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Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment

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 n...

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Autores principales: Turaga, Ravi Chakra, Sharma, Malvika, Mishra, Falguni, Krasinskas, Alyssa, Yuan, Yi, Yang, Jenny J., Wang, Shiyuan, Liu, Chunfeng, Li, Sun, Liu, Zhi-Ren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674520/
https://www.ncbi.nlm.nih.gov/pubmed/32810598
http://dx.doi.org/10.1016/j.jcmgh.2020.08.004
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author Turaga, Ravi Chakra
Sharma, Malvika
Mishra, Falguni
Krasinskas, Alyssa
Yuan, Yi
Yang, Jenny J.
Wang, Shiyuan
Liu, Chunfeng
Li, Sun
Liu, Zhi-Ren
author_facet Turaga, Ravi Chakra
Sharma, Malvika
Mishra, Falguni
Krasinskas, Alyssa
Yuan, Yi
Yang, Jenny J.
Wang, Shiyuan
Liu, Chunfeng
Li, Sun
Liu, Zhi-Ren
author_sort Turaga, Ravi Chakra
collection PubMed
description 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 α(v)β(3) at a novel site and induces apoptosis in integrin α(v)β(3)-expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin α(v)β(3), we aimed to analyze the effects of ProAgio in PDAC tumor. METHODS: Expression of integrin α(v)β(3) 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 (Kras(G12D); p53(R172H); 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.
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spelling pubmed-76745202020-11-24 Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment Turaga, Ravi Chakra Sharma, Malvika Mishra, Falguni Krasinskas, Alyssa Yuan, Yi Yang, Jenny J. Wang, Shiyuan Liu, Chunfeng Li, Sun Liu, Zhi-Ren Cell Mol Gastroenterol Hepatol Original Research 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 α(v)β(3) at a novel site and induces apoptosis in integrin α(v)β(3)-expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin α(v)β(3), we aimed to analyze the effects of ProAgio in PDAC tumor. METHODS: Expression of integrin α(v)β(3) 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 (Kras(G12D); p53(R172H); 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. Elsevier 2020-08-15 /pmc/articles/PMC7674520/ /pubmed/32810598 http://dx.doi.org/10.1016/j.jcmgh.2020.08.004 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Turaga, Ravi Chakra
Sharma, Malvika
Mishra, Falguni
Krasinskas, Alyssa
Yuan, Yi
Yang, Jenny J.
Wang, Shiyuan
Liu, Chunfeng
Li, Sun
Liu, Zhi-Ren
Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment
title Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment
title_full Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment
title_fullStr Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment
title_full_unstemmed Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment
title_short Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment
title_sort modulation of cancer-associated fibrotic stroma by an integrin α(v)β(3) targeting protein for pancreatic cancer treatment
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674520/
https://www.ncbi.nlm.nih.gov/pubmed/32810598
http://dx.doi.org/10.1016/j.jcmgh.2020.08.004
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