title: Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion.
abstract: Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways.
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Sebban
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Marganit
authors.initials: M
authors.lastname: Farago
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Rabinovich
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Lazer
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Idelchuck
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Ilan
authors.affiliation: Department of Immunology and Cancer Research and Department of Pathology, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.affiliation: Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Katzav
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D059016:Tumor Microenvironment
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; C496618:VAV1 protein, human; D016173:Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases