Leek R D, Landers R J, Harris A L, Lewis C E
ICRF Molecular Oncology Laboratory, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, UK.
Br J Cancer. 1999 Feb;79(5-6):991-5. doi: 10.1038/sj.bjc.6690158.
Necrosis is a common feature of invasive carcinoma of the breast and is caused by chronic ischaemia leading to infarction. Although necrosis was previously assumed to be due to a generally poor blood supply in the tumour, in this study we show that it is present in tumours with focal areas of high vascular density situated away from the actual sites of necrosis. This may account, in part, for the previous observation that necrosis is linked to poor prognosis in this disease. Highly angiogenic tumours often display blood vessel shunting from one tumour area to another, which further exacerbates ischaemia and the formation of tumour necrosis. We have recently demonstrated that high focal microphage infiltration into breast tumours is significantly associated with increased tumour angiogenesis and poor prognosis and that the macrophages accumulate in poorly vascularized, hypoxic areas within breast tumours. In order to investigate the interactions of macrophages with chronic ischaemia (as reflected by the presence of necrosis) and angiogenesis in breast tumours, we quantified the levels of these three biological parameters in a series of 109 consecutive invasive breast carcinomas. We found that the degree of tumour necrosis was correlated with both microphage infiltration (Mann-Whitney U, P-value = 0.0009; chi-square, P-value = 0.01) and angiogenesis (Mann-Whitney U P-value = 0.0008, chi square P-value = 0.03). It was also observed that necrosis was a feature of tumours possessing an aggressive phenotype, i.e. high tumour grade (chi-square, P-value < 0.001), larger size (Mann-Whitney U, P-value = 0.003) and low oestrogen receptor status (Mann-Whitney U, P-value = 0.008; chi-square, P-value < 0.008). We suggest, therefore, that aggressive tumours rapidly outgrow their vascular supply in certain areas, leading to areas of prolonged hypoxia within the tumour and, subsequently, to necrosis. This, in turn, may attract macrophages into the tumour, which then contribute to the angiogenic process, giving rise to an association between high levels of angiogenesis and extensive necrosis.
坏死是乳腺浸润性癌的常见特征，由慢性缺血导致梗死引起。虽然坏死以前被认为是由于肿瘤中普遍的血液供应不足，但在本研究中我们表明，在远离实际坏死部位的具有高血管密度局灶区域的肿瘤中也存在坏死。这可能部分解释了先前观察到的坏死与该疾病预后不良相关的现象。高血管生成性肿瘤常表现出从一个肿瘤区域到另一个肿瘤区域的血管分流，这进一步加剧了缺血和肿瘤坏死的形成。我们最近证明，乳腺肿瘤中高局灶性巨噬细胞浸润与肿瘤血管生成增加和预后不良显著相关，并且巨噬细胞在乳腺肿瘤内血管化不良、缺氧的区域积聚。为了研究巨噬细胞与乳腺肿瘤中慢性缺血（以坏死的存在为反映）和血管生成之间的相互作用，我们在一系列连续的109例浸润性乳腺癌中对这三个生物学参数的水平进行了量化。我们发现肿瘤坏死程度与巨噬细胞浸润（曼-惠特尼U检验，P值 = 0.0009；卡方检验，P值 = 0.01）和血管生成（曼-惠特尼U检验，P值 = 0.0008，卡方检验，P值 = 0.03）均相关。还观察到坏死是具有侵袭性表型的肿瘤的特征，即高肿瘤分级（卡方检验，P值 < 0.001）、较大尺寸（曼-惠特尼U检验，P值 = 0.003）和低雌激素受体状态（曼-惠特尼U检验，P值 = 0.008；卡方检验，P值 < 0.008）。因此，我们认为侵袭性肿瘤在某些区域迅速生长超过其血管供应，导致肿瘤内出现长时间缺氧区域，随后导致坏死。这反过来可能会吸引巨噬细胞进入肿瘤，进而促进血管生成过程，导致高血管生成水平与广泛坏死之间产生关联。
