Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

Zhang, Weina; Chen, Lechuang; Ma, Kai; Zhao, Yahui; Liu, Xianghe; Wang, Yu; Liu, Mei; Liang, Shufang; Zhu, Hongxia; Xu, Nuo

doi:10.18632/oncotarget.12207

Cited by 47 publications

(41 citation statements)

References 62 publications

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“…The insulin/IGF/mTOR system has been shown to play a key role in CRC development due to its complex involvement in the cancer’s cellular metabolism, proliferation, and differentiation [ 19 , 20 ]. Here, we showed that the exogenous IGF increased the cancer stem cell properties.…”

Section: Resultsmentioning

confidence: 99%

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Huang

Tzeng

et al. 2018

Cancers

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Background: Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt cancer stemness signaling, may provide improved therapeutic efficacy. Methods: Mimicking the tumor microenvironment, we treated colon cancer cells with exogenous IGF1. The increased stemness of IGF1-cultured cells was determined by ALDH1 activity, side-population, tumor sphere formation assays. Destruxin B (DB) was evaluated for its anti-tumorigenic and stemness properties using cellular viability, colony-formation tests. The mimic and inhibitor of miR-214 were used to treat colon cancer cells to show its functional association to DB treatment. In vivo mouse models were used to evaluate DB’s ability to suppress colon tumor-initiating ability and growth inhibitory function. Results: IGF1-cultured colon cancer cells showed a significant increase in 5-FU resistance and enhanced stemness properties, including an increased percentage of ALDH1+, side-population cells, tumor sphere generation in vitro, and increased tumor initiation in vivo. In support, using public databases showed that increased IGF1 expression was significantly associated with a poorer prognosis in patients with colon cancer. DB, a hexadepsipeptide mycotoxin, was able to suppress colon tumorigenic phenotypes, including colony and sphere formation. The sequential treatment of DB, followed by 5-FU, synergistically inhibited the viability of colon cancer cells. In vivo studies showed that DB suppressed the tumorigenesis by 5-FU resistant colon cells, and in a greater degree when combined with 5-FU. Mechanistically, DB treatment was associated with decreased the mammalian target of rapamycin (mTOR) and β-catenin expression and an increased miR-214 level. Conclusion: We provided evidence of DB as a potential therapeutic agent for overcoming 5-FU resistance induced by IGF1, and suppressing cancer stem-like properties in association with miR-214 regulation. Further investigation is warranted for its translation to clinical application.

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Section: Resultsmentioning

confidence: 99%

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Huang

Tzeng

et al. 2018

Cancers

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“…VCR-sensitive/resistant human colorectal cancer cell line HCT-8, ADR-sensitive/resistant human breast adenocarcinoma cell line MCF-7 (both from Huiying BioTech), ADR-sensitive/resistant human chronic myelogenous leukemia cell line K562, human colorectal cancer cell line HCT-116 (both from KeyGen Biotech), and EGFR knockout HCT-116 cell line [28] [kindly provided by Dr. Ningzhi Xu at Chinese Academy of Medical Sciences] were maintained in RPMI-1640 medium (Sigma-Aldrich), supplemented with 10% FBS at 37°C in a humidified atmosphere with 5% CO 2. Different concentrations of IVM (Meilun BioTech), VCR (YuanchengGongchuang Tech), ADR (KeyGen Biotech) or mitomycin C (Welson Biotech) were used to treat the cells.…”

Section: Methodsmentioning

confidence: 99%

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Jiang

Wang

Sun

et al. 2019

J Exp Clin Cancer Res

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Background Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. Methods We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo . MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro . Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo . Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR. Results Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo . Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription. Conclusions These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1251-7) contains supplementary material, which is available to authorized users.

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“…Contradictory results were found for cetuximab interaction with macrophages. In AOM/DSS-induced colon cancer mouse model, cetuximab (anti-EGFR antibody) treatment inhibited total F4/80+/CD11b+ TAMs and M2 (F4/80+/CD206+) TAM accumulation (148). Down-regulation of gene expression of M2 polarization markers, ARG1, IL-10, and IL-4, was observed in tumor.…”

Section: Tams and Colorectal Cancer Treatmentmentioning

confidence: 99%

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

et al. 2020

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Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth

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Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

Cited by 47 publications

References 62 publications

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

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