The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

Sebastian Kalamajski

Assistant researcher

Default user image.

Inhibition of integrin αvβ6 changes fibril thickness of stromal collagen in experimental carcinomas

Author

  • P. Olof Olsson
  • Renata Gustafsson
  • Alexei V. Salnikov
  • Maria Göthe
  • Kathrin S. Zeller
  • Tomas Friman
  • Bo Baldetorp
  • Louise A. Koopman
  • Paul H. Weinreb
  • Shelia M. Violette
  • Sebastian Kalamajski
  • Nils Erik Heldin
  • Kristofer Rubin

Summary, in English

Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. Methods: The potential role of αVβ6 integrin-mediated activation of latent TGF-β was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal αVβ6 integrin-specific monoclonal antibody 3G9 was used to inhibit the αVβ6 integrin activity. Results: Both KAT-4 and Capan-2 cells expressed the αVβ6 integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-β in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-β1 and -β3 reduced collagen fibril thickness in both tumor models. Conclusion: Our data demonstrate that the αVβ6-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to αVβ6 inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.

Department/s

  • Department of Experimental Medical Science
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2018-07-02

Language

English

Publication/Series

Cell Communication and Signaling

Volume

16

Issue

1

Document type

Journal article

Publisher

BioMed Central (BMC)

Topic

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1478-811X