M2 macrophage-derived IL6 mediates resistance of breast cancer cells to hedgehog inhibition

Xu, Xiaojun; Ye, Jiabao; Huang, Cheng; Yan, Yuchun; Li, Jun

doi:10.1016/j.taap.2018.12.013

Cited by 39 publications

(25 citation statements)

References 41 publications

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“…The presence of TAMs is frequently associated with the failure of antitumoral treatments, such as chemo- and radiotherapy [ 48 , 49 ]. The resistance to these therapies can be mediated by the release of cytokines from TAMs; in particular, IL-6 has been demonstrated to induce tolerance in the treatment of breast [ 50 ], pancreatic [ 51 ], and colorectal cancer [ 52 , 53 ]. TAMs-derived cathepsins B and S were able to prevent paclitaxel-induced tumor cell death in mammary carcinoma [ 54 ].…”

Section: Role Of Macrophages In Tumorsmentioning

confidence: 99%

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Belgiovine

Digifico

Anfray

et al. 2020

JCM

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In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

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Section: Role Of Macrophages In Tumorsmentioning

confidence: 99%

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Belgiovine

Digifico

Anfray

et al. 2020

JCM

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“…Chidamide has a direct inhibitory effect on tumor cells. The Hedgehog signaling pathway is highly activated not only in solid tumors such as gastrointestinal tumors [35,36], lung cancer [37,38], and breast cancer [39,40] but also in leukemia [41,42], lymphoma [43,44], myeloma [45,46], and brain tumor [47,48]. According to a previous report, the inhibition of Hedgehog signaling also inhibited the growth of glioma cells [17].…”

Section: Discussionmentioning

confidence: 94%

Chidamide Inhibits Glioma Cells by Increasing Oxidative Stress via the miRNA-338-5p Regulation of Hedgehog Signaling

Zhou

Liang

Wang³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. Chidamide has a broad spectrum of antitumor activity but its function on glioma remains unknown. The increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS) may control glioma risk by promoting its apoptosis and necrosis. Hedgehog pathway is crucial to glioma cell proliferation and controls ROS production. We aimed to explore the effects of chidamide on the levels of miR-338-5p (glioma cell inhibitor), which may regulate Hedgehog signaling, resulting in the changes of RNS. Materials and Methods. Migration and invasion activities of glioma cells were measured by using the Transwell chamber assay. The expression levels of Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), Desert Hedgehog (Dhh), miR-338-5p, and related molecules were detected by using real-time PCR (RT-PCR) and or Western Blot in U87 and HS683 glioma cells. The effects of chidamide on these molecules were measured by using the miR-338-5p inhibitor or mimics in U87 and HS683 glioma cell lines. ROS and RNS were measured by DCF DA and DAF-FM DA fluorescence. Biomarkers of oxidative stress were measured by using a corresponding kit. Apoptosis and necrosis rates were measured by using flow cytometry. Results. Chidamide inhibited the growth rate, migration, and invasion of human malignant glioma cells and increased the level of miR-338-5p. miR-338-5p inhibitor or mimics increased or inhibited the growth rate of U87 and HS683 glioma cells. Chidamide inhibited the levels of Shh, Ihh, migration protein E-cadherin, and invading protein MMP-2. The increase in the level of Shh and Ihh led to the reduction in the ROS and RNS levels. miR-338-5p inhibitor or mimics also showed a promoting or inhibitory function for the levels of Shh and Ihh. Furthermore, miR-338-5p mimics and inhibitor inhibited or promoted the migration and invasion of the glioma cells (P<0.05). Evaluated levels of miR-338-5p increased oxidative stress level and apoptosis and necrosis rate by regulating the levels of biomarkers of oxidative stress (P<0.05). Conclusion. Chidamide inhibits glioma cells by increasing oxidative stress via the miRNA-338-5p regulation of Hedgehog signaling. Chidamide may be a potential drug in the prevention of glioma development.

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“…It is believed that use of drugs or natural compounds that can suppress oncogenic cytokines (e.g., CXCL1, CCL18, CCL8, CCL2, IL-4, IL-8, IL-6, etc.) (17,(48)(49)(50)(51)(52)(53) such as apigenin, EGCG or butein can curtail these biochemical driven events and provide therapeutic advantages against aggressive inflammatory breast cancers (54,55).…”

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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M2 macrophage-derived IL6 mediates resistance of breast cancer cells to hedgehog inhibition

Cited by 39 publications

References 41 publications

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Chidamide Inhibits Glioma Cells by Increasing Oxidative Stress via the miRNA-338-5p Regulation of Hedgehog Signaling

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

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