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

Olof Olsson, P. LU ; Gustafsson, Renata LU ; Salnikov, Alexei V. LU ; Göthe, Maria; Zeller, Kathrin S. LU ; Friman, Tomas; Baldetorp, Bo LU ; Koopman, Louise A.; Weinreb, Paul H. and Violette, Shelia M., et al. (2018) In Cell Communication and Signaling 16(1).
Abstract

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... (More)

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.

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Cell Communication and Signaling
volume
16
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85049514733
ISSN
1478-811X
DOI
10.1186/s12964-018-0249-7
language
English
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yes
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ecc1464b-61c1-4cdf-875f-15827de3faca
date added to LUP
2018-07-23 12:03:35
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2019-03-27 14:48:44
@article{ecc1464b-61c1-4cdf-875f-15827de3faca,
  abstract     = {<p>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 α<sub>V</sub>β<sub>6</sub> 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 α<sub>V</sub>β<sub>6</sub> integrin-specific monoclonal antibody 3G9 was used to inhibit the α<sub>V</sub>β<sub>6</sub> integrin activity. Results: Both KAT-4 and Capan-2 cells expressed the α<sub>V</sub>β<sub>6</sub> 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 α<sub>V</sub>β<sub>6</sub>-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to α<sub>V</sub>β<sub>6</sub> inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.</p>},
  articleno    = {36},
  author       = {Olof Olsson, P. and Gustafsson, Renata and Salnikov, Alexei V. and Göthe, Maria and Zeller, Kathrin S. and Friman, Tomas and Baldetorp, Bo and Koopman, Louise A. and Weinreb, Paul H. and Violette, Shelia M. and Kalamajski, Sebastian and Heldin, Nils Erik and Rubin, Kristofer},
  issn         = {1478-811X},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Cell Communication and Signaling},
  title        = {Inhibition of integrin α<sub>v</sub>β<sub>6</sub> changes fibril thickness of stromal collagen in experimental carcinomas},
  url          = {http://dx.doi.org/10.1186/s12964-018-0249-7},
  volume       = {16},
  year         = {2018},
}