Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment
| العنوان: | Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment |
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| المؤلفون: | Zhi-Ren Liu, Jenny J. Yang, Malvika Sharma, Shiyuan Wang, Falguni Mishra, Sun Li, Ravi Chakra Turaga, Alyssa M. Krasinskas, Yi Yuan, Chunfeng Liu |
| المصدر: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 1, Pp 161-179 (2021) |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, endocrine system diseases, Angiogenesis, Dck, deoxycytidine kinase, medicine.medical_treatment, PDAC, pancreatic ductal adenocarcinoma, OrKPC, KPC 961 cell line, IGF1, insulin-like growth factor 1, Apoptosis, Metastasis, GEM, genetically engineered mouse, Mice, 0302 clinical medicine, CAPaSC, cancer-associated pancreatic stellate cells, Original Research, Pancreatic Stellate Cells, Gastroenterology, Shh, Sonic hedgehog, Pancreatic Cancer Treatment, mRNA, messenger RNA, Integrin αvβ3, 030211 gastroenterology & hepatology, Collagen, IGF1R, Insulin-like growth factor 1 receptor, Carcinoma, Pancreatic Ductal, Primary Cell Culture, Antineoplastic Agents, Mice, Transgenic, 03 medical and health sciences, Cda, cytidine deaminase, Stroma, Pancreatic cancer, Cell Line, Tumor, medicine, Tdk, Thymidine kinase, Animals, Humans, lcsh:RC799-869, CAF, cancer-associated fibroblast, KPC, LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx-1-Cre, Hepatology, business.industry, Growth factor, Cancer, dFDC, 2′,2′-difluorodeoxcytidine, dFdU, 2′,2′-difluorodeoxyuridine, medicine.disease, Integrin alphaVbeta3, Gemcitabine, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, dFdCTP, gemcitabine triphosphate, Disease Models, Animal, 030104 developmental biology, Cancer cell, LSL, Lox-Stop-Lox, Hepatic stellate cell, Cancer research, Gem, gemcitabine, lcsh:Diseases of the digestive system. Gastroenterology, α-SMA, α smooth muscle actin, business |
| الوصف: | Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics owing to dense fibrotic stroma orchestrated by cancer-associated pancreatic stellate cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein, ProAgio, that targets integrin αvβ3 at a novel site and induces apoptosis in integrin αvβ3-expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin αvβ3, we aimed to analyze the effects of ProAgio in PDAC tumor. Methods Expression of integrin αvβ3 was examined in both patient tissue and cultured cells. The effects of ProAgio on CAPaSC were analyzed using an apoptosis assay kit. The effects of ProAgio in PDAC tumor were studied in 3 murine tumor models: subcutaneous xenograft, genetic engineered (KrasG12D; p53R172H; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. Results ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse–KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. Conclusions Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors. Graphical abstract |
| اللغة: | English |
| تدمد: | 2352-345X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8771aab570fac7daa58c9d33c3452dcdTest http://europepmc.org/articles/PMC7674520Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8771aab570fac7daa58c9d33c3452dcd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2352345X |
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