T-cadherin Supports Angiogenesis and Adiponectin Association with the Vasculature in a Mouse Mammary Tumor Model

Abstract

T-cadherin delineates endothelial, myoepithelial, and ductal epithelial cells in the normal mouse mammary gland, and becomes progressively restricted to the vasculature during mammary tumorigenesis. To test the function of T-cadherin in breast cancer, we inactivated the T-cadherin (Cdh13) gene in mice and evaluated tumor development and pathology after crossing the mutation into the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyV-mT) transgenic model. We report that T-cadherin deficiency limits mammary tumor vascularization and reduces tumor growth. Tumor transplantation experiments confirm the stromal role of T-cadherin in tumorigenesis. In comparison with wild-type MMTV-PyV-mT controls, T-cadherin-deficient tumors are pathologically advanced and metastasize to the lungs. T-cadherin is a suggested binding partner for high molecular weight forms of the circulating, fat-secreted hormone adiponectin. We discern adiponectin in association with the T-cadherin-positive vasculature in the normal and malignant mammary glands and report that this interaction is lost in the T-cadherin null condition. This work establishes a role for T-cadherin in promoting tumor angiogenesis and raises the possibility that vascular T-cadherin-adiponectin association may contribute to the molecular cross-talk between tumor cells and the stromal compartment in breast cancer.

Adiponectin Reduces Hepatic Stellate Cell Migration by Promoting Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Secretion

“…Western Blot Analysis-Frozen liver tissue and activated HSCs treated with fAd (5 g/ml), TIMP-1 (0.25 g/ml), CD63 antibody (0.25 g/ml), IgG antibody control (0.25 g/ml), and/or rat TIMP-1 recombinant protein was lysed and blotted as previously described (21). Membranes were incubated with antibodies against AMPK, p-AMPK, FAK, pFAK Y397 (Cell Signaling), ␣SMA (Sigma), CD63 (Secrotec), TIMP-1, and ␤1-integrin (Millipore) overnight in TBS-Tween containing 5% BSA at 4°C followed by HRP-conjugated secondary antibodies (Sigma) and visualization by chemiluminescence (SuperSignal West Pico; Thermo Scientific).…”

Malignant Transformation in Skin is Associated with the Loss of T-Cadherin Expression in Human Keratinocytes and Heterogeneity in T-Cadherin Expression in Tumor Vasculature

“…However, as shown in numerous studies, Tcadherin expression is altered in tumor vessels: in Lewis carcinoma lung metastasis and F9 teratocarcinoma, PC-3 prostate cancer, in A673 rhabdomyosarcoma the expression of Т-cadherin is upregulated on endothelial cells of the blood vessels penetrating the tumor (Riou et al, 2006;Wyder et al, 2000), while no T-cadherin could be detected in the blood vessels of B16F10 melanoma lung metastasis (Wyder et al, 2000). Using mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyV-mT) transgenic model with inactivated T-cadherin gene it was shown that T-cadherin deficiency limits mammary tumor vascularization and reduces tumor growth (Hebbard et al, 2008). In tumor neovascularization of hepatocellular carcinoma (Н ) T-cadherin is also upregulated in intratumoral capillary endothelial cells, whereas in surrounding tumor tissue as well as in normal liver nо Т-cadherin could be detected (Adachi et al, 2006).…”

Adipokines – Toward the Molecular Dissection of Interactions Between Stromal Adipocytes and Breast Cancer Cells

“…Adiponectin acts as an inhibitory factor for the proliferation of human breast carcinoma cells and mammary tumor development (Arditi et al 2007;Dieudonne et al 2006;Grossmann et al 2008a;Hebbard et al 2008;Jarde et al 2008a;Kang et al 2005;Nakayama et al 2008;Pfeiler et al 2008;Wang et al 2006a). In vitro treatment with adiponectin at physiological concentrations attenuates the growth of an ER-negative human breast carcinoma MDA-MB-231 cells by inhibiting cell proliferation and inducing apoptosis (Kang et al 2005;Wang et al 2006a).…”