炎症癌相关成纤维细胞介导结直肠癌细胞耐药的机制研究

蔡家洛; 朱锐秋; 李森; 曹亦军; 黄坊

doi:10.19401/j.cnki.1007-3639.2023.12.001

您当前的位置：

首页 >

文章列表页 >

炎症癌相关成纤维细胞介导结直肠癌细胞耐药的机制研究

论著 | 更新时间：2025-12-31

- 炎症癌相关成纤维细胞介导结直肠癌细胞耐药的机制研究
- Mechanism of inflammatory cancer-associated fibroblast-mediated drug resistance in colorectal cancer cells
- 中国癌症杂志 2023年33卷第12期页码：1065-1072
- 作者机构：
  
  1. 上海中医药大学附属普陀医院普外科，上海 200062
  2. 华东理工大学药学院，上海 200237
  3. 安徽医科大学上海普陀中心临床学院，上海 200062
  4. 上海中医药大学附属普陀医院病理科，上海 200062
- 作者简介：
  
  [ "蔡家洛（ORCID: 0009-0001-8102-026X），硕士。" ]
  黄坊（ORCID: 0009-0005-2372-4639），硕士，主治医师。
- 基金信息：
  
  上海市普陀区中心医院雏鹰计划(2022-RCCY-08)
- DOI：10.19401/j.cnki.1007-3639.2023.12.001
  中图分类号： R735.3+5；R735.3+7
- 收稿：2022-11-17，
  
  修回：2023-10-20，
  
  纸质出版：2023-12-30
- 稿件说明：
移动端阅览
蔡家洛, 朱锐秋, 李森, 等. 炎症癌相关成纤维细胞介导结直肠癌细胞耐药的机制研究[J]. 中国癌症杂志, 2023,33(12):1065-1072.

Jialuo CAI, Ruiqiu ZHU, Sen LI, et al. Mechanism of inflammatory cancer-associated fibroblast-mediated drug resistance in colorectal cancer cells[J]. China Oncology, 2023, 33(12): 1065-1072.
蔡家洛, 朱锐秋, 李森, 等. 炎症癌相关成纤维细胞介导结直肠癌细胞耐药的机制研究[J]. 中国癌症杂志, 2023,33(12):1065-1072. DOI： 10.19401/j.cnki.1007-3639.2023.12.001.

Jialuo CAI, Ruiqiu ZHU, Sen LI, et al. Mechanism of inflammatory cancer-associated fibroblast-mediated drug resistance in colorectal cancer cells[J]. China Oncology, 2023, 33(12): 1065-1072. DOI： 10.19401/j.cnki.1007-3639.2023.12.001.

摘要

背景与目的：

结直肠癌（colorectal cancer，CRC）是常见的消化系统恶性肿瘤之一，但是其产生肿瘤耐药的机制仍不清楚。肿瘤微环境（tumor microenvironment，TME），尤其是其中的癌相关成纤维细胞（cancer-associated fibroblast，CAF），在肿瘤的发生、发展及耐药过程中都发挥重要作用。本研究旨在探讨炎症CAF（inflammatory CAF，iCAF）对CRC细胞耐药的影响及可能的分子机制。

方法：

提取来自上海中医药大学附属普陀医院（2022年8月——2022年9月）诊治的CRC患者并经手术切除的CRC组织以获得原代CAF[获得上海中医药大学附属普陀医院伦理委员会批准，编号：PTEC-A-2023-5（S）-1

]

，按照CAF的表面标志物血小板源性生长因子受体α（platelet derived growth factor receptor alpha，PDGFRA）对原代细胞进行分选，筛选出iCAF。使用不添加血清的培养基分别对人结肠成纤维细胞（human intestinal fibroblast，HIF）和iCAF进行培养以获取HIF条件培养基（HIF-conditioned medium，HIF-CM）和iCAF条件培养基（iCAF-conditioned medium，iCAF-CM）。根据处理方式将结肠癌细胞分为对照组（不处理）、实验组1（加入HIF-CM）和实验组2（加入iCAF-CM）。观察经HIF或iCAF刺激后CRC细胞的存活率变化、凋亡率、蛋白水平、mRNA水平变化及对Wnt/β-catenin信号转导通路的影响。

结果：

经iCAF刺激后，CRC细胞的半数抑制浓度（half inhibition concentration，IC

）较对照组和HIF-CM组升高（

0.05）。与对照组和HIF-CM组相比，iCAF-CM组肿瘤细胞的凋亡率明显下降，凋亡蛋白caspase-3的表达量下降，抗凋亡蛋白Bcl-2、Bcl-xL和survivin表达量均上升（

0.05）。iCAF-CM组Wnt/β-catenin信号转导通路被激活。

结论：

iCAF可以介导CRC细胞产生耐药，其机制与激活Wnt/β-catenin信号转导通路有关。

Abstract

Background and purpose:

Colorectal cancer (CRC) is one of the common malignancies

but the mechanism by which it develops resista

nce to drug remains unclear. The tumor microenvironment (TME)

especially cancer-associated fibroblast (CAF)

plays an important role in the occurrence

development and drug resistance of tumors. This study aimed to investigate the effect of inflammatory cancer-associated fibroblasts (iCAF) on drug resistance in CRC cells and its possible mechanism.

Methods:

The primary CAFs were collected from CRC patients underwent surgery in Putuo Hospital

Shanghai University of Traditional Chinese Medicine from Aug. 2022 to Sep. 2022

and the primary cells were sorted according to the surface marker of CAF[approved by the Ethics Committee of Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine: PTEC-A-2023-5(S)-1

]

platelet derived growth factor receptor alpha (PDGFRA)

to screen iCAF. Human intestinal fibroblast (HIF) and iCAF cells were cultured using serum-free medium to obtain conditioned medium. According to the treatment method

colon cancer cells were divided into control group (no treatment)

experimental group 1(treated with HIF-CM) and experimental group 2 (treated with iCAF-CM). We observed the changes in the survival rate and apoptotic rate of CRC cells

the changes in protein and mRNA levels and the effect on the Wnt/β-catenin signaling pathway after stimulation with HIF-CM or iCAF-CM.

Results:

After iCAFs stimulation

the half inhibition concentration (IC

) of CRC cells was higher compared with the control group and HIF-CM group (

0.05). Compared with the control group and HIF-CM group

the apoptotic rate of tumor cells in iCAF-CM group decreased significantly

the expression of caspase-3 was decreased

and the expressions of Bcl-2

Bcl-xL and survivin were increased (

0.05). The Wnt/β-catenin signaling pathway was activated in the iCAF-CM group.

Conclusion:

iCAFs can mediate drug resistance in CRC cells

and the mechanism is related to the activation of Wnt/β-catenin signaling pathway.

关键词

Keywords

references

周昌明 , 王泽洲 , 郑莹 . 2023年美国癌症数据解读及对中国癌症防治的启示 [J ] . 中国癌症杂志 , 2023 , 33 ( 2 ): 117 - 125 . DOI: 10.19401/j.cnki.1007-3639.2023.02.004 http://doi.org/10.19401/j.cnki.1007-3639.2023.02.004

ZHOU C M , WANG Z Z , ZHENG Y . Interpretation of US cancer statistics 2023 and its implications for cancer prevention and treatment in China [J ] . China Oncol , 2023 , 33 ( 2 ): 117 - 125 .

NIKOLAOU M , PAVLOPOULOU A , GEORGAKILAS A G , et al . The challenge of drug resistance in cancer treatment: a current overview [J ] . Clin Exp Metastasis , 2018 , 35 ( 4 ): 309 - 318 . DOI: 10.1007/s10585-018-9903-0 http://doi.org/10.1007/s10585-018-9903-0

SUN Y . Tumor microenvironment and cancer therapy resistance [J ] . Cancer Lett , 2016 , 380 ( 1 ): 205 - 215 . DOI: 10.1016/j.canlet.2015.07.044 http://doi.org/10.1016/j.canlet.2015.07.044

ELYADA E , BOLISETTY M , LAISE P , et al . Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts [J ] . Cancer Discov , 2019 , 9 ( 8 ): 1102 - 1123 . DOI: 10.1158/2159-8290.CD-19-0094 http://doi.org/10.1158/2159-8290.CD-19-0094

BU L K , BABA H , YASUDA T , et al . Functional diversity of cancer-associated fibroblasts in modulating drug resistance [J ] . Cancer Sci , 2020 , 111 ( 10 ): 3468 - 3477 . DOI: 10.1111/cas.v111.10 http://doi.org/10.1111/cas.v111.10 https://onlinelibrary.wiley.com/toc/13497006/111/10 https://onlinelibrary.wiley.com/toc/13497006/111/10

YOSHIDA G J . Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways [J ] . J Exp Clin Cancer Res , 2020 , 39 ( 1 ): 112 . DOI: 10.1186/s13046-020-01611-0 http://doi.org/10.1186/s13046-020-01611-0

CHEN Z H , ZHOU L J , LIU L L , et al . Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma [J ] . Nat Commun , 2020 , 11 ( 1 ): 5077 . DOI: 10.1038/s41467-020-18916-5 http://doi.org/10.1038/s41467-020-18916-5

SUNG H , FERLAY J , SIEGEL R L , et al . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J ] . CA Cancer J Clin , 2021 , 71 ( 3 ): 209 - 249 . DOI: 10.3322/caac.v71.3 http://doi.org/10.3322/caac.v71.3 https://acsjournals.onlinelibrary.wiley.com/toc/15424863/71/3 https://acsjournals.onlinelibrary.wiley.com/toc/15424863/71/3

KADEL D , ZHANG Y , SUN H R , et al . Current perspectives of cancer-associated fibroblast in therapeutic resistance: potential mechanism and future strategy [J ] . Cell Biol Toxicol , 2019 , 35 ( 5 ): 407 - 421 . DOI: 10.1007/s10565-019-09461-z http://doi.org/10.1007/s10565-019-09461-z

SAHAI E , ASTSATUROV I , CUKIERMAN E , et al . A framework for advancing our understanding of cancer-associated fibroblasts [J ] . Nat Rev Cancer , 2020 , 20 ( 3 ): 174 - 186 . DOI: 10.1038/s41568-019-0238-1 http://doi.org/10.1038/s41568-019-0238-1

李学勤 , 徐克 . 肿瘤相关成纤维细胞促进肿瘤侵袭转移的作用机制 [J ] . 中国生物化学与分子生物学报 , 2019 , 35 ( 4 ): 386 - 392 . DOI: 10.13865/j.cnki.cjbmb.2019.04.06 http://doi.org/10.13865/j.cnki.cjbmb.2019.04.06

LI X Q , XU K . Mechanism of cancer-associated fibroblasts promoting tumor metastasis and invasion [J ] . Chin J Biochem Mol Biol , 2019 , 35 ( 4 ): 386 - 392 .

HU J L , WANG W , LAN X L , et al . CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer [J ] . Mol Cancer , 2019 , 18 ( 1 ): 91 . DOI: 10.1186/s12943-019-1019-x http://doi.org/10.1186/s12943-019-1019-x

ZHANG F , CUI J Y , GAO H F , et al . Cancer-associated fibroblasts induce epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer via CXCL12/CXCR4 axis [J ] . Future Oncol , 2020 , 16 ( 32 ): 2619 - 2633 . DOI: 10.2217/fon-2020-0095 http://doi.org/10.2217/fon-2020-0095 https://www.futuremedicine.com/doi/10.2217/fon-2020-0095 https://www.futuremedicine.com/doi/10.2217/fon-2020-0095

JUNG Y S , PARK J I . Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex [J ] . Exp Mol Med , 2020 , 52 ( 2 ): 183 - 191 . DOI: 10.1038/s12276-020-0380-6 http://doi.org/10.1038/s12276-020-0380-6

FERRARI N , RANFTL R , CHICHEROVA I , et al . Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts [J ] . Nat Commun , 2019 , 10 ( 1 ): 130 . DOI: 10.1038/s41467-018-07987-0 http://doi.org/10.1038/s41467-018-07987-0

浏览量

2649

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

靶向治疗及免疫治疗联合化疗为产AFP阳性结肠癌患者带来显著获益1例病例报告并文献复习

Tepoxalin通过ABCB1影响结直肠癌细胞生长及耐药的分子机制研究

运动干预在结直肠癌患者全程管理中作用的研究进展及展望

基于人工智能辅助腹腔镜右半结肠癌根治术的手术技能评价

结直肠癌新辅助免疫治疗的进展与展望