McEwen A, Emmanuel C, Medbury H, Leick A, Walker D M, Zoellner H
The Cellular and Molecular Pathology Research Unit, The Department of Oral Medicine and Oral Pathology, Faculty of Dentistry, The University of Sydney, Westmead Centre for Oral Health, Westmead Hospital, Westmead, NSW 2145, Australia.
J Pathol. 2003 Nov;201(3):395-403. doi: 10.1002/path.1457.
Although tumour cells are believed to migrate between endothelial cells early in metastasis, the possibility remains that endothelial apoptosis may also contribute to the tumour's breach of the vascular barrier. Although seemingly inconsistent with tumour angiogenesis, one publication describes the induction of contact-dependent apoptosis in cultured endothelium by tumour cells. The cell culture data are, however, open to challenge on technical grounds while there are no confirmatory reports. The present paper describes experiments overcoming these limitations. SAOS-2 human osteosarcoma cells and two rat carcinoma cell lines were co-cultured with human umbilical vein endothelial cells (HUVECs) and cultures labelled by surface lectin histochemistry for endothelium. The HUVEC culture density was determined and SAOS-2 cells, but not rat carcinoma cells, were found significantly to reduce HUVEC survival despite the release of potent growth factors as determined in separate experiments with tumour cell conditioned medium. Lectin labelling combined with light microscopy, transmission electron microscopy, flow cytometry for both lectin binding and DNA content, and DNA gel electrophoresis of SAOS-2/HUVEC co-cultures revealed extensive HUVEC apoptosis. These findings indicate contact-dependent endothelial apoptosis by SAOS-2, while this activity appeared weaker and overwhelmed by HUVEC proliferation with rat carcinoma cells. Importantly, this study supports the suggestion that endothelial apoptosis may be important for metastasis and suggests a complex interplay between endothelial proliferation and apoptosis in tumours.
尽管人们认为肿瘤细胞在转移早期在内皮细胞之间迁移，但内皮细胞凋亡也可能导致肿瘤突破血管屏障，这种可能性依然存在。虽然这似乎与肿瘤血管生成不一致，但有一篇出版物描述了肿瘤细胞在培养的内皮细胞中诱导接触依赖性凋亡。然而，基于技术原因，细胞培养数据仍有待质疑，且尚无确凿报告。本文描述了克服这些局限性的实验。将SAOS-2人骨肉瘤细胞和两种大鼠癌细胞系与人脐静脉内皮细胞（HUVECs）共培养，并用表面凝集素组织化学标记内皮细胞进行培养。测定了HUVEC的培养密度，结果发现，尽管在单独的肿瘤细胞条件培养基实验中确定释放了强效生长因子，但SAOS-2细胞而非大鼠癌细胞显著降低了HUVEC的存活率。凝集素标记结合光学显微镜、透射电子显微镜、用于凝集素结合和DNA含量的流式细胞术以及SAOS-2/HUVEC共培养物的DNA凝胶电泳显示，HUVEC出现广泛凋亡。这些发现表明SAOS-2可诱导接触依赖性内皮细胞凋亡，而在与大鼠癌细胞共培养时，这种活性似乎较弱且被HUVEC增殖所掩盖。重要的是，本研究支持内皮细胞凋亡可能对转移很重要这一观点，并提示肿瘤内皮细胞增殖与凋亡之间存在复杂的相互作用。
