Oncolytic Ad co-expressing decorin and Wnt decoy receptor overcomes chemoresistance of desmoplastic tumor through degradation of ECM and inhibition of EMT. (10th September 2019)

• Record Type: Journal Article
• Authors: Li, Yan; Hong, JinWoo; Jung, Bo-Kyeong; Oh, Eonju; Yun, Chae-Ok
• Is Part Of: Cancer letters. Volume 459(2019)
• Page Start: 15
• Page End: 29
• Publication Date: 2019-09-10
• Subjects: Decorin -- sLRP6E1E2 -- Oncolytic adenovirus -- Pancreatic cancer -- Metastasis -- Extracellular matrix -- Chemosensitivity; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.05.033
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Pancreatic cancer is a highly lethal disease. Excessive accumulation of tumor extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) phenotype are two main contributors to drug resistance in desmoplastic pancreatic tumors. To overcome desmoplasia and chemoresistance of pancreatic cancer, we utilized an oncolytic adenovirus (Ad) co-expressing decorin and soluble Wnt decoy receptor (HEmT-DCN/sLRP6). An orthotopic pancreatic xenograft tumor model was established in athymic nude mice using Mia PaCa-2 cells, and the antimetastatic and antitumor efficacy of systemically administered HEmT-DCN/sLRP6 was evaluated. Immunohistochemical analysis of tumor tissues was performed to assess ECM degradation, induction of apoptosis, viral dispersion, and inhibition of the Wnt/β-catenin signaling pathway. HEmT-DCN/sLRP6 effectively degraded tumor ECM and inhibited EMT, leading to enhanced viral distribution, induction of apoptosis, and attenuation of tumor cell proliferation in tumor tissue. HEmT-DCN/sLRP6 prevented metastasis of pancreatic cancer. Importantly, HEmT-DCN/sLRP6 sensitized pancreatic tumor to gemcitabine treatment. Furthermore, HEmT-DCN/sLRP6 augmented drug penetration and dispersion within pancreatic tumor xenografts and patient-derived tumor spheroids. Collectively, these results illustrate that HEmT-DCN/sLRP6 can enhance the dispersion of both oncolytic Ad and a chemotherapeutic agent in chemoresistant and desmoplastic pancreatic tumor, effectively overcoming the preexisting limitations of standard treatments. Highlights: ECM and EMT phenotype are two main contributors to drug resistance in desmoplastic pancreatic tumors. Oncolytic Ad-mediated co-expression of DCN and Wnt decoy receptor (HEmT-DCN/sLRP6) can degrade aberrant tumor ECM and inhibit EMT. HEmT-DCN/sLRP6 can induce apoptosis and attenuate tumor cell proliferation in tumor tissue. HEmT-DCN/sLRP6 can enhance the dispersion of both oncolytic Ad and a chemotherapeutic agent, effectively overcoming the preexisting limitations of standard treatments.