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Natalia Isabel Díaz-Valdivia
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-02 - Nintedanib Selectively Inhibits Angiogenesis Induced by the Conditioned Medium of Lung Adenocarcinoma TAFs in Vitro (ID 2193)
09:45 - 18:00 | Presenting Author(s): Natalia Isabel Díaz-Valdivia
- Abstract
Background
Nintedanib is an antifibrotic and antiangiogenic drug that was clinically approved to treat EGFR-wild-type lung adenocarcinoma (ADC) patients based on the positive therapeutic results elicited in combination with docetaxel in the LUME-Lung1 clinical trial in ADC but not in squamous cell carcinoma (SCC) patients. However, the mechanisms underlying the selective therapeutic effects of nintedanib in ADC remain poorly understood. Tumor-associated fibroblasts (TAFs) are the most abundant stromal cell type and have been implicated in all steps of tumor progression, including growth, angiogenesis, invasion, metastasis and resistance to therapies. Of note, we recently reported that nintedanib elicits larger antifibrotic effects in ADC-TAFs compared to SCC-TAFs in vitro. However, the antiangiogenic effects of nintedanib in TAFs remain unknown.
Method
ADC-TAFs and SCC-TAFs were activated with TGF-β1 in the presence or absence of nintedanib, and the corresponding conditioned medium was used to stimulate endothelial cells (HUVECs and HMVECs) to either migrate or form vascular networks on Matrigel.
Result
Our results showed that the conditioned medium from ADC-TAFs and SCC-TAFs induced an increase in human endothelial cell migration. In contrast, the conditioned medium from ADC-TAFs promoted an increase in angiogenesis that was selectively inhibited by nintedanib, whereas such inhibition was not observed in SCC-TAFs.
Conclusion
Our results reveal that nintedanib inhibits the pro-angiogenic effects elicited by factors secreted by ADC-TAFs but not SCC-TAFs, thereby supporting that angiogenesis may be regulated by TAFs through distinct mechanisms in ADC and SCC.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-17 - Optimization of an Ex-Vivo Preclinical Model for Drug Testing (ID 2385)
10:15 - 18:15 | Author(s): Natalia Isabel Díaz-Valdivia
- Abstract
Background
Predicting drug response in advanced lung cancer patients remains a major challenge. A promising approach to tackle this challenge is based on testing drugs in an ex-vivo preclinical model using cultured precision-cut fresh tumour slices, which maintain not only the tumour itself but also its microenvironment. However, even though different protocols have been reported for ex-vivo models with different time-windows in a growing list of cancer types, no standard protocols are currently defined in lung cancer. To address this limitation, we have begun to optimize a protocol for an ex-vivo preclinical model for drug testing in lung cancer, using samples from the standard in vivo model of bleomycin-induced lung fibrosis, which resembles the fibrotic stroma of non-small cell lung cancers.
Method
Bleomycin-induced fibrotic and control rat lungs were precision-cut with a tissue-chopper and cultured on cell culture inserts up to 12 days in a sterile setting. Two main variables were tested: the coating of the cell culture insert (bare or collagen-I coated), and the interaction with the culture medium (submerged or floating). Small lung pieces were collected at days 0, 2, 6, 9 and 12 and examined by hematoxylin-eosin staining to assess their integrity and viability.
Result
Tissue architecture was maintained equally well in all culture conditions up to 12 days. In contrast, cellular content appeared to decline after day 6; since only subsets of cells in the periphery of the explants remained viable at day 9-12. No contamination was detected at any culture time.
Conclusion
Our preliminary results suggest that our protocols for an ex-vivo preclinical model maintain the integrity and viability of lung cells and their microenvironment up to one week, which is comparable to time-windows previously reported in other cancer types. This time-window is expected to be sufficient to test drug responses, thereby underlying the potential of this preclinical model for drug testing as well as for the study of drug resistance mechanisms.
