ICAM-1 通过与表皮生长因子受体直接相互作用,在推动三阴性乳腺癌转移进展方面发挥肿瘤内在作用

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-10-16 DOI:10.1186/s12943-024-02150-4
Jae-Hyeok Kang, Nizam Uddin, Seungmo Kim, Yi Zhao, Ki-Chun Yoo, Min-Jung Kim, Sung-Ah Hong, Sangsu Bae, Jeong-Yeon Lee, Incheol Shin, Young Woo Jin, Heather M. O’Hagan, Joo Mi Yi, Su-Jae Lee
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引用次数: 0

摘要

三阴性乳腺癌(TNBC)是侵袭性最强的亚型乳腺癌,由于缺乏已获批准的靶向疗法,该病面临着严峻的挑战。因此,亟需确定针对这一病症的有效治疗靶点。虽然表皮生长因子受体(EGFR)在 TNBC 中表达显著,并被认为是一个治疗靶点,但由于其相关副作用和有限的疗效,抗 EGFR 疗法尚未被批准用于乳腺癌治疗。在这里,我们发现细胞间粘附分子-1(ICAM-1)在转移性乳腺癌中的表达水平升高,是表皮生长因子受体活化的关键结合适配体,在恶性进展中起着至关重要的作用。肿瘤表达的 ICAM-1 对表皮生长因子受体(EGFR)的激活会启动 JAK1/STAT3 通路中的偏向性信号转导,从而推动上皮细胞向间质转化,并在不影响肿瘤生长的情况下促进转移。值得注意的是,在乳腺癌异位移植小鼠模型中,ICAM-1 中和抗体治疗能显著抑制癌症转移。总之,我们发现 ICAM-1 是表皮生长因子受体活化的新型肿瘤内在调控因子,这为开发 TNBC 特异性抗表皮生长因子受体疗法提供了宝贵的启示。
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Tumor-intrinsic role of ICAM-1 in driving metastatic progression of triple-negative breast cancer through direct interaction with EGFR
Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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