白藜芦醇抑制肿瘤相关成纤维细胞-乳腺癌杂交类器官的生长和VCAN表达

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-17 DOI:10.1016/j.intimp.2025.114451

Yixin Shi , Gengxi Cai , Chuling Zhang , Hong Li , Yichu Nie , Sifei Yu , Beiying Zhang , Moli Wu , Wei Luo , Jia Liu , Zhanwen Guan

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引用次数: 0

摘要

癌症相关成纤维细胞（CAF）是肿瘤微环境（TME）的主要组成部分，促进乳腺癌（BC）的进展和耐药。二维细胞培养不足以模拟CAFs对肿瘤的保护作用，导致药物疗效分析的实验偏差。本研究应用的cafa -类器官共培养模型可能有助于解决这一问题。白藜芦醇（Res）已被发现可以抑制BC的生长，但其对cafa保护的BC的影响尚不清楚。方法采集手术切除的BC组织，分别建立BC类器官（BCOs，病理鉴定）和分离CAFs（免疫荧光鉴定）。建立BCO-CAF共培养体系，测定cas对BCOs的保护作用。然后用Res处理该系统，进行EdU增殖试验和calcein-AM/PI活/非活细胞标记。生物成因分析表明，来自CAFs的VCAN可能在这一过程中起重要作用。采用免疫组织化学、qRT-PCR和Western blotting方法评估经或未经Res治疗的cas中Versican （VCAN）表达水平。结果19例BCO培养成功，病理证实。Res对19例BCO中15例（78.95%）有抑制作用。虽然CAFs能促进BCOs的类器官生长69.75±14.78%，但Res消除了这一作用，并导致caf包被BCOs的细胞大量死亡（84.97%±5.06%），同时cas中VCAN和TGF-β表达降低。结论Res对BCOs的抑制作用进一步证实了其抗bc的价值。

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Resveratrol suppresses growth and VCAN expression in a Cancer-associated fibroblast-breast Cancer hybrid organoid

Background

Cancer-associated fibroblast (CAF) is a major component of the tumor microenvironment (TME) and promotes breast cancer (BC) progression and drug resistance. Two-dimensional cell culture is insufficient to simulate the protective effects of CAFs on tumors, resulting in experimental bias in drug efficacy assays. CAF-organoid co-culture model applied in this study may help solve this problem. Resveratrol (Res) has been found to suppresses BC growth, yet its effects on CAF-protected BC remain unknown.

Methods

Surgical resected BC tissues were harvested and established for BC organoids (BCOs, identified with pathological examination) and isolated for CAFs (identified with immunofluorescence) respectively. BCO-CAF co-culture system was established and was measured for the protection effects of CAFs on BCOs. The system was then treated with Res and tested for EdU proliferation assay and calcein-AM/PI viable/non-viable cell labeling. Biogenic analysis was performed and showed that VCAN from CAFs may be important in this process. Versican (VCAN) expression levels in CAFs with or without Res treatment were evaluated by immunohistochemistry, qRT-PCR, and Western blotting.

Results

19 BCO cases were successfully cultured and confirmed with pathological examination. Res showed inhibitory effects on 15 of the 19 BCO cases (78.95 %). Although CAFs facilitated organoid growth of BCOs by 69.75 ± 14.78 %, Res treatment eliminated this effect and caused extensive cell death (84.97 % ±5.06 %) in CAF-coated BCOs, accompanied by a decrease in VCAN and TGF-β expression in CAFs.

Conclusions

The anti-BC value of Res was further proved by showing its promising suppressive effects on BCOs with or without the presence of CAFs.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.