Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors.
OBJECTIVE
The host microenvironment differs between primary and metastatic sites, affecting gene expression and various physiological functions. Here we show the differences in the physiological parameters between orthotopic primary and metastatic breast tumor xenografts using intravital microscopy and reveal the relationship between angiogenic gene expression and microvascular functions in vivo.


METHODS
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.
Monsky
Wayne L
WL
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Mouta Carreira
Carla
C
Tsuzuki
Yoshikazu
Y
Gohongi
Takeshi
T
Fukumura
Dai
D
Jain
Rakesh K
RK
D042683:Angiopoietin-1; D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000503:physiopathology / Q000556:secondary; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology; D016228:Endothelial Growth Factors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D008222:Lymphokines / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor