Hebbard Lionel W, Garlatti Michèle, Young Lawrence J T, Cardiff Robert D, Oshima Robert G, Ranscht Barbara
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Cancer Res. 2008 Mar 1;68(5):1407-16. doi: 10.1158/0008-5472.CAN-07-2953.
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.
T-钙黏蛋白在正常小鼠乳腺中可区分内皮细胞、肌上皮细胞和导管上皮细胞，在乳腺肿瘤发生过程中逐渐局限于脉管系统。为了测试T-钙黏蛋白在乳腺癌中的功能，我们使小鼠中的T-钙黏蛋白（Cdh13）基因失活，并在将该突变引入小鼠乳腺肿瘤病毒（MMTV）-多瘤病毒中T抗原（PyV-mT）转基因模型后评估肿瘤发展和病理学情况。我们报告称，T-钙黏蛋白缺陷会限制乳腺肿瘤血管生成并降低肿瘤生长。肿瘤移植实验证实了T-钙黏蛋白在肿瘤发生中的间质作用。与野生型MMTV-PyV-mT对照相比，T-钙黏蛋白缺陷型肿瘤在病理学上更为进展，并会转移至肺部。T-钙黏蛋白被认为是循环中脂肪分泌激素脂联素高分子量形式的结合伴侣。我们在正常和恶性乳腺中发现脂联素与T-钙黏蛋白阳性脉管系统相关，并报告称这种相互作用在T-钙黏蛋白缺失的情况下消失。这项工作确立了T-钙黏蛋白在促进肿瘤血管生成中的作用，并提出血管T-钙黏蛋白-脂联素关联可能有助于乳腺癌中肿瘤细胞与间质成分之间分子相互作用的可能性。
