Man Yan-Gao, Sang Qing-Xiang Amy
Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology and American Registry of Pathology, Washington, DC 20306-6000, USA.
Exp Cell Res. 2004 Dec 10;301(2):103-18. doi: 10.1016/j.yexcr.2004.08.037.
Human breast epithelium and the stroma are separated by a layer of myoepithelial (ME) cells and basement membrane, whose disruption is a prerequisite for tumor invasion. The dissolution of the basement membrane is traditionally attributed primarily to an over-production of proteolytic enzymes by the tumor or the surrounding stromal cells. The results from matrix metalloproteinase inhibitor clinical trials, however, suggest that this "protease-centered" hypothesis is inadequate to completely reflect the molecular mechanisms of tumor invasion. The causes and signs of ME cell layer disruption are currently under-explored. Our studies revealed that a subset of pre- and micro-invasive tumors contained focal disruptions in the ME cell layers. These disruptions were associated with immunohistochemical and genetic alterations in the overlying tumor cells, including the loss of estrogen receptor expression, a higher frequency of loss of heterozygosity, and a higher expression of cell cycle, angiogenesis, and invasion-related genes. Focal ME layer disruptions were also associated with a higher rate of epithelial proliferation and leukocyte infiltration. We propose the novel hypothesis that a localized death of ME cells and immunoreactions that accompany an external environmental insult or internal genetic alterations are triggering factors for ME layer disruptions, basement membrane degradation, and subsequent tumor progression and invasion.
人类乳腺上皮和基质被一层肌上皮（ME）细胞和基底膜分隔开，基底膜的破坏是肿瘤侵袭的先决条件。传统上，基底膜的溶解主要归因于肿瘤或周围基质细胞蛋白水解酶的过度产生。然而，基质金属蛋白酶抑制剂临床试验的结果表明，这种“以蛋白酶为中心”的假说不足以完全反映肿瘤侵袭的分子机制。目前，ME细胞层破坏的原因和迹象尚未得到充分研究。我们的研究表明，一部分原位癌和微浸润癌的ME细胞层存在局灶性破坏。这些破坏与上层肿瘤细胞的免疫组化和基因改变有关，包括雌激素受体表达的丧失、杂合性缺失频率的增加以及细胞周期、血管生成和侵袭相关基因的高表达。ME层局灶性破坏还与上皮细胞增殖率和白细胞浸润率较高有关。我们提出了一个新的假说，即ME细胞的局部死亡以及伴随外部环境损伤或内部基因改变的免疫反应是ME层破坏、基底膜降解以及随后肿瘤进展和侵袭的触发因素。
