title: Relationship of the K-ras/c-mos expression patterns with angiogenesis in non-small cell lung carcinomas.
abstract: BACKGROUND
  Neo-angiogenesis is an acquired capability vital for a tumor to grow and metastasize. Evidence has shown that the mitogen-activated protein (MAP) kinase pathway is involved in this process. Alterations of K-ras and c-mos, two pivotal components of this pathway, have been implicated in non-small cell lung carcinogenesis. In the present report, we examine, in a series of non-small cell lung carcinomas (NSCLCs), the status of K-ras and c-mos oncoproteins in correlation with the tumor neo-angiogenesis state and the major angiogenic factor, vascular endothelial growth factor (VEGF).
  
  
  METHODS
  c-mos and p-ERK1/2 status was evaluated immunohistochemically in a total of 65 NSCLCs, whereas the presence of K-ras mutations was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) in available matched normal tumor material from 56 cases. Microvessel density (MVD) was estimated by immunodetection of CD3, endothelial marker, and VEGF expression was assessed by immunohistochemistry. All possible associations were examined by a series of statistical methods.
  
  
  RESULTS
  Expression of oncogenic activated K-ras and c-mos overexpression was observed in 12 of 49 (25%) and in 16 of 61 (26%) informative cases, respectively. Only 1 of the 25 deregulated for K-ras or c-mos cases exhibited both alterations, suggesting a mutually exclusive relationship between activated K-ras and c-mos overexpression (p = 0.074) in a subset of NSCLCs. In these cases, the MAPK kinase kinase/MEK/ERK pathway was found to be activated. MVD and VEGF expression were 36.9 +/- 10.6 mv/mm2 and 73.1 +/- 20.0%, respectively. The most intriguing finding was that the [K-ras(No)/c-mos(P)] profile was significantly associated with low MVD levels compared to normal cases (p = 0.004); by contrast, no correlation was found between the other K-ras/c-mos patterns and MVD. Furthermore, the former group exhibited the lowest VEGF levels.
  
  
  CONCLUSIONS
  The mutually exclusive relationship between mutated K-ras and c-mos overexpression in a subset of NSCLCs implies a common signal transduction pathway in lung carcinogenesis. The effect of this pathway on NSCLC neo-angiogenesis seems to depend upon the status of c-mos, which acts as a molecular "switch," possibly exerting a negative selective pressure on tumor progression.
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Zacharatos
authors.forename: A
authors.initials: A
authors.lastname: Kotsinas
authors.forename: P
authors.initials: P
authors.lastname: Tsantoulis
authors.forename: K
authors.initials: K
authors.lastname: Evangelou
authors.forename: D
authors.initials: D
authors.lastname: Kletsas
authors.forename: P J
authors.initials: PJ
authors.lastname: Asimacopoulos
authors.forename: I
authors.initials: I
authors.lastname: Doussis-Anagnostopoulou
authors.forename: F
authors.initials: F
authors.lastname: Pezzella
authors.forename: K
authors.initials: K
authors.lastname: Gatter
authors.forename: A G
authors.initials: AG
authors.lastname: Papavassiliou
authors.forename: C
authors.initials: C
authors.lastname: Kittas
authors.forename: V G
authors.initials: VG
authors.lastname: Gorgoulis
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016228:Endothelial Growth Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016258:Genes, mos; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008222:Lymphokines / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D017231:Proto-Oncogene Proteins c-mos / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017231:Proto-Oncogene Proteins c-mos; D018631:ras Proteins