Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma.
BACKGROUND
Cell-retained isoforms of vascular endothelial growth factor A (VEGF-A) have been reported to play an essential role in tumor progression through stromal neovascularization in malignant solid tumors. While more than 95% of nonsmall cell lung carcinoma (NSCLC) expresses cell-retained VEGF-A isoform, the clinicopathologic implications of neuropilin (NRP), considered the specific receptor for limited types of VEGF-A isoform, are not well understood.


METHODS
The authors examined NRP1 and NRP2 mRNA expression in 68 NSCLCs and 15 extraneoplastic tissues by a densitometry-assisted, semi-quantitative reverse transcription-polymerase chain reaction. The authors determined the distinct expression of NRPs using the expression level of NRPs relative by optical density to beta2-microglobulin. The authors also investigated VEGF-A isoforms, their receptors, and the clinical implications. Vascularity of NSCLC was morphologically estimated on sections immunostained with anti-CD34 antibody.


RESULTS
Eleven of 15 extraneoplastic specimens showed NRP1 expression (73.3%) and 8 showed NRP2 expression (53.3%). The expression level of NRP1 or NRP2 of neoplasmic tissue was higher than that of extraneoplastic tissues (P < 0.01, Mann-Whitney U test). Fifty-five and 44 NSCLCs expressed NRP1 and NRP2, respectively. Forty patients co-expressing NRP1 and NRP2 showed significantly poorer prognosis and increased vessel counts as compared to those 28 cases without co-expression (P < 0.05, log-rank test; P < 0.05, Mann-Whitney U test).


CONCLUSIONS
The co-expression of NRP1 and NRP2 genes is significantly correlated with tumor progression through neovascularization in NSCLC. These results suggest that both NRP1 and NRP2 are key molecules for stromal vascularization by cell-retained VEGF in NSCLC.
Kawakami
Tsutomu
T
Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan.
Tokunaga
Tetsuji
T
Hatanaka
Hiroyuki
H
Kijima
Hiroshi
H
Yamazaki
Hitoshi
H
Abe
Yoshiyuki
Y
Osamura
Yoshiyuki
Y
Inoue
Hiroshi
H
Ueyama
Yoshito
Y
Nakamura
Masato
M
D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism; D039943:Neuropilin-2 / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D039943:Neuropilin-2; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1