may also have weaker Th2-mediated humoral immunity rendering them more prone to infections, while patients whose tumor mutations lead to a circulating Th2 profile might ward off infection effectively but be unable to mount a cellular immune response against the tumor.…”

Section: Discussionmentioning

confidence: 99%

Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q

et al. 2009

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Introduction Chromosome 10q allelic loss commonly occurs in glioblastoma. Disruption of PTEN, one of three known 10q tumor suppressor genes, affects the immune system by increasing tumor expression of immunosuppressive protein B7-H1 and by increasing tumor release of Th2-inducing cytokines. While the former might impair antitumor cellular immunity, a consideration for immunotherapy, the latter could cause 10q-maintaining tumor patients to experience comparatively higher rates of bacterial infections, a source of morbidity and mortality in glioblastoma patients. Methods We retrospectively reviewed 58 glioblastoma patients whose tumors were designated ''normal-10q'' (n = 16) or ''LOH-10q'' (n = 42) using loss of heterozygosity (LOH) assays of microsatellite markers in constitutional/tumor DNA pairs. Records were reviewed for symptomatic, microbiologically or radiographically confirmed infections in the first 2 years after diagnosis. Results Infection occurred more frequently in ''normal-10q'' than ''LOH-10q'' patients (56% vs. 14% of patients experiencing infection; P = 0.001). ''Normal-10q'' patients more commonly developed all four infection types studied (urinary tract = 38% vs. 13%, craniotomy wound = 19% vs. 0%, pneumonia = 19% vs. 5%, sepsis = 6% vs. 3%). ''Normal10q'' and ''LOH-10q'' patients had similar survival, ages, chemotherapy treatment rates, and frequency of patients on dexamethasone 1 month after radiation therapy (P = 0.4-0.98), making these factors unlikely to explain the observed difference in infection rates. Conclusion While tumor mutations may inhibit antitumor immunity, the effects of these mutations on systemic immunity remain undetermined. We found higher infection rates after glioblastoma diagnosis in patients whose tumors maintained chromosome 10q than in patients whose tumors had allelic 10q loss. Differing effects of this genetic alteration on antitumor and systemic immunity may warrant further investigation, potentially providing insight into mechanisms of antitumor immunity and host defenses against local and systemic infections.

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Section: Discussionmentioning

confidence: 99%

Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q

et al. 2009

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“…Intracranial DBT-FG tumors are similar to human glioblastomas in their aggressive growth pattern, histopathological characteristics and immunoreactivity for glial fibrillary acidic protein (Kumanishi, 1967;Chicoine et al, 2001). Mice were stereotactically injected with 10 000 DBT-FG cells in the right frontal lobe of the brain.…”

Section: Kcc009 Induces Cell Death In Glioblastomas L Yuan Et Almentioning

confidence: 99%

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

et al. 2006

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Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cell-extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N 0 -bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of fibronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.

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“…Tumors generated after either intracranial or s.c. implantation of the DBT cells are analogous to human glioblastomas in their aggressive growth pattern, histopathologic characteristics, and immunoreactivity for glial fibrillary acidic protein (11,12). DBT cells were grown in culture to confluence.…”

Section: In Vitro Putrescine Incorporation Assaymentioning

confidence: 99%

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Choi

Khosla

et al. 2005

Molecular Cancer Therapeutics

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Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3B (GSK-3B), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-NV -bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferasemediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas. [Mol Cancer Ther 2005;4(9):1293 -302]

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Intratumoral Injection of Lipopolysaccharide Causes Regression of Subcutaneously Implanted Mouse Glioblastoma Multiforme

Abstract: Intratumoral injections of LPS caused dramatic regression of subcutaneously implanted delayed brain tumor cell mouse gliomas. Investigation of this antitumoral effect may improve treatment responses for patients with malignant gliomas.

Cited by 66 publications

References 31 publications

Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q

Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

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