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Molecular Oncology, Markers, Clinical Correlates |
Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Vascular
endothelial growth factors (VEGFs) C and D are novel members of the
VEGF family that show some selectivity toward lymphatic endothelial
cells. Recent studies suggest that VEGF-C may be involved in
lymphangiogenesis and spread of cancer cells via lymphatic vessels.
However, whether other VEGF family members play a role in lymph node
metastasis is largely unknown. The aim of the present study was to
explore whether expressions of VEGF-A, VEGF-B, VEGF-C, and VEGF-D are
correlated with lymph node status in lung adenocarcinoma. Total RNA was
isolated from 60 surgical specimens of lung adenocarcinoma with
(n = 27) or without (n = 33)
lymph node metastasis. The relative mRNA abundance of VEGF-A, VEGF-B,
VEGF-C, and VEGF-D was measured by real-time reverse transcription-PCR
analysis based on TaqMan fluorescence methodology. We found that, as
single factors, expression of none of the four VEGF family members
clearly correlated with the presence of lymph node metastasis. The only
tendency noted was for higher VEGF-B and VEGF-C and lower VEGF-D levels
in the node-positive group. However, two-way scatterplot analysis
revealed that tumors with lymph node metastasis were associated with a
pattern of low VEGF-D and high VEGF-A, VEGF-B, or VEGF-C, such that the
ratios of VEGF-D:VEGF-A, VEGF-D:VEGF-B, or VEGF-D:VEGF-C were
significantly lower in the node-positive group. Strikingly, none of
the 11 tumors with high VEGF-D levels metastasized to lymph nodes.
Furthermore, a low VEGF-D:VEGF-C ratio correlated with the presence of
lymphatic invasion, and six of seven tumors with a pattern of very high
expression of VEGF-C and low expression of VEGF-D displayed lymph
vessel invasion that extended along the bronchovascular tree beyond the
main tumor. Finally, levels of VEGF-A, but not VEGF-B or VEGF-C, were
higher in tumors with large nodal metastasis (
1 cm) than in those
with small (<1 cm) nodal metastasis. These results support the
hypothesis that two VEGF family members are involved in lymph node
metastasis at two distinct steps; VEGF-C facilitates entry of cancer
cells into the lymph vasculature, whereas VEGF-A promotes the growth of
metastatic tumor through angiogenesis. The results also suggest that
the balance between VEGF-C and VEGF-D could be important rather than
the level of VEGF-C alone. Whether a low VEGF-D level plays a causative
role in lymph node metastasis requires further investigation.
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