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Role of Host Microenvironment in Angiogenesis and Microvascular Functions in Human Breast Cancer Xenografts: Mammary Fat Pad versus Cranial Tumors¹

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Purpose: The host microenvironment differs between primaryand metastatic sites, affecting gene expression and variousphysiological functions. Here we show the differencesin the physiological parameters between orthotopic primaryand metastatic breast tumor xenografts using intravitalmicroscopy and reveal the relationship between angiogenic gene expression and microvascular functions in vivo.

Experimental Design: ZR75-1, a human estrogen-dependent mammary carcinoma, was implanted into the mammary fat pad (primary site) of ovariectomized SCID female mice carrying estrogen pellets. The same tumor line was also grown in the cranial window (metastasis site). When tumors reached the diameter of 2.5 mm, angiogenesis, hemodynamics, and vascular permeability were measured by intravital microscopy, and expression of angiogenic growth factors was determined by quantitative reverse transcription-PCR.

Results: ZR75-1 tumors grown in the mammary fat pad had higher microvascular permeability but lower vascular density than the same tumors grown in the cranial window (2.5- and 0.7-fold, respectively). There was no significant difference in RBC velocity, vessel diameter, blood flow rate, and shear rate between two sites. The levels of vascular endothelial growth factor (VEGF), its receptors VEGFR1 and VEGFR2, and angiopoietin-1 mRNA tended to be higher in the mammary fat pad tumors than in the cranial tumors (1.5-, 1.5-, 3-, and 2-fold, respectively).

Conclusions: The primary breast cancer exhibited higher vascular permeability, but the cranial tumor showed more angiogenesis, suggesting that the cranial environment is leakage resistant but proangiogenic. Collectively, host microenvironment is an important determinant of tumor gene expression and microvascular functions, and, thus, orthotopic breast tumor models should be useful for obtaining clinically relevant information.

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