ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

被引：100

作者：

Kuninty, Praneeth R. ^{[1
]}

Bansal, Ruchi ^{[1
]}

De Geus, Susanna W. L. ^{[2
]}

Mardhian, Deby F. ^{[1
]}

Schnittert, Jonas ^{[1
]}

van Baarlen, Joop ^{[3
]}

Storm, Gert ^{[1
,4
]}

Bijlsma, Maarten F. ^{[5
]}

van Laarhoven, Hanneke W. ^{[5
]}

Metselaar, Josbert M. ^{[6
,7
]}

Kuppen, Peter J. K. ^{[2
]}

Vahrmeijer, Alexander L. ^{[2
]}

Ostman, Arne ^{[8
]}

Sier, Cornelis F. M. ^{[2
]}

Prakash, Jai ^{[1
,6
,8
]}

机构：

[1] Univ Twente, Fac Sci & Technol, Dept Biomat Sci & Technol, Sect Targeted Therapeut, Enschede, Netherlands

[2] Leiden Univ, Dept Surg, Med Ctr, Leiden, Netherlands

[3] Lab Pathol Oost Netherlands LabPON, Hengelo, Netherlands

[4] Univ Utrecht, Dept Pharmaceut, Utrecht, Netherlands

[5] Univ Amsterdam, Amsterdam Univ Med Ctr, Amsterdam, Netherlands

[6] ScarTec Therapeut BV, Enschede, Netherlands

[7] RWTH Univ Clin, Inst Expt Mol Imaging, Dept Nanomed & Theranost, Forckenbeckstr 55, D-52074 Aachen, Germany

[8] Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden

来源：

SCIENCE ADVANCES | 2019年 / 5卷 / 09期

基金：

瑞典研究理事会;

关键词：

TUMOR STROMA; ALPHA-5-BETA-1; INTEGRIN; FIBROSIS; FIBROBLASTS; EXPRESSION; CROSSTALK; CULTURE; TARGETS;

D O I：

10.1126/sciadv.aax2770

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin alpha 5 (ITGA5) receptor in the PDAC stroma. ITGA5 was over-expressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

引用

页数：15

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