Chemotherapy induces breast cancer stemness in association with dysregulated monocytosis

Liang Liu, Lin Yang, Wei Yan, Jing Zhai, Donald P. Pizzo, Peiguo Chu, Andrew R. Chin, Meng Shen, Chuan Dong, Xianhui Ruan, Xiubao Ren, George Somlo, Shizhen Emily Wang

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    Abstract

    Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer to allow optimal surgery and aim for pathologic response. However, many breast cancers are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapytriggered events occurring systemically and locally, potentially promoting a cancer stem–like cell (CSC) phenotype and contributing to tumor relapse. Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of breast cancer cells. Using cell lines, patient-derived xenograft models, and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors. Results: In human patients and mice, we detected a therapyinduced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte–macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT. Conclusions: Our data establish a mechanism of chemotherapy- induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings.

    Original languageEnglish (US)
    Pages (from-to)2370-2382
    Number of pages13
    JournalClinical Cancer Research
    Volume24
    Issue number10
    DOIs
    StatePublished - May 15 2018

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Liu, L., Yang, L., Yan, W., Zhai, J., Pizzo, D. P., Chu, P., Chin, A. R., Shen, M., Dong, C., Ruan, X., Ren, X., Somlo, G., & Wang, S. E. (2018). Chemotherapy induces breast cancer stemness in association with dysregulated monocytosis. Clinical Cancer Research, 24(10), 2370-2382. https://doi.org/10.1158/1078-0432.CCR-17-2545