Hypoxia Induces a Human Macrophage Cell Line to Release Tumor Necrosis Factor-α and Its Soluble Receptors in Vitro

Scannell, Gianna; Waxman, Kenneth; Kaml, Gary J.; Ioli, Gene R.; Gatanaga, Tetsuya; Yamamoto, Robert S.; Granger, Gale A.

doi:10.1006/jsre.1993.1044

Cited by 106 publications

(64 citation statements)

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“…We recently demonstrated that TAMs congregate at highest density in relatively avascular, hypoxic sites in breast carcinomas (Leek et al, 1996). The very low levels of oxygen present in such tumour areas have been shown to regulate both the expression of TNF-oc and its receptors by macrophages in vitro (Scannell et al, 1993), as well as the cytotoxic effects of TNF-X on its target cells (Lewis and Balkwill, 1997). It is possible that the TNF-oc hotspots recorded here and elsewhere (Miles et al, 1994;Pusztai et al, 1994;Lewis and McGee, 1996) may be a product, in part, of tumour hypoxia in these regions.…”

Section: Discussionmentioning

confidence: 99%

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

Leek

Landers²,

Fox³

et al. 1998

Br J Cancer

195

118

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Summary Angiogenesis is an essential requirement for tumour growth and metastasis and is regulated by a complex network of factors produced by both stromal cells and neoplastic cells within solid tumours. The cytokine tumour necrosis factor alpha (TNF-ca) and the enzyme thymidine phosphorylase (TP) are two factors known to promote tumour angiogenesis. We have demonstrated recently that high numbers of tumour-associated macrophages (TAMs) are significantly associated with increased tumour angiogenesis and poor prognosis in invasive carcinoma of the breast. We have also shown that TAMs are a major source of TNF-a in invasive breast carcinomas, and that macrophagelike stromal cells as well as tumour cells synthesize TP in such tumours. However, little is known of the factors that regulate the production or activity of these factors in the tumour microenvironment. As TNF-a has been shown to up-regulate TP expression in tumour cells in vitro we performed an immunohistochemical study to investigate the possibility that TNF-a may be involved in the regulation of TP expression by malignant breast epithelial cells in vivo. To do this, we used a cocktail of non-neutralizing monoclonal anti-TNF-a antibodies to visualize both TNF-a-expressing macrophages and TNF-a bound to its receptors on tumour cells and endothelial cells in a series of 93 invasive carcinomas of the breast. A semiquantitative grading system was then used to compare these staining patterns with that for TP in the same biopsies. TNF-a immunoreactivity was also compared with various important tumour variables known to relate to outcome in this disease (microvessel density, node status, grade, stage, receptor status and macrophage infiltration), as well as relapse-free and overall survival data for these patients. Our data show significant positive correlations between TNF-a bound to its receptors on tumour cells and: (1) TP protein production by tumour cells, and (2) axillary lymph node status (i.e. metastasis). These results suggest that tumour cell responsiveness to TNF-a produced by neighbouring TAMs may play a part in the regulation of TP expression by tumour cells as well as their metastatic behaviour. This may explain, in part, the relationship between increased macrophage infiltration and angiogenesis in breast cancer, and further supports the contention that TAMs may represent an important target for future anti-angiogenic therapies.

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Section: Discussionmentioning

confidence: 99%

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

Leek

Landers²,

Fox³

et al. 1998

Br J Cancer

195

118

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“…We have also shown that high levels of macrophages in focal areas (MØI) are associated with increased vascular density and that macrophage clusters are found in avascular areas of breast tumours (Leek et al, 1997). As macrophages have been shown to release such proangiogenic cytokines as vascular endothelial growth factor (Harney et al, 1998) tumour recrosis factor α (TNF-α) in response to hypoxia (Scannell et al, 1993), it is possible that, once macrophages reach hypoxic/ischaemic tumour sites, they may promote tumour growth and metastasis by releasing these factors to stimulate angiogenesis. Therefore, the purpose of this study was to assess quantitatively the degree of central necrosis in a consecutive series of invasive breast carcinomas and to examine its relationship to both focal microphage infiltration and angiogenesis, as measured by quantitative CD68 and CD31 immunohistochemistry of vessel and macrophage 'hotspots' respectively (Fox et al, 1995;Leek et al, 1996Leek et al, , 1997.…”

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confidence: 85%

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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“…88,93 For example, exposure of macrophages to hypoxia is known to enhance their gene expression, including that of MMP-7 93 as well as their release of elastase 94 and cytokines. 91 We have provided data that suggest that some portions of the AAA wall are under a state of hypoxia caused by the presence of an ILT layer. 19 As a consequence, the mural cells within these zones likely respond to this environment.…”

Section: Hypoxia-mediated Wall Weakeningmentioning

confidence: 99%

Biomechanical Determinants of Abdominal Aortic Aneurysm Rupture

Vorp

Geest

2005

ATVB

232

172

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Abstract-Rupture of abdominal aortic aneurysm (AAA) represents a significant clinical event, having a mortality rate of 90% and being currently ranked as the 13th leading cause of death in the US. The ability to reliably evaluate the susceptibility of a particular AAA to rupture on a case-specific basis could vastly improve the clinical management of these patients. Because AAA rupture represents a mechanical failure of the degenerated aortic wall, biomechanical considerations are important to understand this process and to improve our predictions of its occurrence. Presented here is an overview of research to date related to the biomechanics of AAA rupture. This includes a summary of results related to ex vivo and in vivo mechanical testing, noninvasive AAA wall stress estimations, and potential mechanisms of AAA wall weakening. We conclude with a demonstration of a biomechanics-based approach to predicting AAA rupture on a patient-specific basis, which may ultimately prove to be superior to the widely and currently used maximum diameter criterion. Key Words: abdominal aortic aneurysm Ⅲ biomechanics Ⅲ rupture Ⅲ strength Ⅲ stress A bdominal aortic aneurysm (AAA) is a focal enlargement of the infrarenal aorta, which occurs over a time course of several years. This condition is present in Ϸ2% of the elderly population, with Ϸ150 000 new cases diagnosed each year, and the incidence is increasing. 1,2 If left untreated, AAA will gradually expand until rupture; it is an event that carries a mortality rate of 90% and that is ranked as the 13th most common cause of death in the US. 3 Current AAA repair procedures are expensive and carry significant morbidity and mortality risks.Open repair of AAA is a major surgical procedure that requires patients to be hospitalized typically for 1 week and to recuperate at home for several more weeks. The mean postoperative mortality for elective repair is Ϸ5% and for emergency operations 47% (range 27% to 69%). 4 The major drawback of open repair is the compromised quality of life after surgery because of postoperative pain, the prolonged recovery period, and the high costs associated with both the surgery and the recovery.An alternative approach that avoids the extensive tissue dissection associated with open repair is the minimally invasive endovascular repair procedure. The potential advantages of endovascular AAA repair include reductions in mortality, morbidity, blood loss, hospital stay, intensive careOriginal

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Hypoxia Induces a Human Macrophage Cell Line to Release Tumor Necrosis Factor-α and Its Soluble Receptors in Vitro

Cited by 106 publications

References 0 publications

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

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

Biomechanical Determinants of Abdominal Aortic Aneurysm Rupture

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