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Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression.

Yasuoka H, Kodama R, Tsujimoto M, Yoshidome K, Akamatsu H, Nakahara M, Inagaki M, Sanke T, Nakamura Y - BMC Cancer (2009)

Bottom Line: Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival.In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival.Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan. hyasuoka@mail.wakayama-med.ac.jp

ABSTRACT

Background: Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125-132).

Methods: The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells.

Results: Nrp2 expression was observed in 53.1% (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells.

Conclusion: Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression in vitro.

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Effect of neutralizing anti-Nrp2 antibody on CXCL12-induced chemotaxisis. The chemotactic responses of MDA-MB-231 cells were significantly blocked by neutralizing anti-Nrp2 antibody. *Indicates significant difference (p < 0.05) from control and/or anti-Nrp2 antibody-treated cells.
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Figure 4: Effect of neutralizing anti-Nrp2 antibody on CXCL12-induced chemotaxisis. The chemotactic responses of MDA-MB-231 cells were significantly blocked by neutralizing anti-Nrp2 antibody. *Indicates significant difference (p < 0.05) from control and/or anti-Nrp2 antibody-treated cells.

Mentions: As we had previously shown, endogenous cytoplasmic or nuclear CXCR4 expression was observed in the MDA-MB-231 cell line [14]. In this study, treatment of the cells with anti-Nrp2 antibody significantly inhibited cytoplasmic CXCR4 protein expression, although nuclear CXCR4 protein expression was unchanged in the treated cells (Figure 3). As shown in Figure 4, MDA-MB-231 cells showed significant chemotactic response to CXCL12. Furthermore, the chemotactic responses of MDA-MB-231 cells were significantly blocked by neutralizing anti-Nrp2 antibody.


Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression.

Yasuoka H, Kodama R, Tsujimoto M, Yoshidome K, Akamatsu H, Nakahara M, Inagaki M, Sanke T, Nakamura Y - BMC Cancer (2009)

Effect of neutralizing anti-Nrp2 antibody on CXCL12-induced chemotaxisis. The chemotactic responses of MDA-MB-231 cells were significantly blocked by neutralizing anti-Nrp2 antibody. *Indicates significant difference (p < 0.05) from control and/or anti-Nrp2 antibody-treated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719661&req=5

Figure 4: Effect of neutralizing anti-Nrp2 antibody on CXCL12-induced chemotaxisis. The chemotactic responses of MDA-MB-231 cells were significantly blocked by neutralizing anti-Nrp2 antibody. *Indicates significant difference (p < 0.05) from control and/or anti-Nrp2 antibody-treated cells.
Mentions: As we had previously shown, endogenous cytoplasmic or nuclear CXCR4 expression was observed in the MDA-MB-231 cell line [14]. In this study, treatment of the cells with anti-Nrp2 antibody significantly inhibited cytoplasmic CXCR4 protein expression, although nuclear CXCR4 protein expression was unchanged in the treated cells (Figure 3). As shown in Figure 4, MDA-MB-231 cells showed significant chemotactic response to CXCL12. Furthermore, the chemotactic responses of MDA-MB-231 cells were significantly blocked by neutralizing anti-Nrp2 antibody.

Bottom Line: Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival.In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival.Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan. hyasuoka@mail.wakayama-med.ac.jp

ABSTRACT

Background: Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125-132).

Methods: The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells.

Results: Nrp2 expression was observed in 53.1% (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells.

Conclusion: Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression in vitro.

Show MeSH
Related in: MedlinePlus