Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer.
Angiogenesis
Gli1
NSCLC
Pericyte
bFGF
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
16 Mar 2024
16 Mar 2024
Historique:
received:
25
12
2023
accepted:
04
03
2024
medline:
18
3
2024
pubmed:
17
3
2024
entrez:
17
3
2024
Statut:
epublish
Résumé
Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear. Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression. Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis. The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.
Sections du résumé
BACKGROUND
BACKGROUND
Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear.
METHODS
METHODS
Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression.
RESULTS
RESULTS
Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis.
CONCLUSION
CONCLUSIONS
The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.
Identifiants
pubmed: 38493151
doi: 10.1186/s13046-024-03003-0
pii: 10.1186/s13046-024-03003-0
doi:
Substances chimiques
Zinc Finger Protein GLI1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
83Subventions
Organisme : the National Key Research and Development Program of China under grant
ID : 2022YFE0209700
Organisme : Natural Science Foundation of Guangdong Province
ID : 2023A1515010340
Organisme : National Natural Science Foundation of China
ID : 82104492
Organisme : National Natural Science Foundation of China
ID : 82104201
Informations de copyright
© 2024. The Author(s).
Références
N Engl J Med. 2018 Jun 14;378(24):2288-2301
pubmed: 29863955
Angiogenesis. 2017 Nov;20(4):409-426
pubmed: 28660302
Oncogene. 2017 Aug 10;36(32):4641-4652
pubmed: 28368412
Transl Lung Cancer Res. 2015 Oct;4(5):515-23
pubmed: 26629420
Cancer Lett. 2017 Dec 28;411:136-149
pubmed: 28965853
Cancer Lett. 2013 Mar 1;330(1):22-32
pubmed: 23200667
Cell Biol Int. 2021 Jan;45(1):61-73
pubmed: 32936498
Acta Pharm Sin B. 2022 Oct;12(10):3877-3890
pubmed: 36213531
Cell Mol Neurobiol. 2021 Aug;41(6):1227-1244
pubmed: 32504326
Cell Discov. 2018 Jan 16;4:3
pubmed: 29423271
Nat Cancer. 2022 Apr;3(4):486-504
pubmed: 35469015
Anticancer Res. 2016 Mar;36(3):1119-26
pubmed: 26977007
Horm Cancer. 2018 Oct;9(5):338-348
pubmed: 29956066
Clin Lung Cancer. 2020 Jul;21(4):308-313
pubmed: 32291211
CA Cancer J Clin. 2022 Jan;72(1):7-33
pubmed: 35020204
Signal Transduct Target Ther. 2019 Dec 17;4:61
pubmed: 31871778
Pharmacol Rev. 2015;67(2):441-61
pubmed: 25769965
Arch Pharm Res. 2018 Jul;41(7):711-724
pubmed: 29961196
Nature. 2018 Jan 24;553(7689):446-454
pubmed: 29364287
Nature. 2017 May 11;545(7653):224-228
pubmed: 28467822
Sci Rep. 2020 Feb 19;10(1):2939
pubmed: 32076044
J Clin Invest. 2007 Oct;117(10):2766-77
pubmed: 17909625
Angiogenesis. 2021 Aug;24(3):647-656
pubmed: 33656628
Cell Death Dis. 2020 Apr 14;11(4):232
pubmed: 32286274
Lancet Oncol. 2019 Dec;20(12):1655-1669
pubmed: 31591063
Cancer Res. 2020 Apr 1;80(7):1498-1511
pubmed: 32041837
Nat Med. 2013 Nov;19(11):1410-22
pubmed: 24202394
J Clin Oncol. 2020 Aug 1;38(22):2530-2542
pubmed: 32459597
Nat Commun. 2020 Jul 24;11(1):3704
pubmed: 32709869
Stem Cell Reports. 2020 Jul 14;15(1):110-124
pubmed: 32668219
Nat Commun. 2017 Jul 18;8:16106
pubmed: 28719590
J Transl Med. 2020 Feb 3;18(1):52
pubmed: 32014047
Med Oncol. 2022 Jul 14;39(10):144
pubmed: 35834029
Lancet Oncol. 2019 May;20(5):625-635
pubmed: 30975627
Lancet. 2016 Jul 30;388(10043):518-29
pubmed: 26853587
Eur Cytokine Netw. 2009 Dec;20(4):225-34
pubmed: 20167562
J Hematol Oncol. 2020 May 24;13(1):58
pubmed: 32448366
Lancet. 2014 Aug 23;384(9944):665-73
pubmed: 24933332
Cell Death Differ. 2021 Jul;28(7):2221-2237
pubmed: 33637972
Cell Metab. 2018 Jul 03;28(1):104-117.e5
pubmed: 29861385