Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors

Negus, Rupert; Turner, Lynn; Burke, Frances; Balkwill, Frances R.

doi:10.1002/jlb.63.6.758

Cited by 87 publications

(62 citation statements)

References 41 publications

(49 reference statements)

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“…Hypoxia may have time-dependent effects on cell migration because we have found that hypoxia is a rapid and potent 'stop' signal, inhibiting migration after as little as 30 minutes of exposure (Grimshaw and Balkwill, 2001;Negus et al, 1998;Turner et al, 1999), and this may account for the accumulation of macrophages seen in areas of necrosis in solid ovarian tumours. The upregulation of chemokine receptor expression reported here peaked much later at 24 hours.…”

Section: Discussionmentioning

confidence: 87%

“…Thus, microenvironmental control of chemokine receptor expression will track an individual cell along an appropriate gradient. Hypoxia is an important factor in solid tumours; it can be an important prognostic indicator in gynaecological cancer (Hockel et al, 1998) and has been shown to regulate the expression of the chemokines CCL2 (Negus et al, 1998) and CXCL8 (IL-8) (Xu et al, 1999) and the chemokine receptor CXCR1 (Grutkoski et al, 1999). Moreover, it is being exploited as a therapeutic strategy in tumours (Griffiths et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages accumulate in regions of necrosis, which are usually hypoxic (Negus et al, 1998) and hypoxia can affect the migration of THP-1 cells and monocytes, but not lymphocytes (Turner et al, 1999). Thus THP-1 cells were cultured under hypoxic conditions for 24 h, and CCR1/2b mRNA expression was assayed by Northern blot analysis during this time ( Figure 5).…”

Section: The Regulation Of CC Chemokine Receptors By Hypoxiamentioning

confidence: 99%

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Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

Scotton¹,

Milliken

Wilson³

et al. 2001

Br J Cancer

100

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SummaryTo understand the chemokine network in a tissue, both chemokine and chemokine receptor expression should be studied. Human epithelial ovarian tumours express a range of chemokines but little is known about the expression and localisation of chemokine receptors. With the aim of understanding chemokine action in this cancer, we investigated receptors for CC-chemokines and their ligands in 25 biopsies of human ovarian cancer. CC-chemokine receptor mRNA was generally absent from solid tumours, the exception being CCR1 which was detected in samples from 75% of patients. CCR1 mRNA localised to macrophages and lymphocytes and there was a correlation between numbers of CD8 + and CCR1 expressing cells (P = 0.031). mRNA for 6 CC-chemokines was expressed in a majority of tumour samples. In a monocytic cell line in vitro, we found that CCR1 mRNA expression was increased 5-fold by hypoxia. We suggest that the CC-chemokine network in ovarian cancer is controlled at the level of CC-chemokine receptors and this may account for the phenotypes of infiltrating cells found in these tumours. The leukocyte infiltrate may contribute to tumour growth and spread by providing growth survival factors and matrix metalloproteases. Thus, CCR1 may be a novel therapeutic target in ovarian cancer.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: The Regulation Of CC Chemokine Receptors By Hypoxiamentioning

confidence: 99%

See 1 more Smart Citation

Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

Scotton¹,

Milliken

Wilson³

et al. 2001

Br J Cancer

100

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“…42 The formation of MCP-1 is reduced by hypoxia in ovarian cancer cells, 43 macrophages 44,45 and human synovial fibroblasts. 46 However, hypoxia upregulated MCP-1 formation in cultured neonatal mouse cardiac myocytes and MCP-1 decreased hypoxia-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

Regulation of monocyte chemoattractant protein 1 (MCP-1) release by explants of human visceral adipose tissue

Fain

Madan

2005

Int J Obes

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BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine involved in monocyte recruitment during inflammation whose plasma level is elevated in obesity. OBJECTIVE: The present studies were designed to examine the release of MCP-1 in primary culture by explants of visceral adipose tissue from morbidly obese women. RESULTS: Most of the MCP-1 released by adipose tissue explants was derived from the nonfat cells in adipose tissue. The release of MCP-1 by adipose tissue explants was upregulated almost five-fold between 3 and 48 h of incubation. Approximately half of this upregulation was due to the release of endogenous tumor necrosis factor a (TNFa) and IL-1b based on the ability of a combination of a soluble TNFa receptor (etanercept) and a blocking antibody against IL-1b to reduce MCP-1 release. The release of MCP-1 over 48 h was unaffected by insulin or dexamethasone but significantly reduced by the combination of both agents. MCP-1 release was reduced by 60% in the presence of an inhibitor of the nuclear factor kB (NF-kB) pathway. There were no significant effects of inhibitors of p44/42 mitogen-activated protein kinase (ERK), Jun N-terminal kinase (JNK) and p38 mitogenactivated protein kinase (p38 MAPK) pathways on MCP-1 release. However, inhibition of MCP-1 release in the presence of inhibitors of both the p38 MAPK and NF-kB pathways was greater than that seen with only the NF-kB inhibitor. DISCUSSION: The present data shows that MCP-1 formation is upregulated over a 48-h incubation of primary explants of visceral adipose tissue. Half of this upregulation is dependent upon endogenous TNFa and Il-1b and involves the p38 MAPK and NF-kB pathways.

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“…In addition, hypoxia downregulates the expression of CCL2 by TNF-a-stimulated human ovarian carcinoma cell lines, and in interferon-g-stimulated murine macrophages and human monocytic cells lines by inhibiting gene transcription and reducing mRNA stability. 38,39 Therefore, TAMs may also be entrapped in hypoxic areas because of downregulation of chemoattractant receptors, chemoattractants or both.…”

Section: Monocyte Recruitment Into Tumorsmentioning

confidence: 99%

Macrophage migration and gene expression in response to tumor hypoxia

Murdoch

Lewis

2005

Intl Journal of Cancer

182

143

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Monocytes are recruited into tumors from the circulation along defined chemotactic gradients and they then differentiate into tumor-associated macrophages (TAMs). Recent evidence has shown that large numbers of TAMs are attracted to and retained in avascular and necrotic areas, where they are exposed to tumor hypoxia. At these sites, TAMs appear to undergo marked phenotypic changes with activation of hypoxia-inducible transcription factors, dramatically upregulating the expression of a large number of genes encoding mitogenic, proangiogenic and prometastatic cytokines and enzymes. As a consequence, high TAMs density has been correlated with increased tumor growth and angiogenesis in various tumor types. Since hypoxia is a hallmark feature of malignant tumors and hypoxic tumor cells are relatively resistant to radio-and chemotherapy, these areas have become a target for novel forms of anticancer therapy. These include hypoxiatargeted gene therapy in which macrophages are armed with therapeutic genes that are activated by hypoxia-responsive promoter elements. This restricts transgene expression to hypoxic areas, where the gene product is then released and acts on neighboring hypoxic tumor cells or proliferating blood vessels. In this way, the responses of macrophages to tumor hypoxia can be exploited to deliver potent antitumor agents to these poorly vascularized, and thus largely inaccessible, areas of tumors. ' 2005 Wiley-Liss, Inc.

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Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors

Cited by 87 publications

References 41 publications

Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

Regulation of monocyte chemoattractant protein 1 (MCP-1) release by explants of human visceral adipose tissue

Macrophage migration and gene expression in response to tumor hypoxia

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