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Frank Hillberg
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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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P2.03-35 - Stromal TIMP-1 Drives Tumor Progression in Lung Adenocarcinoma Through CD63 Interaction (ID 2196)
10:15 - 18:15 | Author(s): Frank Hillberg
- Abstract
Background
Tumor associated fibroblasts (TAFs) are important regulators of tumor growth and resistance to therapies. We have recently shown that TAFs in vitro from lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) respond positively to the antifibrotic drug nintedanib in the former only, thereby mimicking the selective therapeutic effects of nintedanib in ADC reported in the LUME-Lung1 clinical trial. We also showed that the tumor-promoting effects of TAFs are driven by different mechanisms in ADC and SCC. However, it remains to be elucidated the key signaling molecules involved in the aberrant fibroblast-carcinoma crosstalk in ADC. Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a multifunctional protein that has been associated with poor prognosis in lung cancer and other cancer types, and is downregulated by nintedanib in a bleomycin model of pulmonary fibrosis. Moreover, our preliminary analysis revealed that the TIMP-1 cell surface binding protein CD63, is overexpressed in ADC compared to SCC. Therefore, our objective was to study whether the selective tumor-promoting effects of ADC-TAFs are mediated by the interaction of stromal TIMP-1 with epithelial CD63.
Method
ADC-TAFs and SCC-TAFs were stimulated with TGF-β1 in the presence or absence of nintedanib, and the TIMP-1 content in their conditioned medium was determined by ELISA. TIMP-1 was reduced in ADC-TAFs by siRNA, and the corresponding conditioned medium was used to assess the impact of TIMP-1 on the growth, invasion and survival of the CD63-high ADC cell line H1437. Likewise, CD63 expression in H1437 cells was reduced, by siRNA. In addition we performed immunohistochemical analyses of CD63 in tissue sections from lung cancer patients.
Result
Our results showed that TIMP-1 secretion induced by TGF-β1 is significantly larger in ADC-TAFs compared to SCC-TAFs. Likewise, nintedanib elicited a larger downregulation of TIMP-1 secretion in ADC-TAFs compared to SCC-TAFs. We also confirmed that CD63 expression is higher in ADC patients than SCC, and revealed that knocking-down CD63 in H1437 ADC cells is sufficient to reduce the growth and invasion elicited by the conditioned medium of activated ADC-TAFs. Likewise, knocking-down TIMP-1 in ADC-TAFs was sufficient to downregulate the growth, invasion and survival of H1437 elicited by the conditioned medium of these TAFs.
Conclusion
Collectively, our results unveil a novel stroma-carcinoma interaction driven by TIMP-1 and CD63 selectively in lung ADC, and support that such crosstalk is a major regulator of the aberrant tumor-promoting effects of ADC-TAFs that are downregulated selectively by nintedanib.
