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  3. Paracrine secretion of IL8 by breast cancer stem cells promotes therapeutic resistance and metastasis of the bulk tumor cells

Paracrine secretion of IL8 by breast cancer stem cells promotes therapeutic resistance and metastasis of the bulk tumor cells

  • Cell Commun Signal. 2023 Mar 13;21(1):59. doi: 10.1186/s12964-023-01068-6.
Mingming Wu # 1 2,  Xiao Zhang # 1 2,  Weijie Zhang 1 2,  Linlin Yan 1 2,  Xiangtian Liu 1 2,  Min Zhang 1 2,  Yueyin Pan 1,  Peter E Lobie 3 4,  Xinghua Han 5,  Tao Zhu 6 7 8
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Institute of Biopharmaceutical and Health Engineering, Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China. pelobie@sz.tsinghua.edu.cn.
  • 4 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. pelobie@sz.tsinghua.edu.cn.
  • 5 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. hxhmail@ustc.edu.cn.
  • 6 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. zhut@ustc.edu.cn.
  • 7 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. zhut@ustc.edu.cn.
  • 8 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. zhut@ustc.edu.cn.
  • # Contributed equally.
PMID: 36915147 DOI: 10.1186/s12964-023-01068-6
Abstract

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.

Keywords

Bulk cancer cell; Cancer stem cell; IL8; Metastasis; Tamoxifen resistance.

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