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Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

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Abstract
Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological-or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca(2+)calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction.
Keywords
3D invasion model, Tumour progression, ECM, Arachidonic acid metabolite, Signal transduction, PHOSPHOLIPASE-C-EPSILON, LIGHT-CHAIN KINASE, IN-VITRO, COLORECTAL-CANCER, KAPPA-B, ENDOTHELIAL-CELLS, ARACHIDONIC-ACID, BARRIER FUNCTION, CARCINOMA-CELLS, CAMP PRODUCTION

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Citation

Please use this url to cite or link to this publication:

Chicago
Stadler, Serena, Chi Huu Nguyen, Helga Schachner, Daniela Milovanovic, Silvio Holzner, Stefan Brenner, Julia Eichsteininger, et al. 2017. “Colon Cancer Cell-derived 12(S)-HETE Induces the Retraction of Cancer-associated Fibroblast via MLC2, RHO/ROCK and Ca2+ Signalling.” Cellular and Molecular Life Sciences 74 (10): 1907–1921.
APA
Stadler, S., Nguyen, C. H., Schachner, H., Milovanovic, D., Holzner, S., Brenner, S., Eichsteininger, J., et al. (2017). Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling. CELLULAR AND MOLECULAR LIFE SCIENCES, 74(10), 1907–1921.
Vancouver
1.
Stadler S, Nguyen CH, Schachner H, Milovanovic D, Holzner S, Brenner S, et al. Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling. CELLULAR AND MOLECULAR LIFE SCIENCES. 2017;74(10):1907–21.
MLA
Stadler, Serena et al. “Colon Cancer Cell-derived 12(S)-HETE Induces the Retraction of Cancer-associated Fibroblast via MLC2, RHO/ROCK and Ca2+ Signalling.” CELLULAR AND MOLECULAR LIFE SCIENCES 74.10 (2017): 1907–1921. Print.
@article{8515615,
  abstract     = {Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological-or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca(2+)calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction.},
  author       = {Stadler, Serena and Nguyen, Chi Huu and Schachner, Helga and Milovanovic, Daniela and Holzner, Silvio and Brenner, Stefan and Eichsteininger, Julia and Stadler, Mira and Senfter, Daniel and Krenn, Liselotte and Schmidt, Wolfgang M and Huttary, Nicole and Krieger, Sigurd and Koperek, Oskar and Bago-Horvath, Zsuzsanna and Brendel, Konstantin Alexander and Marian, Brigitte and De Wever, Olivier and Mader, Robert M and Giessrigl, Benedikt and Jäger, Walter and Dolznig, Helmut and Krupitza, Georg},
  issn         = {1420-682X},
  journal      = {CELLULAR AND MOLECULAR LIFE SCIENCES},
  keywords     = {3D invasion model,Tumour progression,ECM,Arachidonic acid metabolite,Signal transduction,PHOSPHOLIPASE-C-EPSILON,LIGHT-CHAIN KINASE,IN-VITRO,COLORECTAL-CANCER,KAPPA-B,ENDOTHELIAL-CELLS,ARACHIDONIC-ACID,BARRIER FUNCTION,CARCINOMA-CELLS,CAMP PRODUCTION},
  language     = {eng},
  number       = {10},
  pages        = {1907--1921},
  title        = {Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling},
  url          = {http://dx.doi.org/10.1007/s00018-016-2441-5},
  volume       = {74},
  year         = {2017},
}

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