乳腺癌干细胞旁分泌的 IL8 促进了 bulk 肿瘤细胞的治疗抵抗和转移。
Paracrine secretion of IL8 by breast cancer stem cells promotes therapeutic resistance and metastasis of the bulk tumor cells.
机构信息
Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China.
The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
出版信息
Cell Commun Signal. 2023 Mar 13;21(1):59. doi: 10.1186/s12964-023-01068-6.
BACKGROUND
Breast tumors consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population.
METHODS
Co-culture systems in vitro and co-implantation systems in vivo were designed to characterize the interactions between breast cancer stem cells (BCSCs) and bulk cancer cells. RNA sequencing was performed to study the functional and mechanistic implications of the BCSC secretome on bulk cancer cells. A cytokine antibody array was employed to screen the differentially secreted cytokines in the BCSC secretome. Tail vein injection metastatic models and orthotopic xenograft models were applied to study the therapeutic potential of targeting IL8.
RESULTS
We identified that the BCSC secretome potentiated estrogen receptor (ER) activity in the bulk cancer cell population. The BCSC secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of the BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden.
CONCLUSION
Taken together, this study delineates the mechanism by which BCSCs determine the therapeutic response and metastasis of bulk cancer cells; and thereby suggests potential therapeutic strategies to ameliorate breast cancer outcomes. Video Abstract.
背景
乳腺肿瘤由在分子特性和功能属性上存在差异的异质性细胞亚群组成。癌症干细胞（CSC）在癌症治疗失败和转移中起着关键作用。然而，CSC 如何决定大量癌细胞群体的进展仍不确定。
方法
设计了体外共培养系统和体内共植入系统，以表征乳腺癌干细胞（BCSC）与大量癌细胞之间的相互作用。进行 RNA 测序以研究 BCSC 分泌组对大量癌细胞的功能和机制影响。采用细胞因子抗体阵列筛选 BCSC 分泌组中差异分泌的细胞因子。尾静脉注射转移模型和原位异种移植模型用于研究靶向 IL8 的治疗潜力。
结果
我们发现 BCSC 分泌组增强了大量癌细胞群体中的雌激素受体（ER）活性。BCSC 分泌组使大量癌细胞群体对抗雌激素和 CDK4/6 抑制剂治疗产生耐药性；并增加了归因于大量癌细胞的转移负担。对 BCSC 分泌组的筛选确定了 IL8 作为一个关键因素，通过调节大量癌细胞的行为，增强 ERα 活性、赋予他莫昔芬耐药性并增加转移负担。IL8 的药理学抑制通过逆转他莫昔芬耐药性和消除转移负担，增加了氟维司群和/或 palbociclib 的疗效。
结论
综上所述，本研究阐述了 BCSC 决定大量癌细胞治疗反应和转移的机制；并提出了改善乳腺癌结局的潜在治疗策略。视频摘要。
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