Adiponectin Deficiency Limits Tumor Vascularization in the MMTV-PyV-mT Mouse Model of Mammary Cancer

Abstract

PURPOSE: High levels of the fat-secreted cytokine adiponectin (APN) are present in the circulation of healthy people, whereas low levels correlate with an increased incidence of breast cancer in women. The current study experimentally probes the physiologic functions of APN in mammary cancer in a newly generated genetic mouse model. EXPERIMENTAL DESIGN: We established an APN null mouse model of mammary cancer by introducing the polyoma virus middle T (PyV-mT) oncogene expressed from mouse mammary tumor virus (MMTV) regulatory elements into APN null mice. MMTV-PyV-mT-induced tumors resemble ErbB2-amplified human breast cancers. We monitored tumor onset, kinetics, and animal survival, and analyzed vascular coverage, apoptosis, and hypoxia in sections from the primary tumors. Metastatic spreading was evaluated by analyses of the lungs. RESULTS: APN prominently localized to the vasculature in human and mouse mammary tumors. In APN null mice, MMTV-PyV-mT-induced tumors appeared with delayed onset and exhibited reduced growth rates. Affected animals survived control tumor-bearing mice by an average of 21 days. Pathologic analyses revealed reduced vascularization of APN null tumors along with increased hypoxia and apoptosis. At the experimental end point, APN null transgenic mice showed increased frequency of pulmonary metastases. CONCLUSION: The current work identifies a proangiogenic contribution of APN in mammary cancer that, in turn, affects tumor progression. APN interactions with vascular receptors may be useful targets for developing therapies aimed at controlling tumor vascularization in cancer patients.