Abstract
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). 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. 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. 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.
Highlights
A vascular network is vital for a tumor to grow beyond a critical size and metastasize [1]
Estimation of Microvessel density (MVD) in Tumor Areas: Relationship With vascular endothelial growth factor (VEGF) Status and Clinicopathologic Parameters of the Patients MVD ranged from 14–62 microvessels per square millimeter, with a mean value of 36.9 Ϯ 10.6 mv/mm2 (Table 1 and Fig. 3)
Deregulation of oncogenes is implicated in the release of cells from controlled proliferation, programmed cell death, migration, and adhesion, little is known about their involvement in tumor angiogenesis [8,34,35]
Summary
A vascular network is vital for a tumor to grow beyond a critical size and metastasize [1]. P. Zacharatos et al.: Correlation of K-ras and c-mos Status With Neo-angiogenesis in NSCLCs 591 and leads to a vascular quiescence. Otherwise, when the angiogenic switch is “on,” the balance is tipped in favor of angiogenesis [3] Among these factors, the members of the VEGF family are specific for the vascular endothelium with crucial roles in the angiogenic process [4]. Alterations of K-ras and c-mos, two pivotal components of this pathway, have been implicated in non-small cell lung carcinogenesis. 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 neoangiogenesis state and the major angiogenic factor, vascular endothelial growth factor (VEGF). All possible associations were examined by a series of statistical methods
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