Mbalaviele G, Dunstan C R, Sasaki A, Williams P J, Mundy G R, Yoneda T
University of Texas Health Science Center, Department of Medicine, San Antonio 78284-7877, USA.
Cancer Res. 1996 Sep 1;56(17):4063-70.
The molecular mechanisms by which human cancer cells spread to bone are largely unexplored. The process likely involves cell adhesion molecules (CAMs) that are responsible for homophilic and heterophilic cell-cell interactions. One relevant CAM may be the calcium-dependent transmembrane glycoprotein E-cadherin. To investigate the involvement of E-cadherin in breast cancer metastasis to bone, we used an in vivo model in which osteolytic bone metastases preferentially occur after injections of cancer cells directly into the arterial circulation through the left ventricle of the hearts of nude mice. We have found that E-cadherin-negative human breast cancer cells MDA-MB-231 (MDA-231) develop radiographically detectable multiple osteolytic bone metastases and cachexia in this model. However, MDA-231 breast cancer cells that were transfected with E-cadherin cDNA showed a dramatically impaired capacity to form osteolytic metastases and induce cachexia. Histological and histomorphometrical analyses of bones of mice bearing mock-transfected MDA-231 revealed aggressive metastatic tumor, whereas metastatic tumor burden was significantly decreased in the bones of mice bearing E-cadherin-expressing MDA-231. Nude mice bearing E-cadherin-transfected MDA-231 breast cancer cells survived longer than mice bearing mock-transfected MDA-231 breast cancer cells. Anchorage-dependent and -independent growth in culture and tumor enlargement in the mammary fat pad of nude mice were unchanged between mock-transfected and E-cadherin-expressing MDA-231, suggesting that these differences in metastatic behavior are not due to an impairment of cell growth and tumor-igenicity. Our results show the suppressive effects of E-cadherin expression on bone metastasis by circulating breast cancer cells and suggest that the modulation of expression of this CAM may reduce the destructive effects of breast cancer cells on bone.
人类癌细胞扩散至骨骼的分子机制在很大程度上尚未得到探索。该过程可能涉及负责同嗜性和异嗜性细胞间相互作用的细胞黏附分子（CAMs）。一种相关的CAM可能是钙依赖性跨膜糖蛋白E-钙黏蛋白。为了研究E-钙黏蛋白在乳腺癌骨转移中的作用，我们使用了一种体内模型，在该模型中，将癌细胞直接通过裸鼠心脏的左心室注射到动脉循环后，优先发生溶骨性骨转移。我们发现，E-钙黏蛋白阴性的人乳腺癌细胞MDA-MB-231（MDA-231）在该模型中会发展出影像学上可检测到的多发性溶骨性骨转移和恶病质。然而，用E-钙黏蛋白cDNA转染的MDA-231乳腺癌细胞形成溶骨性转移和诱导恶病质的能力显著受损。对携带mock转染的MDA-231的小鼠骨骼进行组织学和组织形态计量学分析，发现有侵袭性转移性肿瘤，而携带表达E-钙黏蛋白的MDA-231的小鼠骨骼中的转移瘤负荷显著降低。携带E-钙黏蛋白转染的MDA-231乳腺癌细胞的裸鼠比携带mock转染的MDA-231乳腺癌细胞的小鼠存活时间更长。mock转染和表达E-钙黏蛋白的MDA-231在培养中的贴壁依赖性和非依赖性生长以及裸鼠乳腺脂肪垫中的肿瘤增大情况没有变化，这表明这些转移行为的差异不是由于细胞生长和肿瘤致瘤性受损所致。我们的结果显示了E-钙黏蛋白表达对循环乳腺癌细胞骨转移的抑制作用，并表明调节这种CAM的表达可能会降低乳腺癌细胞对骨骼的破坏作用。
