Identification of gene expression differences between lymphangiogenic and non-lymphangiogenic non-small cell lung cancer cell lines

Erin Regan, Robert C. Sibley, Bercin Kutluk Cenik, Asitha Silva, Luc Girard, John D. Minna, Michael T. Dellinger

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

It is well established that lung tumors induce the formation of lymphatic vessels. However, the molecular mechanisms controlling tumor lymphangiogenesis in lung cancer have not been fully delineated. In the present study, we identify a panel of non-small cell lung cancer (NSCLC) cell lines that induce lymphangiogenesis and use genome-wide mRNA expression to characterize the molecular mechanisms regulating tumor lymphangiogenesis. We show that Calu-1, H1993, HCC461, HCC827, and H2122 NSCLC cell lines form tumors that induce lymphangiogenesis whereas Calu-3, H1155, H1975, and H2073 NSCLC cell lines form tumors that do not induce lymphangiogenesis. By analyzing genome-wide mRNA expression data, we identify a 17-gene expression signature that distinguishes lymphangiogenic from non-lymphangiogenic NSCLC cell lines. Importantly, VEGF-C is the only lymphatic growth factor in this expression signature and is approximately 50-fold higher in the lymphangiogenic group than in the non-lymphangiogenic group. We show that forced expression of VEGF-C by H1975 cells induces lymphangiogenesis and that knockdown of VEGF-C in H1993 cells inhibits lymphangiogenesis. Additionally, we demonstrate that the triple angiokinase inhibitor, nintedanib (small molecule that blocks all FGFRs, PDGFRs, and VEGFRs), suppresses tumor lymphangiogenesis in H1993 tumors. Together, these data suggest that VEGF-C is the dominant driver of tumor lymphangiogenesis in NSCLC and reveal a specific therapy that could potentially block tumor lymphangiogenesis in NSCLC patients.

Original languageEnglish (US)
Article numbere150963
JournalPLoS One
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2016

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Lymphangiogenesis
lung neoplasms
Gene expression
Non-Small Cell Lung Carcinoma
Tumors
vascular endothelial growth factor C
Cells
cell lines
Gene Expression
Cell Line
gene expression
Vascular Endothelial Growth Factor C
neoplasms
cells
Neoplasms
Tumor Cell Line
Genes
genome
neoplasm cells
Genome

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Identification of gene expression differences between lymphangiogenic and non-lymphangiogenic non-small cell lung cancer cell lines. / Regan, Erin; Sibley, Robert C.; Cenik, Bercin Kutluk; Silva, Asitha; Girard, Luc; Minna, John D.; Dellinger, Michael T.

In: PLoS One, Vol. 11, No. 3, e150963, 01.03.2016.

Research output: Contribution to journalArticle

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