Vascular endothelial growth factor (VEGF) plays critical roles in cancer aggressiveness. We investigated the clinical and biological significance of neuropilin (NP)-1, a member of the VEGF receptor family, in colon carcinoma. We transfected NP-1-specific small interfering RNA (siRNA) into a human colon adenocarcinoma cell line, WiDR, and investigated its effect on proliferation, migration, and apoptosis. We also examined the relationship between clinicopathologic features and NP-1 expression in 146 patients with advanced colorectal carcinoma who had undergone surgery. Inhibition of NP-1 expression in WiDR cells by RNA interference decreased cell migration (no treatment, 143.3/field; mock, 146.8/field; scrambled siRNA, 134.6/field; NP-1 siRNA 79.6/field) and promoted apoptosis (no treatment, 3.52%; scrambled siRNA, 3.80%; NP-1 siRNA, 14.22%), but did not alter cell proliferation. In patients with advanced colorectal carcinoma, those with tumors with high levels of NP-1 staining showed a significantly higher incidence of lymph node (73.0%) or liver (86.2%) metastasis, greater microvessel density (MVD) (60.4/field), greater number of proliferating carcinoma cells (48.6%), and lesser number of apoptotic carcinoma cells (5.70‰) than those with tumors with low levels of NP-1 staining (lymph node, 56.9%; liver, 59.8%; MVD, 47.8/field; proliferating cells, 42.0%; apoptosis, 8.44‰). Survival for patients with tumors with high levels of NP-1 staining was significantly shorter than for those with tumors with low levels of NP-1 staining. Our results suggest that autocrine-NP-1 pathways control the migration and survival of colon carcinoma cells. NP-1 expression may stimulate tumor growth by enhanced angiogenesis and suppression of tumor cell apoptosis, which lead to metastasis and poor prognosis.

The spread of tumor cells to regional lymph nodes is an early event of gastric cancer metastasis. In our study, we assessed the expression of lymphangiogenic factors and lymphatic endothelial markers in gastric carcinoma tissues and compared expression levels with the status of lymph node metastasis. We also examined the correlation between lymphatic vessel density (LVD) in primary tumors and lymph node metastasis. Paired biopsy samples (tumor and corresponding normal mucosa) of gastric tissue were obtained from 39 patients with gastric carcinoma. The expression of VEGF-C, VEGF-D, VEGFR-3 and podoplanin mRNAs was assessed by real-time quantitative PCR. The expression of VEGF-C (but not of VEGF-D) was significantly greater in patients with lymph node metastasis than in those without metastasis. The expression of lymphatic endothelial markers VEGFR-3 and podoplanin was also significantly greater in the node-positive group. LVD, as assessed by immunohistochemistry for podoplanin, was correlated with lymph node metastasis. These results indicate that quantitative analysis of lymphangiogenic markers in gastric biopsy specimens may be useful in predicting metastasis of gastric cancer to regional lymph nodes. ' 2005 Wiley-Liss, Inc.

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