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Angiogenesis, Metastasis, and the Cellular Microenvironment

HER-2/neu Overexpression Increases the Viable Hypoxic Cell Population within Solid Tumors without Causing Changes in Tumor Vascularization¹

Departments of ¹ Advanced Therapeutics, ² Medical Biophysics, and ³ Medical Oncology, British Columbia Cancer Agency; Departments of ⁴ Pharmaceutical Sciences and ⁵ Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada and ⁶ Genta, Inc., Salt Lake City, Utah

Requests for reprints: Wieslawa H. Dragowska, Department of Advanced Therapeutics, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6. Phone: 604-877-6000; Fax: 604-877-6011. E-mail: vdragows{at}bccrc.ca

The effects of HER-2/neu overexpression on the tumor microenvironment in an aggressive breast cancer xenograft model were investigated. These studies focused on tumors derived following the subcutaneous injection of MDA-MB-435/LCC6 cells transfected with human c-erbB2 (LCC6^HER-2) into SCID-Rag2M mice. LCC6^HER-2 tumors were more viable (H&E-stained tumor sections) than isogenic vector control tumors (LCC6^Vector). Correspondingly, a 2.7-fold increase in trypan blue–excluding cells (P = 0.00056) and a 4.8-fold increase in clonogenic cells (P = 0.00146) were noted in cell suspensions derived from disaggregated LCC6^HER-2 versus LCC6^Vector tumors. Tumor sections stained with the antibody detecting 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), a marker of hypoxia, showed a greater fraction of hypoxic tissue in LCC6^HER-2 tumors compared with control tumors. Flow cytometric analyses based on viable tumor cells (DNA content 2N) in cell suspensions from disaggregated tumors confirmed that there were significantly more EF5-positive cells (i.e., hypoxic) in LCC6^HER-2 than in LCC6^Vector tumors (16.41 ± 8.1% and 5.96 ± 4.1%, respectively; P = 0.0015). Protein levels of phosphorylated (Ser⁵³⁶) nuclear factor-B p65 were significantly elevated in LCC6^HER-2 tumors (P = 0.00048), and a trend in increased hypoxia-inducible factor-1 protein levels was observed in LCC6^HER-2 compared with LCC6^Vector tumors. Despite the substantial viable hypoxic cell fraction and a 1.7-fold increase of vascular endothelial growth factor protein (P = 0.05) in LCC6^HER-2 tumors, no significant differences were found (P > 0.05) between LCC6^HER-2 and LCC6^Vector vasculature (CD31 staining and Hoechst 33342 perfusion). These results suggest that HER-2/neu overexpression may be linked with overall increased tumor viability and a significant increase in the population of viable hypoxic cells, which is not due to differences in tumor vascularization.

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