Author of

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  P72 - Tumor Biology and Systems Biology - Basic and Translational Science - Tumor Microenvironment (ID 211)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35900

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    P72.01 - Stress-Induced Upregulation of TNFSF4 in Cancer Associated Fibroblasts Facilitates Chemoresistance of Lung Adenocarcinoma (ID 708)

    00:00 - 00:00  |  Presenting Author(s): Yan Li
    • Abstract
    • Slides

    Introduction
    

    Platinum-based chemotherapy remains the standard regimen for most lung adenocarcinoma patients and the most serious obstacle for the treatment is adaptive chemoresistance. After exposed under chemotherapy, radiotherapy and other stress conditions such as hypoxia, cancer associated fibroblasts (CAFs) in tumor microenvironment might be induced to have some adaptive responses. This study aimed to investigate the changes of CAFs under stress as well as their roles on chemoresistance.

    Methods
    

    Combined with results

    Results
    

    We established several in vitro models to mimic the stress conditions for fibroblasts under treatment (Figure 1A). Through transcriptome analyses, 19 up-regulated genes were identified in lung fibroblasts under chemotherapy, radiotherapy and hypoxia (Figure 1B). Among the identified 19 genes, only TNFSF4 and CDNF could encode secretory molecules that might affect adjacent cells in the tumor microenvironment. TNFSF4 which was more significantly up-regulated was further studied. Four lung adenocarcinoma cases with the tumor tissue samples before and after cisplatin-based chemotherapy were collected. TNFSF4 and α-SMA was stained by immunohistochemistry. TNFSF4 was mainly expressed in α-SMA positive CAFs after the treatment of chemotherapy (Figure 1C). Forty random points (10 for each tumor sample after chemotherapy) on the tumor sections were chosen to analyze the relation between distribution of TNFSF4 and α-SMA. TNFSF4 was significantly colocalized with α-SMA on the tumor section (p<0.01, Figure 1C). The relationship between changes of serum concentration of TNFSF4 and clinical responses of cisplatin-based chemotherapy in lung adenocarcinoma patients were further analyzed. There was a negative correlation between the increase of serum TNFSF4 levels and the shrink of the tumor diameter induced by chemotherapy (Figure 1D and 1E), indicating that TNFSF4 might promote chemoresistance of lung adenocarcinoma. To get the direct evidence, recombinant human TNFSF4 (rhTNFSF4, R&D Systems) was utilized for in vitro experiments, which showed rhTNFSF4 could promote cisplatin resistance of lung adenocarcinoma cells when the concentrations of cisplatin were less than 4μg/ml, especially in SPC-A1 cells (Figure 1F and 1G). The effects of rhTNFSF4 might be dose dependent (U-shaped) and the most effective concentration of rhTNFSF4 was 10ng/ml. Flow cytometry analysis further confirmed that TNFSF4 (10ng/ml) could inhibit apoptosis of lung adenocarcinoma cells induced by cisplatin (Figure 1H).

    Conclusion
    

    TNFSF4 was upregulated in lung adenocarcinoma associated fibroblasts under stress and may facilitate chemoresistance through inhibiting apoptosis of lung adenocarcinoma cells.

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