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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

4134 - A translational drug-screening tool for interrogating the effect of anti-TGF-_ therapy on fibroblast activity and the desmoplastic reaction

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Neel Nissen

Citation

Annals of Oncology (2018) 29 (suppl_8): viii1-viii13. 10.1093/annonc/mdy268

Authors

N.I. Nissen1, N. Willumsen2, N. Gudmann3, S. Rønnow3, M. Karsdal2, D. Leeming4, J. Sand3

Author affiliations

  • 1 Cancer, Nordic Bioscience A/S, 2730 - Herlev/DK
  • 2 Biomarkers And Research, Nordic Bioscience A/S, 2730 - Herlev/DK
  • 3 Fibrosis, Nordic Bioscience A/S, Herlev/DK
  • 4 Fibrosis, Nordic Bioscience A/S, 2730 - Herlev/DK
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Resources

Abstract 4134

Background

Numerous clinical trials are currently evaluating anti-transforming growth factor beta (TGF-β) therapy for treating lung cancer patients. However, interrogating stromal reactivity, and enhancing the mechanistic understanding of desmoplasia in relation to TGF-β signaling represents unmet medical needs and may allow for discovery of novel TGF-β associated biomarkers for use in the clinical setting. Cancer associated fibroblasts are major contributors to the desmoplastic reaction (ECM deposition) upon TGF-β stimulation. Applying the “Scar-in-a-jar” (SiaJ) model, we evaluated the impact of TGF-β, and inhibitors, on lung fibroblasts’ expression of different collagens.

Methods

Primary human healthy lung fibroblasts were cultured for up to 15 days in the presence of ficoll and TGF-β, with or without addition of 1nM-10µM ALK-5/type I TGF-β receptor kinase inhibitor (iTGFβ. ELISAs quantified pro-peptides from type I (PINP), type III (PRO-C3) and type VI (PRO-C6) collagen in cell supernatant as surrogate measures of the TGF-β induced ECM deposition. Cytotoxicity (lactate dehydrogenase (LDH) release) and metabolic activity (AlamarBlue) were evaluated.

Results

Stimulating lung fibroblasts with TGF-β induced PINP, PRO-C3 and PRO-C6 increase up to 8-fold compared to TGF-β (p < 0.001). iTGFβ dose-dependently reduced the PINP, PRO-C3 and PRO-C6 increase induced by TGF-β. No cytotoxicity could be detected. The metabolic activity was decreased at 1uM iTGFβ.

Conclusions

The SiaJ model can be used to evaluate the impact of TGF-β, and inhibitors, on lung fibroblasts’ viability and expression of different collagens. The findings suggest that SiaJ together with PINP, PRO-C3 and PRO-C6 can be used as a translational drug screening tool for interrogating the effect of anti-TGF-β therapy on fibroblast activity and the desmoplastic reaction.

Clinical trial identification

Legal entity responsible for the study

Nordic Bioscience A/S.

Funding

Nordic Bioscience A/S.

Editorial Acknowledgement

Disclosure

N.I. Nissen, N. Willumsen, N. Gudmann, S. Rønnow, J. Sand: Employee: Nordic Bioscience A/S. M. Karsdal, D. Leeming: Employee and stocks: Nordic Bioscience A/S.

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