Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer cells with or without HER-2/neu overexpression.

Angiogenesis is critical for breast cancer progression. Overexpression of HER-2/neu receptors occur in 25-30% of breast cancers, and treatment with trastuzumab inhibits HER-2-overexpressing tumor growth. Notably, HER-2-mediated signaling enhances vascular endothelial growth factor (VEGF) secretion to increase tumor-associated angiogenesis. Squalamine (aminosterol compound) suppresses VEGF-induced activation of kinases in vascular endothelial cells and inhibits tumor-associated angiogenesis. We assessed antitumor effects of squalamine either alone or with trastuzumab in nude mice bearing breast tumor xenografts without (MCF-7) or with HER2-overexpression (MCF-7/HER-2). Squalamine alone inhibited progression of MCF-7 tumors lacking HER2 overexpression, and squalamine combined with trastuzumab elicited marked inhibition of MCF-7/HER2 growth exceeding that of trastuzumab alone. MCF-7/HER-2 cells secrete higher levels of VEGF than MCF-7 cells, but squalamine elicited no growth inhibition of either MCF-7/HER-2 or MCF-7 cells in vitro. However, squalamine did stop growth of human umbilical vein endothelial cells (HUVECs) and reduced VEGF-induced endothelial tube-like formations in vitro. These effects correlated with blockade of focal adhesion kinase phosphorylation and stress fiber assembly in HUVECs. Thus, squalamine effectively inhibits growth of breast cancers with or without HER-2-overexpression, an effect due in part to blockade of tumor-associated angiogenesis.

Clinicopathological significance of human macrophage metalloelastase expression in esophageal squamous cell carcinoma.

OBJECTIVE: Human macrophage metalloelastase is referred to as matrix metalloproteinase (MMP-12), its function in tumors is contradictory. The current study was undertaken to investigate the role of MMP-12 in esophageal squamous cell carcinoma (SCC). PATIENTS AND METHODS: We analyzed the levels of MMP-12 mRNA expression in 67 patients with primary esophageal SCC by Northern blot analysis and the tissues were subjected to in situ hybridization analysis for MMP-12. Immunohistochemical staining was performed to detect the macrophages infiltrated in esophageal SCCs. RESULTS: MMP-12 mRNA was detected in 27 of 67 esophageal SCC samples by Northern blot analysis. In situ hybridization and immunohistochemical staining revealed that MMP-12 mRNA signals are located mainly in tumor cells. The frequency of lymph node metastasis was significantly higher in the MMP-12-positive (MMP-12(+)) subgroup than MMP-12-negative (MMP-12(-)) subgroup (p < 0.05); furthermore, invasion was significantly deeper in the MMP- 12(+) subgroup than in the MMP-12(-) subgroup (p < 0.01). MMP-12 mRNA was inversely correlated with prognosis (p < 0.05). However, Cox multivariate analysis revealed that upregulation of MMP-12 was not related to prognosis. CONCLUSIONS: MMP-12 gene expression was associated with the progression of esophageal SCC; however, it was not an independent prognostic factor.