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Annals of Biomedical Engineering

, Volume 46, Issue 5, pp 657–669 | Cite as

Solid Stress Facilitates Fibroblasts Activation to Promote Pancreatic Cancer Cell Migration

  • Maria Kalli
  • Panagiotis Papageorgis
  • Vasiliki Gkretsi
  • Triantafyllos Stylianopoulos
Article

Abstract

Pancreatic fibroblasts are continuously gaining ground as an important component of tumor microenvironment that dynamically interact with cancer cells to promote tumor progression. In addition, these tumor-infiltrated fibroblasts can acquire an activated phenotype and produce excessive amounts of extracellular matrix creating a highly dense stroma, a situation known as desmoplasia. Desmoplasia, along with the uncontrolled proliferation of cancer cells, leads to the development of compressive forces within the tumor, generating the so-called solid stress. Solid stress is previously shown to affect cancer cell proliferation and migration, however there is no pertinent study taking into account the effects of solid stress on fibroblasts and whether these effects contribute to tumor progression. In this work, we applied a defined compressive stress on pancreatic fibroblasts, similar in magnitude to that experienced by cells in native pancreatic tumors. Our results suggest that solid stress stimulates fibroblasts activation and strongly upregulates Growth Differentiation Factor-15 (GDF15) expression. Moreover, co-culture of compression-induced activated fibroblasts with pancreatic cancer cells significantly promotes cancer cell migration, which is inhibited by shRNA-mediated silencing of GDF15 in fibroblasts. Conclusively, our findings highlight the involvement of biophysical factors, such as solid stress, in tumor progression and malignancy revealing a novel role for GDF15.

Keywords

Mechanical compression Metastasis Co-culture system Tumor microenvironment TGFβ GDF15 

Notes

Acknowledgments

This work has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 336839-ReEngineeringCancer.

Conflicts of interest

None.

Supplementary material

10439_2018_1997_MOESM1_ESM.docx (1.2 mb)
Supplementary material 1 (DOCX 1190 kb)

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Copyright information

© Biomedical Engineering Society 2018

Authors and Affiliations

  • Maria Kalli
    • 1
  • Panagiotis Papageorgis
    • 1
    • 2
  • Vasiliki Gkretsi
    • 1
    • 2
  • Triantafyllos Stylianopoulos
    • 1
  1. 1.Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing EngineeringUniversity of CyprusNicosiaCyprus
  2. 2.Department of Life SciencesEuropean University CyprusNicosiaCyprus

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