Imatinib prevents lung cancer metastasis by inhibiting M2-like polarization of macrophages

Yao, Zhangting; Zhang, Jieqiong; Zhang, Bo; Liang, Guikai; Chen, Xi; Yao, Fengqi; Xu, Xiaqing; Wu, Honghai; He, Qiaojun; Ding, Ling; Yang, Bo

doi:10.1016/j.phrs.2018.05.002

Cited by 85 publications

(43 citation statements)

References 52 publications

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“…Past research has reported that imatinib, a tyrosine kinase inhibitor, inhibited M2 macrophage polarization by blocking the phosphorylation of STAT6 and nuclear translocation, thus preventing lung cancer metastasis. 51 In the present study, myostatin reduced M2 macrophage polarization by inhibiting the JAK1/STAT6 pathway in macrophage cells differentiated from U937 monocytes. Macrophages that respond to environmental changes, including the presence of various cytokines and growth factors, have been implicated in M1/M2 polarization.…”

Section: Discussionsupporting

confidence: 45%

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Kim

Park

et al. 2020

Integr Cancer Ther

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Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

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Section: Discussionsupporting

confidence: 45%

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Kim

Park

et al. 2020

Integr Cancer Ther

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“…Zhang et al . found that imatinib also can inhibit macrophage M2‐like polarization both in vitro and in vivo, which contributes to its anti‐metastatic function in lung cancer . In addition, Shinya et al .…”

Section: Discussionmentioning

confidence: 97%

“…Zhang et al found that imatinib also can inhibit macrophage M2-like polarization both in vitro and in vivo, which contributes to its anti-metastatic function in lung cancer. 45 In addition, Shinya et al found that targeting platelet-derived growth factor signaling between cancer cells undergoing EMT and CAFs was a promising therapeutic target to inhibit cancer progression and improve patient prognosis. 46 Our results showed that CAFs and TAMs were significantly related to STAS and may be effective therapeutic targets in patients with STAS.…”

Section: Discussionmentioning

confidence: 99%

Relationship between stromal cells and tumor spread through air spaces in lung adenocarcinoma

et al. 2019

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BackgroundThe mechanism underlying tumor spread through air spaces (STAS) has not been well studied. We investigated the role of tumor stromal cells in the pathogenesis of STAS from a pathological perspective and evaluated the prognostic significance of tumor stromal cells and STAS in postoperative patients with lung adenocarcinoma.MethodsWe retrospectively analyzed 208 postsurgical patients with stage I–IIIA lung adenocarcinoma. The presence of STAS was evaluated by hematoxylin and eosin staining. The expression of α‐smooth muscle actin (SMA)‐positive cancer‐associated fibroblasts (CAFs) and CD204‐positive tumor‐associated macrophages (TAMs) was analyzed by immunohistochemistry. A logistic regression model was applied to confirm the predictive factors of STAS. Survival analysis was performed to evaluate the effect of α‐SMA‐positive CAFs, CD204‐positive TAMs, and STAS on prognosis. A nomogram was generated to evaluate the prognosis of postoperative patients.ResultsLogistic regression suggested that the expression of α‐SMA‐positive CAFs (P < 0.001) and the number of CD204‐positive TAMs (P < 0.001) were related to the presence of STAS. The multivariate Cox proportional hazards model suggested that STAS (P = 0.004), α‐SMA‐positive CAFs (P < 0.001), and CD204‐positive TAMs (P < 0.001) were independent risk factors for prognosis. Harrell's c‐indexes for overall and recurrence‐free survival prediction based on nomograms were 0.84 (95% confidence interval 0.76–0.91) and 0.82 (95% confidence interval 0.76–0.89), respectively.ConclusionsThe presence of STAS was associated with high expression of α‐SMA and CD204 in lung adenocarcinoma. Nomograms including STAS and stromal cells as variables are recommended as practical models to evaluate the prognosis of lung adenocarcinoma patients.

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“…What we do know, however, is that compounds like apigenin that attenuate the CCL2/CCR2 axis would slow the aggressive nature of TNBC and hormone positive breast cancers (27,28) by attenuating invasion, metastasis, EMT and the development of drug resistance (59)(60)(61)(62). 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).…”

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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Imatinib prevents lung cancer metastasis by inhibiting M2-like polarization of macrophages

Cited by 85 publications

References 52 publications

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Relationship between stromal cells and tumor spread through air spaces in lung adenocarcinoma

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

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