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Targeting Tumor Cell-Derived CCL2 As a Strategy to Overcome Bevacizumab Resistance in ETV5+ Colorectal Cancer

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Targeting Tumor Cell-Derived CCL2 As a Strategy to Overcome Bevacizumab Resistance in ETV5+ Colorectal Cancer Feng et al. Cell Death and Disease (2020) 11:916 https://doi.org/10.1038/s41419-020-03111-7 Cell Death & Disease ARTICLE Open Access Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer Haoran Feng1,2,KunLiu1,3,XiaonanShen4,JuyongLiang1,2, Changgang Wang1,3,WeihuaQiu1,3,2,XiCheng 1,3,2 and Ren Zhao1,3,2 Abstract In our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/ Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti- angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5+ CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5+ CRC. Introduction diagnosis and treatment of CRC over the past few dec- Colorectal cancer (CRC) is one of the most common ades, the prognosis for this disease remains poor2. cancers worldwide, and its morbidity and mortality rank Angiogenesis is a hallmark process in the oncogenesis of – third among all cancers1. Despite advancements in the CRC3 5, and vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR-1/VEGFR-2) play dominant roles in the regulation of this complex process. Correspondence: Weihua Qiu ([email protected])or Attenuation of VEGF-VEGFR signaling can disrupt vas- Xi Cheng ([email protected]) or Ren Zhao ([email protected]) 1 cularization, and this has been considered as a promising Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai 6 Jiao Tong University, 200025 Shanghai, China therapeutic strategy for CRC . 2Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Bevacizumab, a clinically used anti-angiogenic drug, can Shanghai Jiao Tong University, 200025 Shanghai, China specifically target VEGFA to inhibit VEGF–VEGFR sig- Full list of author information is available at the end of the article 6 These authors contributed equally: Haoran Feng, Kun Liu, Xiaonan Shen naling . A combination of Bevacizumab and chemotherapy Edited by S. Tait © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Feng et al. Cell Death and Disease (2020) 11:916 Page 2 of 14 – is the first-line treatment for metastatic CRC6 8. However, fetal bovine serum (FBS) and antibiotics at 37 °C with 5% some CRC patients are resistant to Bevacizumab, and the CO2. Bevacizumab (a humanized monoclonal antibody overall response rate is limited9. Therefore, exploration of that specifically binds to all VEGFA isoforms with high mechanisms of resistance to anti-angiogenic treatments affinity) was purchased from MedChemExpress (Cat. No. will be beneficial for identification of potential targets, that HY-P9906), and it was added to the indicated cells at can be exploited to overcome Bevacizumab resistance concentrations of 250 μg/mL. Tumor-bearing nude mice in CRC. were treated with Bevacizumab at a dose of 2 mg/kg every The ETS transcription factor family contains 28 factors three days. Anti-CCL2 (clone 2H5) antibody, an IgG and can be divided into 12 subfamilies10. E26 monoclonal antibody that neutralizes the bioactivity of transformation-specific variant 5 (ETV5), a member of the human natural or recombinant CCL2, was purchased ETS family, has been reported to be involved in the pro- from BioLegend (Cat. No. 505913), and it was added to gression of hematologic cancer, endometrial cancer11,12, the indicated cells at a concentration of 10 ng/mL. ovarian cancer13,14, prostate cancer, and thyroid can- Tumor-bearing nude mice were treated with antiCCL2 at cer15,16. Previous studies have also revealed that members a dose of 2 mg/kg every 3 days. Recombinant human of the ETS family can trigger angiogenesis in multiple VEGF 165 protein was purchased from Abcam (ab83572) tumors13,17,18. Similarly, our previous study demonstrated systems. Recombinant human CCL2 protein was pur- that ETV5 facilitated CRC angiogenesis via the PDGF-BB/ chased from Invitrogen (RP-75662). A STAT3 inhibitor Src/STAT3/VEGFA signaling pathway19. Additionally, (C188-9) was purchased from Selleck (Cat. No. S8605), chemokine signaling events such as CCL2/CCR2 signaling and it was added to the indicated cells at a concentration and CXCL11/CXCR7 signaling have been reported to play of 5 μΜ. A STAT3 activator (Colivelin) was purchased critical roles in tumor angiogenesis20,21. Paracrine che- from Santa Cruz Biotechnology (Sc-361153), and it was mokine signaling also represents a critical drug resistance added to the indicated cells at a concentration of 0.5 μΜ. mechanism in cancers22. ETV5 has been reported to regulate the expression of chemokines such as Ccl7, Ccl9, RNA extraction and quantitative RT-PCR and Ccl12 in Sertoli cells in mice. However, the ability of Total RNA was extracted from HT29/Control and ETV5 to regulate antiVEGF therapy sensitivity and the HT29/shETV5 cells using TRIzol (Invitrogen, USA) underlying mechanisms require further clarification. according to the manufacturer’s instructions. The cDNA In the present study, we found that ETV5 could pro- was synthesized using a reverse transcription kit (Invi- mote Bevacizumab resistance via the secretion of CCL2 trogen, CA). Quantitative PCR was performed using and CCL2, could also induce angiogenesis by activating TaqMan® Gene Expression Assays (Thermo Fisher Sci- the PI3K/AKT and p38/MAPK signaling pathways in entific). The primers used were: CXCL11: (forward) 5′- human umbilical vein endothelial cells (HUVECs). A GACGCTGTCTTTGCATAGGC-3′, (reverse) 5′-GGATT combination of Bevacizumab and antiCCL2 treatment TAGGCATCGTTGTCCTTT-3′; CXCL5, (forward) 5′-G exerted a synergistically inhibitory effect on tumor growth AGAGCTGCGTTGCGTTTGTTTAC-3′, (reverse) 5′-CC and angiogenesis. Our results indicated that targeting GTTCTTCAGGGAGGCTACCACT-3′; CCL2, (forward) both CCL2 and VEGFA might provide a promising and 5′-CAGCCAGATGCAATCAATGCC-3′, (reverse) 5′-TG effective therapeutic approach for the treatment of GAATCCTGAACCCACTTCT-3′; CCL13, (forward) 5′-T + ETV5 CRC. GCTGACCCAAAGGAGAAG-3′, (reverse) 5′-GCCAGA GGAGAATGGAAAAG-3′. Materials and methods Patient specimens Western blot analysis The tumor tissues and adjacent normal tissues used in Cells were harvested and lysed in the RIPA buffer in the this study were collected from 75 CRC patients who presence of a Protease Inhibitor Cocktail (Pierce, USA) underwent surgery at Ruijin Hospital from 2010 to 2011. and a Protein Phosphatase Inhibitor Cocktail (New Cell & The information regarding these 75 patients has been Molecular Biotech, China). One hundred micrograms of described previously23. Informed consent was obtained protein were separated by 10% SDS-PAGE gel and from all patients. transferred onto PVDF membranes (Tanon, China). The membranes were blocked with 5% bovine serum albumin Cell lines and therapeutic antibodies (BSA) for 2 h and then incubated overnight with primary The human CRC cell lines RKO and HT29 were pur- antibodies at 4 °C. The blots were probed with anti- chased from American Type Culture
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