Inflammation-Induced Chemokine Expression in Uveal Melanoma Cell Lines Stimulates Monocyte Chemotaxis

Jehs, Tina; Faber, Carsten; Juel, Helene Bæk; Bronkhorst, Inge H. G.; Jager, Martine J.; Nissen, Mogens Holst

doi:10.1167/iovs.14-14394

Cited by 29 publications

(25 citation statements)

References 43 publications

(56 reference statements)

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“…There is sufficient evidence to show that initial release of chemokines such as CCL2, GM-CSF [58] mark a potentially irreversible turning point for tumor infiltration, immunological evasion, and tumor immune support [29,59,60]. Natural plant-derived chemicals that can downregulate CCL2 or act as CCR2 receptor antagonists [61] such as luteolin [62] esculetin [63] or EGCG [64,65] typically result in impaired migration, less proclivity for metastasis [66] enabling greater efficacy of immunotherapies and chemotherapy drugs [65].…”

Section: Discussionmentioning

confidence: 99%

Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells

et al. 2017

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Mortality associated with breast cancer is attributable to aggressive metastasis, to which TNFα plays a central orchestrating role. TNFα acts on breast tumor TNF receptors evoking the release of chemotactic proteins (e.g. MCP-1/CCL2). These proteins direct inward infiltration/migration of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory cells (Tregs), T helper IL-17-producing cells (Th17s), metastasis-associated macrophages (MAMs) and cancer-associated fibroblasts (CAFs). Tumor embedded infiltrates collectively enable immune evasion, tumor growth, angiogenesis, and metastasis. In the current study, we investigate the potential of apigenin, a known anti-inflammatory constituent of parsley, to downregulate TNFα mediated release of chemokines from human triple-negative cells (MDA-MB-231 cells). The results show that TNFα stimulation leads to large rise of CCL2, granulocyte macrophage colony-stimulating factor (GMCSF), IL-1α and IL-6, all suppressed by apigenin. While many aspects of the transcriptome for NFkB signaling were evaluated, the data show signaling patterns associated with CCL2 were blocked by apigenin and mediated through suppressed mRNA and protein synthesis of IKBKe. Moreover, the data show that the attenuation of CCL2 by apigenin in the presence TNFα paralleled the suppression of phosphorylated extracellular signal-regulated kinase 1 (ERK 1/ 2). In summary, the obtained findings suggest that there exists a TNFα evoked release of CCL2 and other LSP recruiting cytokines from human breast cancer cells, which can be attenuated by apigenin.

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Section: Discussionmentioning

confidence: 99%

Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells

et al. 2017

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“…Among these T-cell classifier genes are obligate T-cell markers such as CD3 and CD8. Also lymphocyte-attracting chemokines like CCL5 are expressed by T cells and found to be present in the T-cell classifier (25). T-cell-correlated genes is actually not expressed by T cells (Fig.…”

Section: Integration Of T-cell Count With the Expression Profile Of Umentioning

confidence: 95%

Digital PCR-Based T-cell Quantification–Assisted Deconvolution of the Microenvironment Reveals that Activated Macrophages Drive Tumor Inflammation in Uveal Melanoma

Lange

Nell

Lalai

et al. 2018

Molecular Cancer Research

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: Uveal melanoma progression can be predicted by gene expression profiles enabling a clear subdivision between tumors with a good (class I) and a poor (class II) prognosis. Poor prognosis uveal melanoma can be subdivided by expression of immune-related genes; however, it is unclear whether this subclassification is justified; therefore, T cells in uveal melanoma specimens were quantified using a digital PCR approach. Absolute T-cell quantification revealed that T-cell influx is present in all uveal melanomas associated with a poor prognosis. However, this infiltrate is only accompanied by differential immune-related gene expression profiles in uveal melanoma with the highest T-cell infiltrate. Molecular deconvolution of the immune profile revealed that a large proportion of the T-cell-related gene expression signature does not originate from lymphocytes but is derived from other immune cells, especially macrophages. Expression of the lymphocyte-homing chemokine CXCL10 by activated macrophages correlated with T-cell infiltration and thereby explains the correlation of T-cell numbers and macrophages. This was validated by analysis of CXCL10 in uveal melanoma tissue with high T-cell counts. Surprisingly, CXCL10 or any of the other genes in the activated macrophage-cluster was correlated with reduced survival due to uveal melanoma metastasis. This effect was independent of the T-cell infiltrate, which reveals a role for activated macrophages in metastasis formation independent of their role in tumor inflammation. IMPLICATIONS: The current report uses an innovative digital PCR method to study the immune environment and demonstrates that absolute T-cell quantification and expression profiles can dissect disparate immune components.

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“…It should be considered that several of these cytokines may exert immune-suppressive and M2-polarizing effects. In addition, co-culture of UM cells with activated T cells upregulated the expression of chemokines and cytokines such as CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5, VEGF, and granulocyte–macrophage colony-stimulating factor (GM-CSF), which coincided with an enhanced ability to stimulate monocyte chemotaxis [269]. These data suggested that the cross-talk between tumor cells and T cells may result in the recruitment of pro-tumoral macrophages.…”

Section: Inflammationmentioning

confidence: 99%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

186

193

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Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.

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Inflammation-Induced Chemokine Expression in Uveal Melanoma Cell Lines Stimulates Monocyte Chemotaxis

Cited by 29 publications

References 43 publications

Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells

Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells

Digital PCR-Based T-cell Quantification–Assisted Deconvolution of the Microenvironment Reveals that Activated Macrophages Drive Tumor Inflammation in Uveal Melanoma

The biology of uveal melanoma

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