A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in Bone

Li, Xin; Loberg, Robert D.; Liao, Jinhui; Cheng, Ying; Snyder, Linda A.; Pienta, Kenneth J.; McCauley, Laurie K.

doi:10.1158/0008-5472.can-08-2164

Cited by 148 publications

(120 citation statements)

References 28 publications

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“…Interestingly, when efferocytosis was decreased via incubation at 4°C or neutralizing MFG-E8 antibody treatment, M2 polarization was also reduced, suggesting that efferocytosis is important for macrophage polarization into tumor-promoting M2 cells. When macrophages were challenged with efferocytosis, increased secretion of M2-related cytokines such as IL-6 and CCL-2 (MCP-1) was observed (3,(45)(46)(47). Indeed, the observation that IL-6 is increased dramatically (Ͼ 20-fold) with efferocytosis further supports and explains our findings of STAT3 activation in this pathway.…”

Section: Discussionsupporting

confidence: 82%

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Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

Soki

Koh

Jones

et al. 2014

Journal of Biological Chemistry

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151

160

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Background:The growing body of data on tumor-associated macrophages largely neglects phagocytosis of apoptotic cells. Results: MFG-E8, induced during efferocytosis, contributes to macrophage polarization with STAT3/SOCS3 pathway involvement. Conclusion: Efferocytosis induces macrophage polarization into tumor-associated macrophages mediated by MFG-E8. Significance: A novel tumor-promoting mechanism for macrophage polarization through efferocytosis and MFG-E8 and its corresponding signaling pathway were identified.

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Section: Discussionsupporting

confidence: 82%

“…Tumor-associated macrophages (TAMs) 3 have been investigated in the context of cancer (3,4), but their role in bone metastasis remains elusive (3,5,6). Macrophages are activated differentially according to the stimuli provided.…”

mentioning

confidence: 99%

Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

Soki

Koh

Jones

et al. 2014

Journal of Biological Chemistry

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151

160

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“…Among these mRNAs are the chemokines Ccl2 and Ccl7 that are implicated in tumor progression. Targeting CCL2 with a neutralizing antibody caused prostate tumor regression (24)(25)(26). The list also includes mRNAs encoding the matrix metalloproteinases (MMPs) MMP3 and MMP9, which are overexpressed in PC3 prostate cancer cells (27), and promote invasion and metastasis by rearrangement of the ECM (28,29).…”

Section: Resultsmentioning

confidence: 99%

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Furic

Liang

Larsson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

460

566

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Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5′ cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs. PTEN | translational controlA berrations in the control of mRNA translation initiation have been documented in many tumor types (1-4). Translation initiation is controlled in part by eIF4E, the mRNA 5′ cap-binding protein. eIF4E is a proto-oncogene, inasmuch as its overexpression in immortalized rodent fibroblasts or human epithelial cells causes transformation (5, 6), and in mouse models its overexpression engenders tumor formation (7,8). eIF4E is phosphorylated by the MNK1/2 serine/threonine kinases, which are activated in response to mitogenic and stress signaling downstream of ERK1/2 and p38 MAP kinase, respectively (9, 10). eIF4E phosphorylation at serine 209 by MNK1/2 promotes its transformation activity (11,12). To study the role of eIF4E phosphorylation in tumorigenesis in the whole organism, we generated a knock-in (KI) mouse in which eIF4E serine 209 was mutated to alanine. Here, we show that mouse embryonic fibroblasts (MEFs) isolated from eIF4E S209A/S209A embryos display a marked resistance to oncogene-induced transformation. Furthermore, the mutant mice are viable, but are resistant to development of Pten loss-induced prostate cancer, and this resistance is associated with a decrease in MMP3, CCL2, VEGFC, and BIRC2 proteins. Moreover, eIF4E is highly phosphorylated in hormone-refractory prostate cancer, which correlates with poor clinical outcome. These results demonstrate the importance of eIF4E phosphorylation in tumorigenesis and validate the eIF4E phosphorylation pathway as a potential therapeutic target for cancer. ResultsSer209 Is the Only Phosphorylation Site in eIF4E. To address the role of eIF4E phosphorylation in tumorigenesis, a knock-in (KI) mouse in which serine 209 was replaced by an alanine residue was generated. The strategy and targeting vector construction for the generation, selection, and genotyping of the S209A mice is shown in Fig. S1. The eIF4E S...

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“…23,34 Recruitment and differentiation of myeloid cells in tumors are complex processes regulated by multiple pathways, which may lead to differential responses to CSF-1R inhibition. 10,[41][42][43] Several studies have shown that CSF-1/CSF-1R signaling blockade using antibodies or small molecule inhibitors directed against CSF-1R promotes tumor regression, yet the exact mechanism by which this happens is unknown. While some studies have shown that CSF-1R inhibition reduces the number of TAM/myeloid cells, 16,18,23 others have shown that CSF-1R blockade favorably reprograms TAM/myeloid responses without reducing their numbers.…”

Section: Discussionmentioning

confidence: 99%

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

et al. 2016

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Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy.Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection.

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A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in Bone

Cited by 148 publications

References 28 publications

Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

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