Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-β

Park, MY; Dr, Kim; Jung, Hyun–Kyo; Hi, Yoon; Jh, Lee; Ct, Lee

doi:10.1038/cgt.2009.78

Cited by 12 publications

(8 citation statements)

References 32 publications

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“…6,52 Therefore, our results suggested that cancer cells in which PML is downregulated may escape regulation by IFNb in the tumor microenvironment and by IFNb-based gene or cell therapies. 53 In conclusion, we demonstrated that PML repressed MMP2 expression, which decreased lung cancer cell invasion when EGFR was activated. Furthermore, we determined that MMP2 was a novel nEGFR target gene and that PML repressed the nEGFR-induced MMP2 promoter activity.…”

Section: Discussionmentioning

confidence: 61%

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

et al. 2014

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Promyelocytic leukemia protein (PML) is emerging as an important tumor suppressor. Its expression is lost during the progression of several types of cancer, including lung cancer. The EGF receptor (EGFR), a membrane-bound receptor tyrosine kinase, transduces intracellular signals responsible for cell proliferation, differentiation and migration. EGFR activity is frequently abnormally upregulated in lung adenocarcinoma (LAC) and thus is considered to be a driving oncogene for LAC. EGFR translocates into the nucleus and transcriptionally activates genes, such as CCND1, that promote cell growth. Recently, we demonstrated that PML interacted with nuclear EGFR (nEGFR) and suppressed the nEGFR-mediated transcriptional activation of CCND1 in lung cancer cells, thereby restraining cell growth. When we further investigated the interplay between PML and EGFR in lung cancer metastasis, we found that the matrix metalloprotease-2 gene (MMP2) was a novel nEGFR target gene and was repressed by PML. We provide evidence that nEGFR bound to the AT-rich sequence (ATRS) in the MMP2 promoter and enhanced its transcriptional activity. In addition, we demonstrated that PML repressed nEGFR-induced MMP2 transcription and reduced cell invasion. PML was recruited by nEGFR to the MMP2 promoter where it reduced histone acetylation, leading to the transcriptional repression of MMP2. Finally, we demonstrated that PML upregulation by interferon-b (IFNb) in lung cancer cells decreased MMP2 expression and cell invasion. Together, our results suggested that IFNb induced PML to inhibit lung cancer metastasis by repressing the nEGFR-mediated transcriptional activation of MMP2.

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Section: Discussionmentioning

confidence: 61%

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

et al. 2014

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“…This means that several adenoviral gene treatments are required to achieve significant tumor mass reduction, which may result in increased adverse effects. In recent years, combining replication-defective adenovirus with CRAd has been used to overcome these difficulties with promising experimental results reported (Lee et al, 2006; Lee et al, 2004; Oh et al, 2010; Park et al, 2010). We proposed that AdE2F-1-mediated tumor suppression (Dong et al, 1999; Dong et al, 2002; Elliott et al, 2001; Itoshima et al, 2000; Vorburger et al, 2005) could be enhanced by combining treatment with CRAd, in that CRAd supplies E1A to enable AdE2F-1 replication, and AdE2F-1 provides the transcription factor to transactivate the CRAd E2 promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Park et al . developed a potent novel genetic immunotherapy against Lewis lung carcinoma by combining a CRAd (Δ24RGD) with a replication-defective adenovirus expressing interferon-beta (AdIFN-β) (Park et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

Enhanced cancer cell killing by truncated E2F-1 used in combination with oncolytic adenovirus

et al. 2012

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Adenovirus-mediated gene transfer into a tumor mass can be improved by combining it with conditionally-replicating adenovirus (CRAd) when both vectors co-infect the same cancer cell. We investigated the efficiency of enhancing transgene expression and effectiveness of cancer killing of two advenoviruses (Ads), one expressing E2F-1 (AdE2F-1) and another expressing a truncated form of E2F-1 that lacks the transactivation domain (AdE2Ftr), when combined with oncolytic Adhz60. We found that AdE2F-1 with Adhz60 actually decreased E2F-1 expression and viral replication through a mechanism apparently involving repression of the cyclin-E promoter and decreased expression of early and late structural proteins necessary for viral replication. In contrast, AdE2Ftr with Adhz60 resulted in increased E2Ftr expression, AdE2Ftr replication, and cancer cell death both in vitro and in vivo. These results indicate that AdE2Ftr coupled with a CRAd enhances AdE2Ftr-mediated cancer cell death.

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“…Curiously, recent evidence from mouse models has shown that IFNβ signaling plays a pivotal role in the antitumor response induced by radiotherapy [33], [34] and by chemotherapy with anthracyclines [35]. IFNβ gene transfer has been exploited in a considerable number of studies, indicating that IFNβ is sufficient to modulate the tumor microenvironment, inducing or improving immunological response [36], [37], [38], [39], [40].…”

Section: Introductionmentioning

confidence: 99%

Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

Catani

Medrano

Hunger

et al. 2016

Translational Oncology

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Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-β (IFNβ) in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFNβ significantly induced markers of immunogenic cell death. In situ gene therapy with IFNβ, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when using microarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1α, IL1β, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFNβ acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma.

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Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-β

Cited by 12 publications

References 32 publications

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

Enhanced cancer cell killing by truncated E2F-1 used in combination with oncolytic adenovirus

Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

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