Inverse prognostic impact of angiogenic marker expression in tumor cells versus stromal cells in non small cell lung cancer.
OBJECTIVE
The vascular endothelial growth factors (VEGF-A, -C, -D) and the VEGF receptors (VEGFR-1, -2, and -3) are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected non-small cell lung cancer tumors.


METHODS
Tumor tissue samples from 335 resected patients with stage I to IIIA disease were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Microvessel density was assessed by CD34 immunohistochemical staining.


RESULTS
In univariate analyses, high tumor cell expression of VEGF-A (P = 0.0005), VEGFR-1 (P = 0.013), VEGFR-2 (P = 0.006), and VEGFR-3 (P = 0.0003) were negative prognostic indicators for disease-specific survival (DSS). In tumor stroma, however, high expression of VEGF-A (P = 0.017), VEGF-C (P = 0.003), VEGF-D (P = 0.009), VEGFR-1 (P = 0.01), and VEGFR-2 (P = 0.019) correlated with good prognosis. There was no significant correlation between microvessel density and DSS. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = 0.007) was an independent negative prognostic factor for DSS, whereas in stromal cells, high VEGF-C (P = 0.004) expression had an independent positive survival impact.


CONCLUSIONS
These are the first tissue microarray data in non-small cell lung cancers showing a positive prognostic impact by highly expressed angiogenic markers in tumor stroma, with VEGF-C as a major independent prognostic indicator.
Donnem
Tom
T
Institute of Clinical Medicine, University of Tromsö, University Hospital of Northern Norway, Tromsö, Norway. tom.donnem@fagmed.uio.no
Al-Saad
Samer
S
Al-Shibli
Khalid
K
Delghandi
Marit P
MP
Persson
Magnus
M
Nilsen
Marit N
MN
Busund
Lill-Tove
LT
Bremnes
Roy M
RM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000737:chemistry / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000737:chemistry / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000175:diagnosis*; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis*; D017154:Stromal Cells / Q000737:chemistry / Q000473:pathology; D046888:Tissue Array Analysis; D042442:Vascular Endothelial Growth Factors / Q000032:analysis*
D015415:Biomarkers; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor