Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer

Zhou, Lisha; Jiang, Yanyu; Liu, Xiaojun; Li, Lihui; Yang, Xuguang; Dong, Changsheng; Liu, Xiaoli; Lin, Yu‐Li; Yan, Li; Yu, Jinha; He, Rui; Huang, Shenglin; Liu, Guangwei; Zhang, Yanmei; Jeong, Lak Shin; Hoffman, Robert M.; Jia, Lijun

doi:10.1038/s41388-019-0840-4

Cited by 69 publications

(57 citation statements)

References 46 publications

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“…Experimental lung tumor models, in vitro TAMs-tumor cells, coculture models, and human lung cancer biopsies demonstrated that CCL2/CCR2 signaling is one of the central signaling pathways involved in lung cancer growth and metastasis (20,133,134). In the in vivo metastasis lung tumor model and human lung cancer biopsies, infiltration of TAMs was found to be increased by NFKB1-CCL2 signaling via an elevation in neddylation pathway (135). In the flank and orthotopic lung tumor model, blockade of CCL2 reduces lung tumor growth not only by reprogramming TAMs to M1-like phenotype but also by activating CD8 + T cells (136).…”

Section: Chemokines Ccl2mentioning

confidence: 94%

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

et al. 2020

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Regardless of the promising results of certain immune checkpoint blockers, current immunotherapeutics have met a bottleneck concerning response rate, toxicity, and resistance in lung cancer patients. Accumulating evidence forecasts that the crosstalk between tumor and immune cells takes center stage in cancer development by modulating tumor malignancy, immune cell infiltration, and immune evasion in the tumor microenvironment (TME). Cytokines and chemokines secreted by this crosstalk play a major role in cancer development, progression, and therapeutic management. An increased infiltration of Tumor-associated macrophages (TAMs) was observed in most of the human cancers, including lung cancer. In this review, we emphasize the role of cytokines and chemokines in TAM-tumor cell crosstalk in the lung TME. Given the role of cytokines and chemokines in immunomodulation, we propose that TAM-derived cytokines and chemokines govern the cancer-promoting immune responses in the TME and offer a new immunotherapeutic option for lung cancer treatment.

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Section: Chemokines Ccl2mentioning

confidence: 94%

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

et al. 2020

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“…CCL2 inhibitors have been tested in various tumors, tumor cells and xenograft models with CCL2 lowering effects brought about by losartan (63) anlotinib (64) imatinib (65) zoledronic acid (66) oroxylin A (67) aspirin (68) natural compounds in coffee (kahweol acetate, cafestol) (69) or conophylline from Ervatamia microphylla (70) which can reduce invasive inflammatory tumor infiltration. The mechanism of action for CCL2 reducing agents may center around the modification of upstream or downstream targets such as PLEK2/EGRF (71) HER2-EGF/HRG, PI3K-NF-kB axis (27) SRC, PKC (58) the neddylation pathway (72) or the well-known mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt cell signaling pathways (73). While others have reported apigenin to have an effect on NF-kappaB/Snail pathway (74), pSTAT3, pERK or PI3K/pAkt (75), our previous studies suggest the effects of TNFα in TNBC cell lines, as it relates to CCL2 are driven through the higher expression of IKBK epsilon (31).…”

Section: Discussionmentioning

confidence: 99%

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

et al. 2020

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The lack of hormone receptors in triple negative breast cancer (TNBC) is associated with the inefficacy of anti-estrogen chemotherapies, leaving fewer options for patient treatment and higher mortality rates. Additionally, as with numerous types of inflammatory breast cancer, infiltration of tumor associated macrophages and other leukocyte sub-populations within the tumor inevitably lead to aggressive, chemo-resistant, metastatic and invasive types of cancer which escape immune surveillance. These processes are orchestrated by the release of potent cytokines, including TNFα, IL-6 and CCL2 from the stroma, tumor and immune cells within the tumor microenvironment. The present study evaluated apigenin modulating effects on the pro-inflammatory activating action of TNFα in TNBC MDA-MB-468 cells, derived from an African American woman. Initially, cell viability was determined to establish an optimal sub-lethal dose of TNFα and apigenin in MDA-MB-468 cells. Subsequently, various treatments effects were evaluated using whole transcriptomic analysis of mRNA and long intergenic non-coding RNA with Affymetrix HuGene-2.1-st human microarrays. Gene level differential expression analysis was conducted on 48,226 genes where TNFα caused significant upregulation of 53 transcripts and downregulation of 11 transcripts. The largest upward differential shift was for CCL2 [+61.86 fold change (FC); false discovery rate (FDR), P<0.0001]; which was down regulated by apigenin (to +10.71 FC vs. Control; FDR P-value <0.001), equivalent to an 83% reduction. Several TNFα deferentially upregulated transcripts were reduced by apigenin, including CXCL10, C3, PGLYRP4, IL22RA2, KMO, IL7R, ROS1, CFB, IKBKe, SLITRK6 (a checkpoint target) and MMP13. Confirmation of CCL2 experimentally induced transcript alterations was corroborated at the protein level by ELISA assays. The high level of CCL2 transcript in the cell line was comparable to that in our previous studies in MDA-MB-231 cells. The differential effects of TNFα were corroborated by ELISA, where the data revealed a >10-fold higher releasing rate of CCL2 in MDA-MB-468 cells compared with in MDA-MB-231 cells, both of which were attenuated by apigenin. The data obtained in the present study demonstrated a high level of CCL2 in MDA-MB-468 cells and a possible therapeutic role for apigenin in downregulating TNFα-mediated processes in these TNBC cells.

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“…CCL2 binds the chemokine receptor CCR2 expressed on circulating monocytes and promotes their chemoattraction. Increasing data indicate that the CCL2-CCR2 axis is important for mobilizing pro-tumoural monocytes and macrophages in different cancer types, especially in the context of metastasis [21,[38][39][40][41][42][43]. In mouse mammary tumour models, antibodies against CCL2 suppress recruitment of CCR2 + monocytes to the pre-metastatic lung and inhibit metastatic spreading [21,44].…”

Section: Macrophage Recruitment To Tumoursmentioning

confidence: 99%

Biology and therapeutic targeting of tumour‐associated macrophages

Beltraminelli

Palma

2020

The Journal of Pathology

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Macrophages sustain tumour progression by facilitating angiogenesis, promoting immunosuppression, and enhancing cancer cell invasion and metastasis. They also modulate tumour response to anti-cancer therapy in pre-clinical models. This knowledge has motivated the development of agents that target tumour-associated macrophages (TAMs), some of which have been investigated in early clinical trials. Here, we provide a comprehensive overview of the biology and therapeutic targeting of TAMs, highlighting opportunities, setbacks, and new challenges that have emerged after a decade of intense translational and clinical research into these multifaceted immune cells.

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Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer

Cited by 69 publications

References 46 publications

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

Biology and therapeutic targeting of tumour‐associated macrophages

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