VEGF121 promotes lymphangiogenesis in the sentinel lymph nodes of non-small cell lung carcinoma patients.
BACKGROUND
The sentinel lymph node (SLN) concept is that lymphatic flux from a primary tumor initially flows into a SLN. The mechanism mediating tumor metastasis within SLNs remains largely unknown; however, primary tumors overexpressing vascular endothelial growth factor (VEGF)-A appear to induce SLN lymphangiogenesis prior to metastasis in animal model. Our aim was to further investigate the capacity of VEGFs to induce lymphangiogenesis within SLNs and to assess their role in SLN metastasis in non-small cell lung carcinoma (NSCLC).


METHODS
Real-time quantitative RT-PCR was used to assess expression of mRNAs encoding several VEGFs (VEGF121, VEGF165, VEGFR1, VEGFR2, VEGFR3, VEGF-C and VEGF-D) in resected lymph node specimens from 35 NSCLC patients, after which we compared their expression SLNs and non-SLNs. In addition, expression of the lymphatic endothelium-specific hyaluronan receptor (LYVE)-1 was used to assess lymphangiogenesis in SLNs and non-SLNs.


RESULTS
Immunohistochemical staining revealed substantial expression of LYVE-1 in SLNs. Moreover, levels LYVE-1 mRNA were significantly higher in SLNs than non-SLNs (P<0.05), as were levels of VEGF121 and VEGFR2 mRNA (P<0.01 and P=0.02, respectively). In addition metastasis-positive SLNs showed significantly higher levels of VEGF121, VEGF-C and VEGF-D mRNA than metastasis-negative SLNs (P<0.001, P=0.01 and P=0.01, respectively), and VEGF121 induced the proliferation of lymphatic endothelial cells (P<0.01).


CONCLUSIONS
Our findings suggest that active lymphangiogenesis is ongoing within SLNs from NSCLC patients, even before metastasis. This lymphangiogenesis may be promoted by upregulation of VEGF121, which may in turn act in part via induction of VEGF-C.
Kawai
Hideki
H
Department of Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. hkawai@doc.med.akita-u.ac.jp
Minamiya
Yoshihiro
Y
Ito
Manabu
M
Saito
Hajime
H
Ogawa
Junichi
J
D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics
C119248:LYVE1 protein, human; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins