Angiogenesis and inflammation in invasive carcinoma of the breast.

Lee, A. H. S.; Happerfield, Lisa; Bobrow, Lynda G.; Millis, R R

doi:10.1136/jcp.50.8.669

Cited by 90 publications

(77 citation statements)

References 27 publications

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“…Highly necrotic tumours also contained higher levels of focal macrophage infiltration. These results accord well with other previous, albeit only semiquantitative, reports in which simply the presence of necrosis in breast carcinomas was correlated with (1) decreased survival and total vessel counts in highly vascularized tumour areas (Kato et al, 1997) and (2) diffuse tumour infiltration by macrophages (Lee et al, 1997). However, neither of these studies attempted to quantify the actual amount of necrosis present.…”

Section: Discussionsupporting

confidence: 76%

“…However, neither of these studies attempted to quantify the actual amount of necrosis present. Furthermore, Lee et al (1997) only loosely assessed the general level of TAM infiltration per tumour. In the present study, we have used previously published methods to quantify the degree of necrosis as well as the highest density of vessels and macrophages in defined areas of the tumour where 'hotspots' of these cells occur.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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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.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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“…It has been shown to correlate with poor prognosis in carcinomas of the breast (37,38), cervix (39,40), and bladder (41), confirming to some extent the protumorigenic role of macrophages. On the other hand, macrophages in stomach cancer were associated with good prognosis of the disease (42), and there has been varying results with lung cancer (43,44).…”

Section: Discussionmentioning

confidence: 86%

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

Mehibel

Singh

Chinje

et al. 2009

Molecular Cancer Therapeutics

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Tumor-associated macrophages (TAMs) are found in many solid tumors and have often been shown to accumulate in the hypoxic regions surrounding areas of necrosis. TAMs are the major site of expression of nitric oxide synthase (NOS), a heme-containing homodimeric enzyme consisting of oxygenase and reductase domains. The latter has a high degree of sequence homology to cytochrome P450 reductase and a functional consequence of this is the ability of NOS, under hypoxic conditions, to activate the bioreductive drugs tirapazamine and RSU1069. Banoxantrone (AQ4N) is a bioreductive prodrug activated in hypoxia by an oxygen-dependent two-electron reductive process to yield the topoisomerase II inhibitor AQ4. A feature of this process is that the final product could potentially show bystander cell killing. Thus, in this study, we investigated the ability of inducible NOS (iNOS)-expressing TAMs to activate AQ4N and elicit toxicity in cocultured human tumor cells. Murine macrophages were induced to overexpress iNOS by treatment with a combination of cytokines, mixed with HT1080 and HCT116 human tumor cells, and the toxicity of AQ4N was determined under aerobic or hypoxic conditions. The aerobic toxicity of AQ4N toward tumor cells was not affected through coculturing with macrophages. However, under hypoxic conditions, the induction of iNOS activity in the macrophages was associated with an increase in AQ4N metabolism and a substantial increase in tumor cell toxicity, which was dependent on the proportion of macrophages in the culture. This study is the first demonstration of TAM-mediated prodrug activation to result in bystander killing of human tumor cells.

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“…Overexpression of macrophage chemoattractants within tumors has been shown to correlate with poor prognosis [67], and the level of macrophage infiltration in tumors is known to be positively correlated with microvessel density, tumor stage, and angiogenesis in human tumors [68]. TAM presence is, therefore, associated with reduced, relapse-free and overall survival [65, 68 -71] in several tumor types (i.e., melanoma [68] and cervical [69,70] and breast [65,71] cancer). Recently, Naldini and co-workers [72] showed that Tie-2-expressing monocytes are a distinct, hemopoietic lineage of proangiogenic cells that account for most of the angiogenic activity of myeloid cells in mouse tumors.…”

Section: Angiostatic Effectsmentioning

confidence: 99%

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis

Dirkx

Egbrink

Wagstaff

et al. 2006

Journal of Leukocyte Biology

310

252

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The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.

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Angiogenesis and inflammation in invasive carcinoma of the breast.

Cited by 90 publications

References 27 publications

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

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

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis

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