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ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer.
Kuninty, Praneeth R; Bansal, Ruchi; De Geus, Susanna W L; Mardhian, Deby F; Schnittert, Jonas; van Baarlen, Joop; Storm, Gert; Bijlsma, Maarten F; van Laarhoven, Hanneke W; Metselaar, Josbert M; Kuppen, Peter J K; Vahrmeijer, Alexander L; Östman, Arne; Sier, Cornelis F M; Prakash, Jai.
Afiliación
  • Kuninty PR; Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands.
  • Bansal R; Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands.
  • De Geus SWL; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
  • Mardhian DF; Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands.
  • Schnittert J; Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands.
  • van Baarlen J; Laboratory Pathology Oost Netherlands (LabPON), Hengelo, Netherlands.
  • Storm G; Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands.
  • Bijlsma MF; Department of Pharmaceutics, Utrecht University, Utrecht, Netherlands.
  • van Laarhoven HW; Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
  • Metselaar JM; Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
  • Kuppen PJK; ScarTec Therapeutics BV, Enschede, Netherlands.
  • Vahrmeijer AL; Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH University Clinic, Forckenbeckstrasse 55, 52074 Aachen, Germany.
  • Östman A; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
  • Sier CFM; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
  • Prakash J; Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Sci Adv ; 5(9): eaax2770, 2019 09.
Article en En | MEDLINE | ID: mdl-31517053
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 α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Integrinas / Carcinoma Ductal Pancreático / Células Estrelladas Pancreáticas / Peptidomiméticos / Proteínas de Neoplasias Límite: Animals / Humans / Male Idioma: En Revista: Sci Adv Año: 2019 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Integrinas / Carcinoma Ductal Pancreático / Células Estrelladas Pancreáticas / Peptidomiméticos / Proteínas de Neoplasias Límite: Animals / Humans / Male Idioma: En Revista: Sci Adv Año: 2019 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos