Potent anti-tumour activity of a novel conditionally replicating adenovirus for melanoma via inhibition of migration and invasion

Jiang, Guanjun; Cs, Yang; D, Xu; Sun, Cheng; Zheng, Junnian; Tc, Lei; Yq, Liu

doi:10.1038/bjc.2014.177

Cited by 11 publications

(8 citation statements)

References 25 publications

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“…22 A second level of treatment specificity could be given by selective expression of ChR2 in cancer cells. Molecular tools for genetically targeted expression are under active investigations with some promising genetic tools arising, such as cancer cell-specific promoters 35, 36 and systemically deliverable viruses that efficiently target cancer cell surface proteins. 37, 38, 39 The fact that optogenetics induces controlled apoptotic cell death and not necrosis reduces the risk of a spreading inflammation adding a third level of specificity.…”

Section: Discussionmentioning

confidence: 99%

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

et al. 2016

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Channelrhodopsin-2 (ChR2) has become a celebrated research tool and is considered a promising potential therapeutic for neurological disorders. While making its way into the clinic, concerns about the safety of chronic ChR2 activation have emerged; in particular as the high-intensity blue light illumination needed for ChR2 activation may be phototoxic. Here we set out to quantify for the first time the cytotoxic effects of chronic ChR2 activation. We studied the safety of prolonged illumination on ChR2(D156A)-expressing human melanoma cells as cancer cells are notorious for their resistance to killing. Three days of illumination eradicated the entire ChR2(D156A)-expressing cell population through mitochondria-mediated apoptosis, whereas blue light activation of non-expressing control cells did not significantly compromise cell viability. In other words, chronic high-intensity blue light illumination alone is not phototoxic, but prolonged ChR2 activation induces mitochondria-mediated apoptosis. The results are alarming for gain-of-function translational neurological studies but open the possibility to optogenetically manipulate the viability of non-excitable cells, such as cancer cells. In a second set of experiments we therefore evaluated the feasibility to put melanoma cell proliferation and apoptosis under the control of light by transdermally illuminating in vivo melanoma xenografts expressing ChR2(D156A). We show clear proof of principle that light treatment inhibits and even reverses tumor growth, rendering ChR2s potential tools for targeted light-therapy of cancers.

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Section: Discussionmentioning

confidence: 99%

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

et al. 2016

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“…Transwell cell culture chambers as previously described (20). Polyvinylpyrrolidone-free polycarbonate filters with an 8.0-µm pore size were pre-coated with 10 mg/ml collagen IV (c6745; Sigma-Aldrich; Merck KGaA) and placed on the lower surface of Transwell chambers (Costar, 3422; Corning, Inc.).…”

Section: Cell Migration Assay Cell Migration Was Assessed Usingmentioning

confidence: 99%

Role of the p53‑TRPM1/miR‑211‑MMP9 axis in UVB‑induced human melanocyte migration and its potential in repigmentation

Miao

Jiang

et al. 2020

Int J Mol Med

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clinical studies have proven that ultraviolet B (UVB) based phototherapy can induce perifollicular and marginal repigmentation patterns in the skin of vitiligo patients. It is, however, difficult to conceive how melanocytes can easily exit from their tightly interconnected epidermal microenvironment to re-enter a different location in the skin to establish a new network with neighboring keratinocytes. While it is known that matrix metalloprotease 9 (MMP9) is involved in the degradation of the extracellular matrix in physiological or pathological processes, little is known about whether MMP9 affects melanocyte migration in vitiligo repigmentation. To investigate the effects of the p53-transient receptor potential cation channel subfamily M member 1 (TRPM1)/microRNA (miR/miRNA)-211-MMP9 axis to regulate melanocyte migration following exposure to UVB, the expression profile of MMP9 in cultured human melanocytes transfected with or without the miR-211-mimic and p53-GFP lentiviral vector, respectively were determined. Quantitative polymerase chain reaction and western blotting were used to examine p53, TRPM1 and MMP9 mRNA and protein levels in UVB-exposed and unexposed cells. The capacity of melanocytes to migrate on collagen IV substrate was estimated using a Transwell migration assay. Interestingly, the upregulation of p53 and MMP9 at the mRNA and protein levels was evident in melanocytes treated with single or repeat exposures to UVB, whereas levels of TRPM1 and miR-211 were significantly suppressed in UVB-exposed melanocytes compared with the UVB-unexposed control cells. These results indicate that the p53-TRPM1/miR-211-MMP9 axis is significantly activated in melanocytes exposed to UVB. Notably, the ability of melanocyte migration was altered by the overexpression of p53 using a lentiviral vector and by the upregulation of miR-211 using an miRNA mimic. That altered migration could be neutralized by co-treatment with GM6001 (a broad-spectrum MMP inhibitor). Overall, these results show that the MMP9-mediated migration of melanocytes is regulated by a novel mechanism driven by the p53-TRPM1/miR-211-MMP9 axis. Activation of the p53-TRPM1/miR-211-MMP9 axis potentially represents an attractive therapeutic target to improve repigmentation outcomes in vitiligo patients.

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“…Oncolytic viruses (OVs) have been developed to act through tumor tropic mechanisms resulting in direct oncolysis of tumor cells and subsequent antitumor events within the tumor microenvironment, potentiating systemic responses toward antitumor immunity [ 47 ]. Animal melanoma models investigating recombinant adenoviruses or vaccinia pox viruses have shown promising antitumor responses [ 48 , 49 , 50 ]. Translation of these virus-based strategies to human trials has shown up-regulation of anti-tumor immunity in the setting of good patient tolerability with minimal side-effects, although these trials have been very small phase I/II studies [ 51 , 52 , 53 ].…”

Section: Oncolytic Virus-based Vaccinesmentioning

confidence: 99%

The Role of Regional Therapies for in-Transit Melanoma in the Era of Improved Systemic Options

Gabriel¹,

Skitzki²

2015

Cancers

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The incidence of melanoma has been increasing at a rapid rate, with 4%–11% of all melanoma recurrences presenting as in-transit disease. Treatments for in-transit melanoma of the extremity are varied and include surgical excision, lesional injection, regional techniques and systemic therapies. Excision to clear margins is preferred; however, in cases of widespread disease, this may not be practical. Historically, intralesional therapies were generally not curative and were often used for palliation or as adjuncts to other therapies, but recent advances in oncolytic viruses may change this paradigm. Radiation as a regional therapy can be quite locally toxic and is typically relegated to disease control and symptom relief in patients with limited treatment options. Regional therapies such as isolated limb perfusion and isolated limb infusion are older therapies, but offer the ability to treat bulky disease for curative intent with a high response rate. These techniques have their associated toxicities and can be technically challenging. Historically, systemic therapy with chemotherapies and biochemotherapies were relatively ineffective and highly toxic. With the advent of novel immunotherapeutic and targeted small molecule agents for the treatment of metastatic melanoma, the armamentarium against in-transit disease has expanded. Given the multitude of options, many different combinations and sequences of therapies can be offered to patients with in-transit extremity melanoma in the contemporary era. Reported response and survival rates of the varied treatments may offer valuable information regarding treatment decisions for patients with in-transit melanoma and provide rationale for these decisions.

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Potent anti-tumour activity of a novel conditionally replicating adenovirus for melanoma via inhibition of migration and invasion

Cited by 11 publications

References 25 publications

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

Role of the p53‑TRPM1/miR‑211‑MMP9 axis in UVB‑induced human melanocyte migration and its potential in repigmentation

The Role of Regional Therapies for in-Transit Melanoma in the Era of Improved Systemic Options

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