Horak E R, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris A L
Nuffield Department of Pathology and Bacteriology, University of Oxford, John Radcliffe Hospital, UK.
Lancet. 1992 Nov 7;340(8828):1120-4. doi: 10.1016/0140-6736(92)93150-l.
Animal models suggest a role for new vessel formation (angiogenesis) in tumours with metastatic potential, and there is some evidence that this is true for human tumours. What is needed is a sensitive and specific label for endothelial cells, and one candidate would be a monoclonal antibody to platelet/endothelial cell adhesion molecule (PECAM). We have counted microvessels in 103 primary breast cancers using the JC70 antibody to PECAM (or CD31). We compared our findings with various pathological indicators (lymph node status and tumour grade, size, and type and markers (oestrogen receptor, and c-erbB-2 expression and detection of mutant p53). Tumours showed significantly higher vascularisation than normal breast tissue and the number of blood vessels/mm2 was significantly associated with node metastasis. Only 2 out of 50 tumours with 99 vessel/mm2 or less were node positive whereas 31 out of 39 tumours with counts above 140/mm2 were positive (p < 0.0001). Tumour size and grade also correlated with node metastasis and vascularisation also increased with the size of the primary and with poor differentiation. However, within each subgroup of size or differentiation tumours without node involvement had much lower vascular counts, and multivariate analysis showed that vascular count alone explains the association of size and grade with node metastasis. Other markers, conventional or novel, did not correlate with vascularisation. Even with the short follow-up in this series, vascular counts correlated with early death. These results suggest that angiogenesis is closely linked to metastasis, that it is acquired at a critical density of vessels, and that this process occurs as tumours enlarge or become more poorly differentiated. Counting of newly formed microvessels stained with endothelium-specific antibodies may prove to be a useful tool in the early detection of metastatic potential and in the selection of patients for whom anti-angiogenesis drugs might be beneficial.
动物模型表明，新血管形成（血管生成）在具有转移潜能的肿瘤中发挥作用，并且有一些证据表明人类肿瘤也是如此。所需要的是一种针对内皮细胞的敏感且特异的标记物，一种候选物可能是针对血小板/内皮细胞黏附分子（PECAM）的单克隆抗体。我们使用针对PECAM（或CD31）的JC70抗体对103例原发性乳腺癌中的微血管进行了计数。我们将研究结果与各种病理指标（淋巴结状态、肿瘤分级、大小、类型）以及标志物（雌激素受体、c-erbB-2表达和突变型p53检测）进行了比较。肿瘤的血管化程度明显高于正常乳腺组织，每平方毫米的血管数量与淋巴结转移显著相关。每平方毫米血管数为99个或更少的50例肿瘤中，只有2例淋巴结阳性，而每平方毫米血管数高于140个的39例肿瘤中，有31例阳性（p<0.0001）。肿瘤大小和分级也与淋巴结转移相关，血管化程度也随着原发肿瘤大小的增加和分化程度差而升高。然而，在每个大小或分化亚组中，无淋巴结转移的肿瘤血管计数要低得多，多变量分析表明，仅血管计数就能解释大小和分级与淋巴结转移之间的关联。其他传统或新型标志物与血管化无关。即使在本系列研究的短期随访中，血管计数也与早期死亡相关。这些结果表明，血管生成与转移密切相关，在血管达到临界密度时获得，并且这个过程随着肿瘤增大或分化程度变差而发生。用内皮细胞特异性抗体染色计数新形成的微血管可能被证明是早期检测转移潜能以及选择可能从抗血管生成药物中获益的患者的有用工具。
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