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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Hepatocellular Carcinoma | Research

Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1

Authors: Jiali Zhao, En Lin, Zirui Bai, Yingbin Jia, Bo Wang, Yihua Dai, Wenfeng Zhuo, Guifang Zeng, Xialei Liu, Chaonong Cai, Peiping Li, Baojia Zou, Jian Li

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

Due to the high drug resistance of hepatocellular carcinoma (HCC), sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs) play an important regulatory role in the induction of chemoresistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to sorafenib in HCC.

Methods

Immunohistochemistry and immunofluorescence showed that the activation of CAFs was enhanced in HCC tissues. CAFs and paracancerous normal fibroblasts (NFs) were isolated from the cancer and paracancerous tissues of HCC, respectively. Cell cloning assays, ELISAs, and flow cytometry were used to detect whether CAFs induced sorafenib resistance in HCC cells via CXCL12. Western blotting and qPCR showed that CXCL12 induces sorafenib resistance in HCC cells by upregulating FOLR1. We investigated whether FOLR1 was the target molecule of CAFs regulating sorafenib resistance in HCC cells by querying gene expression data for human HCC specimens from the GEO database.

Results

High levels of activated CAFs were present in HCC tissues but not in paracancerous tissues. CAFs decreased the sensitivity of HCC cells to sorafenib. We found that CAFs secrete CXCL12, which upregulates FOLR1 in HCC cells to induce sorafenib resistance.

Conclusions

CAFs induce sorafenib resistance in HCC cells through CXCL12/FOLR1.
Appendix
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Literature
1.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.CrossRefPubMed
2.
Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87.CrossRefPubMedPubMedCentral
3.
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.CrossRefPubMed
4.
Eun JW, Yoon JH, Ahn HR, Kim S, Kim YB, Lim SB, et al. Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib. Cancer Commun (Lond). 2023;43:455–79.CrossRefPubMed
5.
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.CrossRefPubMed
6.
Zhu GQ, Tang Z, Huang R, Qu WF, Fang Y, Yang R, et al. CD36(+) cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor. Cell Discov. 2023;9:25.CrossRefPubMedPubMedCentral
7.
Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res. 2012;10:1403–18.CrossRefPubMedPubMedCentral
8.
Ying F, Chan MSM, Lee TKW. Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma. Cell Mol Gastroenterol Hepatol. 2023;15:985–99.CrossRefPubMedPubMedCentral
9.
Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019;18:70.CrossRefPubMedPubMedCentral
10.
Liu J, Li P, Wang L, Li M, Ge Z, Noordam L, et al. Cancer-associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance. Cell Mol Gastroenterol Hepatol. 2021;11:407–31.CrossRefPubMed
11.
Song M, He J, Pan QZ, Yang J, Zhao J, Zhang YJ, et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology. 2021;73:1717–35.CrossRefPubMed
12.
Zaki MYW, Alhasan SF, Shukla R, McCain M, Laszczewska M, Geh D, et al. Sulfatase-2 from cancer associated fibroblasts: an environmental target for hepatocellular carcinoma? Liver Cancer. 2022;11:540–57.CrossRefPubMedPubMedCentral
13.
Geng X, Chen H, Zhao L, Hu J, Yang W, Li G, et al. Cancer-Associated Fibroblast (CAF) heterogeneity and targeting therapy of CAFs in pancreatic cancer. Front Cell Dev Biol. 2021;9:655152.CrossRefPubMedPubMedCentral
14.
Yoshida GJ. Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res. 2020;39:112.CrossRefPubMedPubMedCentral
15.
Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010;16:2927–31.CrossRefPubMed
16.
Wei L, Ye H, Li G, Lu Y, Zhou Q, Zheng S, et al. Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer. Cell Death Dis. 2018;9:1065.CrossRefPubMedPubMedCentral
17.
Li J, Shu X, Xu J, Su SM, Chan UI, Mo L, et al. S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy. Nat Commun. 2022;13:1481.CrossRefPubMedPubMedCentral
18.
19.
Chu H, Wu C, Zhao Q, Sun R, Yang K, Zhao B, et al. Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells. Carcinogenesis. 2021;42:753–61.CrossRefPubMed
20.
Ladd AD, Duarte S, Sahin I, Zarrinpar A. Mechanisms of drug resistance in HCC. Hepatology. 2023.
21.
22.
Khare T, Bissonnette M, Khare S. CXCL12-CXCR4/CXCR7 Axis in Colorectal cancer: therapeutic target in preclinical and clinical studies. Int J Mol Sci. 2021;22:7371.CrossRefPubMedPubMedCentral
23.
Zheng X, Rui S, Wang XF, Zou XH, Gong YP, Li ZH. circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling. J Exp Clin Cancer Res. 2021;40:157.CrossRefPubMedPubMedCentral
24.
Wei L, Lee D, Law CT, Zhang MS, Shen J, Chin DW, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019;10:4681.CrossRefPubMedPubMedCentral
25.
Sueangoen N, Tantiwetrueangdet A, Panvichian R. HCC-derived EGFR mutants are functioning, EGF-dependent, and erlotinib-resistant. Cell Biosci. 2020;10:41.CrossRefPubMedPubMedCentral
26.
Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013;210:2851–72.CrossRefPubMedPubMedCentral
27.
McAndrews KM, Chen Y, Darpolor JK, Zheng X, Yang S, Carstens JL, et al. Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL6-Mediated therapy resistance in pancreatic cancer. Cancer Discov. 2022;12:1580–97.CrossRefPubMedPubMedCentral
28.
Yi Y, Zeng S, Wang Z, Wu M, Ma Y, Ye X, et al. Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling. Biochim Biophys Acta Mol Basis Dis. 2018;1864:793–803.CrossRefPubMed
29.
Yang J, Zhang L, Jiang Z, Ge C, Zhao F, Jiang J, et al. TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression. Theranostics. 2019;9:5810–27.CrossRefPubMedPubMedCentral
30.
Vila-Coro AJ, Rodríguez-Frade JM, Martín De Ana A, Moreno-Ortíz MC, Martínez AC, Mellado M. The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. Faseb j. 1999;13:1699–710.CrossRefPubMed
31.
Gao D, Tang T, Zhu J, Tang Y, Sun H, Li S. CXCL12 has therapeutic value in facial nerve injury and promotes Schwann cells autophagy and migration via PI3K-AKT-mTOR signal pathway. Int J Biol Macromol. 2019;124:460–8.CrossRefPubMed
32.
Köbel M, Madore J, Ramus SJ, Clarke BA, Pharoah PD, Deen S, et al. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An ovarian tumour tissue analysis consortium study. Br J Cancer. 2014;111:2297–307.CrossRefPubMedPubMedCentral
33.
Liang Z, Dong J, Yang N, Li SD, Yang ZY, Huang R, et al. Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer. Int J Biol Sci. 2021;17:4365–76.CrossRefPubMedPubMedCentral
34.
Cheung A, Opzoomer J, Ilieva KM, Gazinska P, Hoffmann RM, Mirza H, et al. Anti-folate receptor alpha-directed antibody therapies restrict the growth of triple-negative breast cancer. Clin Cancer Res. 2018;24:5098–111.CrossRefPubMedPubMedCentral
35.
Jia L, Li J, Li P, Liu D, Li J, Shen J, et al. Site-specific glycoproteomic analysis revealing increased core-fucosylation on FOLR1 enhances folate uptake capacity of HCC cells to promote EMT. Theranostics. 2021;11:6905–21.CrossRefPubMedPubMedCentral
36.
Li W, Tan G, Ma Y, Li H, He G. Inhibition of α folate receptor resulting in a reversal of taxol resistance in nasopharyngeal carcinoma. Otolaryngol Head Neck Surg. 2012;146:250–8.CrossRefPubMed
37.
Sakai H, Kawakami H, Teramura T, Onodera Y, Somers E, Furuuchi K, et al. Folate receptor α increases chemotherapy resistance through stabilizing MDM2 in cooperation with PHB2 that is overcome by MORAb-202 in gastric cancer. Clin Transl Med. 2021;11:e454.CrossRefPubMedPubMedCentral
38.
39.
Lin YN, Schmidt MO, Sharif GM, Vietsch EE, Kiliti AJ, Barefoot ME, et al. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity. Oncoimmunology. 2022;11:2027136.CrossRefPubMedPubMedCentral
Metadata
Title
Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1
Authors
Jiali Zhao
En Lin
Zirui Bai
Yingbin Jia
Bo Wang
Yihua Dai
Wenfeng Zhuo
Guifang Zeng
Xialei Liu
Chaonong Cai
Peiping Li
Baojia Zou
Jian Li
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11613-8

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