title: Identification of Gene Expression Differences between Lymphangiogenic and Non-Lymphangiogenic Non-Small Cell Lung Cancer Cell Lines.
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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Regan
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Sibley
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Bercin Kutluk
authors.initials: BK
authors.lastname: Cenik
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Asitha
authors.initials: A
authors.lastname: Silva
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, United States of America.|Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dellinger
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics; D023281:Genomics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology*; D042583:Lymphangiogenesis / Q000187:drug effects / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics
chemical_list: D007211:Indoles; D042582:Vascular Endothelial Growth Factor C; C530716:nintedanib