Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JWCCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355): 222-225

Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, New York, New York 10461, USA.
Nature (Impact Factor: 41.46). 06/2011; 475(7355):222-5. DOI: 10.1038/nature10138
Source: PubMed


Macrophages, which are abundant in the tumour microenvironment, enhance malignancy. At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells. Here we define the origin of these macrophages by showing that Gr1-positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumours in mice. This process also occurs for human inflammatory monocytes in pulmonary metastases of human breast cancer cells. The recruitment of these inflammatory monocytes, which express CCR2 (the receptor for chemokine CCL2), as well as the subsequent recruitment of metastasis-associated macrophages and their interaction with metastasizing tumour cells, is dependent on CCL2 synthesized by both the tumour and the stroma. Inhibition of CCL2-CCR2 signalling blocks the recruitment of inflammatory monocytes, inhibits metastasis in vivo and prolongs the survival of tumour-bearing mice. Depletion of tumour-cell-derived CCL2 also inhibits metastatic seeding. Inflammatory monocytes promote the extravasation of tumour cells in a process that requires monocyte-derived vascular endothelial growth factor. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer. Our data provide the mechanistic link between these two clinical associations and indicate new therapeutic targets for treating metastatic breast cancer.

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    • "Tumor-promoting inflammation + [251] + [252] + [253] [254] 0 + [255] + [252] [256] + [257] NA + [258] + [259] Evasion of anti-growth signaling + [260] 0 +/− [261] [262] 0 + [246] +/− [263] [264] [265] +/− [266] [267] + [268] + [269] [270] + [271] [272] Resistance to apoptosis 0 + [273] + [274] 0 + [275] + [276] + [277] + [278] + [279] + [280] Replicative immortality 0 0 + [281] [282] [283] 0 0 0 +/− [284] [285] 0 0 0 Deregulated metabolism + [286] + [287] [288] + [289] [290] [291] 0 + [292] + [293] [294] + [295] 0 + [296] + [297] Immune system evasion + [298] + [299] [300] + [301] [302] + [303] + [304] [305] + [306] + [307] + [308] [309] + [310] [311] + [312] [313] Invasion and metastasis + [287] + [15] [314] + [315] + [316] + [317] [318] [319] + [320] + [321] [322] [323] + [324] + [323] + [325] [326] Interactions in the tumor micro-environment + [260] + [327] + [328] + [329] + [330] + [327] + [331] + [332] + [333] [334] + [335] Our 10 identified targets of anti-angiogenesis therapy are presented in the top row. 10 other cancer " hallmarks " are listed in the column to the left. "
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    ABSTRACT: Deregulation of angiogenesis – the growth of new blood vessels from an existing vasculature – is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding “the most important target” may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the “Halifax Project” within the “Getting to know cancer” framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
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    • "These drugs were designed to sequester TNFa [25] or block TNFRs [26] [27] such as infliximab (Remicade), adalimumab (Humira), all of which downregulate TAMS [10] or other tumor infiltrating leucocytes in the tumor microenvironment [12]. Likewise, drugs or agents that can suppress CCL2–CCR2 signaling, can block monocyte recruitment and inhibit metastasis in vivo [28]. "
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    ABSTRACT: TNFα receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NFκB and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNFα induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNFα mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNFα initiates a rise in NFκB mRNA, which is not reversed by DADS. However, TNFα induced heightened expression of IKKε and phosphorylated ERK. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNFα was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNFα invoked CCL2 production primarily through reduction of IKKε and phosphorylated-ERK, thereby impairing MAPK/ERK, and NFκB pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNFα surface receptors. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Cytokine
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    • "In particular, hostderived CCL2 appears to be involved in the ability of prostate cancers to metastasise and successfully colonise distant sites (Loberg et al., 2007). Similarly, in a mouse model of breast cancer metastasis, monocytes recruited by CCL2 promoted metastatic seeding (Qian et al., 2011). The CCL2/CCR2 axis appears to have a major role in metastasis, including the early stages of progression, homing of metastatic cells and the final stages of the establishment of new, distant tumours. "

    Full-text · Dataset · May 2015
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