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).
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.
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).
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.