Decorin‐expressing adenovirus decreases collagen synthesis and upregulates MMP expression in keloid fibroblasts and keloid spheroids

Lee, Won Jai; Ahn, Hyo Min; Roh, Hyun; Na, Youjin; Choi, In Hong; Kim, Yong Oock; Lew, Dae Hyun; Yun, Chae Ok

doi:10.1111/exd.12719

Cited by 32 publications

(26 citation statements)

References 65 publications

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“…TGF-β inhibits the proliferation, differentiation, and function of macrophages, T cells, B cells, and NK cells [34–37]. Previously, we demonstrated that a DCN-expressing oncolytic Ad suppresses TGF-β expression in keloid fibroblasts [38]. We hypothesized that oncolytic Ad-mediated DCN expression would ameliorate TGF-β-induced immunosuppression in a tumor microenvironment, leading to enhanced induction of the antitumor immune response mediated by IL-12.…”

Section: Resultsmentioning

confidence: 99%

Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model

Choi

Hong

et al. 2016

Oncotarget

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Section: Resultsmentioning

confidence: 99%

Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model

Choi

Hong

et al. 2016

Oncotarget

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“…This pathway regulates cell growth, differentiation, migration and induces the epithelial‐to‐mesenchymal transition . DCN has been reported to suppress the biological activity of TGF‐β by preventing TGF‐β binding to its receptor . Therefore, we performed ELISA to assess whether DCN expression mediated by oncolytic Ads affects the intratumoral expression level of TGF‐β.…”

Section: Resultsmentioning

confidence: 99%

Potent antitumor effect of tumor microenvironment‐targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Hong

et al. 2017

Intl Journal of Cancer

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Pancreatic cancer is a leading cause of cancer-related death. Desmoplastic pancreatic tumors exhibit excessive extracellular matrix (ECM) and are thus highly resistant to anticancer therapeutics, since the ECM restricts drug penetration and dispersion. Here, we designed and generated two hypoxia-responsive and cancer-specific hybrid promoters, H(mT)E and H(E)mT. Transgene expression driven by each hybrid promoter was markedly higher under hypoxic conditions than normoxic conditions. Moreover, H(E)mT-driven transgene expression was highly cancer-specific and was superior to that of H(mT)E-driven expression. A decorin-expressing oncolytic adenovirus (Ad; oH(E)mT-DCN) replicating under the control of the H(E)mT promoter induced more potent and highly cancer-specific cell death compared with its cognate control oncolytic Ad, which harbored the endogenous Ad E1A promoter. Moreover, oH(E)mT-DCN exhibited enhanced antitumor efficacy compared with both the clinically approved oncolytic Ad ONYX-015 and its cognate control oncolytic Ad lacking DCN. oH(E)mT-DCN treatment also attenuated the expression of major ECM components, such as collagen I/III, elastin and fibronectin and induced tumor cell apoptosis, leading to extensive viral dispersion within orthotopic pancreatic tumors and pancreatic cancer patient-derived tumor spheroids. Collectively, these findings demonstrate that oH(E)mT-DCN exhibits potent antitumor efficacy by degrading the ECM and inducing apoptosis in a multifunctional process. This process facilitates the dispersion and replication of oncolytic Ad, making it an attractive candidate for the treatment of aggressive and desmoplastic pancreatic cancer.Pancreatic cancer is the fourth leading cause of cancerrelated death in Europe and the United States.1 Only 10-20% of all patients with pancreatic cancer are resectable at presentation. The US National Cancer Institute recently reported that the overall 5-year relative survival rate for 2002-2008 was 5.8%, and nearly 90% of all patients were dead 1 year after diagnosis, with a median survival of <6 months. 2,3 One experimental treatment option of particular interest for pancreatic cancer is oncolytic virotherapy, which uses viral vectors to preferentially replicate in tumor cells and induce cancer cell death. Among the various viral vectors that have been tested, adenovirus (Ad) has been most extensively used in gene therapy applications, and sufficient data from randomized clinical trials support its safety in patients. 4-6Although oncolytic Ad-mediated cancer gene therapy is highly promising, significant therapeutic efficacy of oncolytic Ad for the treatment of localized tumors has not yet been achieved in clinical trials; thus, further improvements are needed. 7,8 Hypoperfusion and desmoplasia are two prominent features of pancreatic cancer that attenuate the therapeutic efficacy of cancer therapeutics.9 Aberrant extracellular matrix (ECM) functions as a protective layer that prevents drug penetration and diffusion into the pancreatic tumors, contributing t...

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“…To balance the two processes, an agent which binded to several targets is more refined. One typical example is decorin, a small leucine‐rich proteoglycan, which exists in the interstitial matrix of the dermis and combines with collagen fibrils preferentially, and then setting their assembly . And the normal scar is replaced by HSs with increased production of collagen‐I/III, fibronectin, laminin, and decreased expression of hyaluronic acid and decorin .…”

Section: Biotherapy Aimed At Main Cytokines and Protein Involved In Hssmentioning

confidence: 99%

Biological approaches for hypertrophic scars

Zhong

2019

International Wound Journal

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Scar formation is usually the pathological consequence of skin trauma. And hypertrophic scars (HSs) frequently occur in people after being injured deeply. HSs are unusually considered as the result of tissue contraction and excessive extracellular matrix component deposition. Myofibroblasts, as the effector cells, mainly differentiated from fibroblasts, play the crucial role in the pathophysiology of HSs. A number of growth factors, inflammatory cytokines involved in the process of HS occurrence. Currently, with in‐depth exploration and clinical research of HSs, various creative and effective treatments budded. In here, we summarize the progress in the molecular mechanism of HSs, and review the available biotherapeutic methods for their pathophysiological characteristics. Additionally, we further prospected that the comprehensive therapy may be more suitable for HS treatment.

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Decorin‐expressing adenovirus decreases collagen synthesis and upregulates MMP expression in keloid fibroblasts and keloid spheroids

Cited by 32 publications

References 65 publications

Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model

Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model

Potent antitumor effect of tumor microenvironment‐targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Biological approaches for hypertrophic scars

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