Targeting the CCL2-CCR2 signaling axis in cancer metastasis

Lim, Su Yin; Yuzhalin, Arseniy E.; Gordon-Weeks, Alex; Muschel, Ruth J.

doi:10.18632/oncotarget.7376

Cited by 402 publications

(356 citation statements)

References 112 publications

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“…However, in contrast to the promising preclinical studies, neutralizing monoclonal antibodies against CCL2 administered to patients with metastatic, solid tumors did not produce favorable outcomes. Meta-analysis of the data from these clinical trials indicated that initial CCL2 inhibition may have unexpectedly caused subsequent increases in circulating CCL2 levels, possibly due to a compensatory feedback loop (45). Lack of therapeutic benefits from inhibiting this axis indicates that CCL2-CCR2 interaction represents a complex signaling network that is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma

et al. 2017

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In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we employed two genetically engineered mouse models where oncogenic drivers and fluorescent reporters were expressed coordinately under the control of the monocyte/microglia-selective Cx3cr1 or Ccr2 promoters, respectively. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the glioblastoma, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2− microglia-like cells. Infiltrating macrophages/monocytes constituted ~85% of the total TAM population, with resident microglia accounting for the ~15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via Ccl2 genetic ablation prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm.

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Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma

et al. 2017

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“…4,5 In tumor cells, the binding of the MCP-1 protein to its receptor, C–C chemokine receptor type 2 (CCR2), promotes monocyte migration from the bone marrow to cancer metastatic sites. 6–8 MCP-1-CCR2 signaling also contributes to the upregulation of tumor-promoting genes and the recruitment of tumor-associated monocytes and macrophages, which further enhances cancer metastasis. 6,9 It was reported that elevated MCP-1 and CCR2 expressions in patients with prostate, breast, colorectal, pancreatic, and ovarian cancers correlate with disease progression.…”

Section: Introductionmentioning

confidence: 99%

“…6–8 MCP-1-CCR2 signaling also contributes to the upregulation of tumor-promoting genes and the recruitment of tumor-associated monocytes and macrophages, which further enhances cancer metastasis. 6,9 It was reported that elevated MCP-1 and CCR2 expressions in patients with prostate, breast, colorectal, pancreatic, and ovarian cancers correlate with disease progression. 10–15 Therefore, there is a clear clinical relevance and need to develop an effective therapeutic that inhibits the interaction between MCP-1 and CCR2 in order to control cancer development and progression.…”

Section: Introductionmentioning

confidence: 99%

Protein Mimetic and Anticancer Properties of Monocyte-Targeting Peptide Amphiphile Micelles

Poon

Chowdhuri

Kuo³

et al. 2017

ACS Biomater. Sci. Eng.

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Monocyte chemoattractant protein-1 (MCP-1) stimulates the migration of monocytes to inflammatory sites, leading to the progression of many diseases. Recently, we described a monocyte-targeting peptide amphiphile micelle (MCP-1 PAM) incorporated with the chemokine receptor CCR2 binding motif of MCP-1, which has a high affinity for monocytes in atherosclerotic plaques. We further report here the biomimetic components of MCP-1 PAMs and the influence of the nanoparticle upon binding to monocytes. We report that MCP-1 PAMs have enhanced secondary structure compared to the MCP-1 peptide. As a result, MCP-1 PAMs displayed improved binding and chemoattractant properties to monocytes, which upregulated the inflammatory signaling pathways responsible for monocyte migration. Interestingly, when MCP-1 PAMs were incubated in the presence of prostate cancer cells in vitro, the particle displayed anticancer efficacy by reducing CCR2 expression. Given that monocytes play an important role in tumor cell migration and invasion, our results demonstrate that PAMs can improve the native biofunctional properties of the peptide and may be used as an effective inhibitor to prevent chemokine–receptor interactions that promote disease progression.

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“…CCL2 is a chemokine which orchestrates immune cell recruitment via its preferential binding to the CCR2 receptor 11. It is induced during inflammatory responses when immune cells are required for tissue repair 11.…”

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confidence: 99%

“…It is induced during inflammatory responses when immune cells are required for tissue repair 11. Both human and murine studies have shown that CCL2 contributes to fibrosis through a variety of mechanisms involving inflammation, angiogenesis and myofibroblast accumulation 12.…”

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confidence: 99%