Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast

Abstract

Summary 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.

Proportion of infiltrating IgG-binding immune cells predict for tumour hypoxia

“…Thus they have the capacity to affect tumour vascularization, growth rate, stroma formation, and apoptotic cell death (Mantovani et al, 1992). Leek et al (1997) have shown that higher numbers of macrophages are found in angiogenic breast tumours and that they are concentrated in avascular, hypoxic regions of the tumour, consistent with many other reports indicating high macrophage numbers in avascular necrotic sites . Hypoxia is known to stimulate the angiogenic activity of macrophages, and macrophage-derived VEGF is upregulated under low oxygen tensions (Harmey et al, 1998).…”

“…Consistent with these theories, breast cancer patients with low macrophage indices have a lower risk of recurrence and increased overall survival rates (Leek et al, 1997), furthermore, experimental studies have shown a trend between high macrophage numbers and radioresistance (Milas et al, 1987). These studies suggest that radiobiologically hypoxic tumours are targets for angiogenic activity, presumably to improve nutrient supply and drainage, and unsurprisingly have poor response rates to therapy.…”

“…It has been suggested, that macrophages are attracted to the tumour matrix by following a falling oxygen gradient or by chemoattractants released from stressed or necrotic cells (Leek et al, 1997). Consistent with these theories, breast cancer patients with low macrophage indices have a lower risk of recurrence and increased overall survival rates (Leek et al, 1997), furthermore, experimental studies have shown a trend between high macrophage numbers and radioresistance (Milas et al, 1987).…”

“…In a study of 20 human tumour biopsies of differing histology, Svennevig et al detected up to 28% of the biopsied tissue contained macrophages (1979). More recently, high proportions of macrophages have been measured in human breast carcinoma (Leek et al, 1997(Leek et al, , 1999.…”

“…Indeed, macrophages can account for up to 50% of the tumour mass in breast carcinoma (Kelly et al, 1988;O'Sullivan and Lewis, 1994;Leek et al, 1994). Macrophages are known to be involved in the angiogenic process, and can be stimulated in hypoxic, avascular regions of the tumour microenvironment to secrete a wide range of angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast factor (bFGF), tumour necrosis factor α (TNFα), endothelial growth factor (EGF), interferons, and others (Leek et al, 1997). Additionally, tumour hypoxia alone can also alter the effects of growth factors and cytokines, induce transcription factors and DNA repair enzymes, and has been associated with increased tumour aggressiveness (Brizel et al, 1996;Dachs and Stratford, 1996).…”