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  • Olsson, P. OlofDept Expt Med Sci, Medicon Village 406, SE-22381 Lund, Sweden (author)

Inhibition of integrin alpha(V)beta(6) changes fibril thickness of stromal collagen in experimental carcinomas

  • Article/chapterEnglish2018

Publisher, publication year, extent ...

  • 2018-07-02
  • BMC,2018
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:uu-360192
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-360192URI
  • https://doi.org/10.1186/s12964-018-0249-7DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • De fyra första författarna delar förstaförfattarskapet.
  • 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 beta 1 and -beta 3 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 a(v)beta(6) integrin-mediated activation of latent TGF-beta 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 a(v)beta(6) integrin-speafic monoclonal antibody 3G9 was used to inhibit the a(v)beta(6) integrin activity.Results: Both KAT-4 and Capan-2 cells expressed the a(v)beta(6) integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-beta 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-beta 1 and -beta 3 reduced collagen fibril thickness in both tumor models.Conclusion: Our data demonstrate that the a(v)beta(6)-directed activation of latent TGF-beta plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to a(v)beta(6) inhibition depends on the simultaneous presence of alternative paths for latent TGF-beta activation and the extent of desmoplasia.

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  • Gustafsson, RenataDept Expt Med Sci, Medicon Village 406, SE-22381 Lund, Sweden (author)
  • Salnikov, Alexei, VUniv Hosp Lund, Dept Clin Sci, Oncol Clin, SE-22185 Lund, Sweden (author)
  • Göthe, MariaUppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi (author)
  • Zeller, Kathrin S.Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)katze443 (author)
  • Friman, TomasUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)tofri255 (author)
  • Baldetorp, BoUniv Hosp Lund, Dept Clin Sci, Oncol Clin, SE-22185 Lund, Sweden (author)
  • Koopman, Louise A.Biogen, 225 Binney St, Cambridge, MA 02142 USA (author)
  • Weinreb, Paul H.Biogen, 225 Binney St, Cambridge, MA 02142 USA (author)
  • Violette, Shelia M.Biogen, 225 Binney St, Cambridge, MA 02142 USA (author)
  • Kalamajski, SebastianUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)sebka151 (author)
  • Heldin, Nils-ErikUppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)neheldin (author)
  • Rubin, KristoferUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)krisrubi (author)
  • Dept Expt Med Sci, Medicon Village 406, SE-22381 Lund, SwedenUniv Hosp Lund, Dept Clin Sci, Oncol Clin, SE-22185 Lund, Sweden (creator_code:org_t)

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  • In:Cell Communication and Signaling: BMC161478-811X

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