Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo.
OBJECTIVE
Adipocytes represent one of the most abundant constituents of the mammary gland. They are essential for mammary tumor growth and survival. Metabolically, one of the more important fat-derived factors ("adipokines") is adiponectin (APN). Serum concentrations of APN negatively correlate with body mass index and insulin resistance. To explore the association of APN with breast cancer and tumor angiogenesis, we took an in vivo approach aiming to study its role in the mouse mammary tumor virus (MMTV)-polyoma middle T antigen (PyMT) mammary tumor model.


METHODS
We compared the rates of tumor growth in MMTV-PyMT mice in wild-type and APN-null backgrounds.


RESULTS
Histology and micro-positron emission tomography imaging show that the rate of tumor growth is significantly reduced in the absence of APN at early stages. PyMT/APN knockout mice exhibit a reduction in their angiogenic profile resulting in nutrient deprivation of the tumors and tumor-associated cell death. Surprisingly, in more advanced malignant stages of the disease, tumor growth develops more aggressively in mice lacking APN, giving rise to a larger tumor burden, an increase in the mobilization of circulating endothelial progenitor cells, and a gene expression fingerprint indicative of more aggressive tumor cells.


CONCLUSIONS
These observations highlight a novel important contribution of APN in mammary tumor development and angiogenesis, indicating that APN has potent angio-mimetic properties in tumor vascularization. However, in tumors deprived of APN, this antiangiogenic stress results in an adaptive response that fuels tumor growth through mobilization of circulating endothelial progenitor cells and the development of mechanisms enabling massive cell proliferation despite a chronically hypoxic microenvironment.
Landskroner-Eiger
Shira
S
Department of Cell Biology, Center of Reproductive Biology and Womens' Health, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Qian
Binzhi
B
Muise
Eric S
ES
Nawrocki
Andrea R
AR
Berger
Joel P
JP
Fine
Eugene J
EJ
Koba
Wade
W
Deng
Yingfeng
Y
Pollard
Jeffrey W
JW
Scherer
Philipp E
PE
D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D017209:Apoptosis; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D011120:Polyomavirus / Q000235:genetics; D049268:Positron-Emission Tomography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D052242:Adiponectin; C499919:Adipoq protein, mouse; D000957:Antigens, Viral, Tumor; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; C089946:2,4-thiazolidinedione; D005947:Glucose