Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis
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 chemotherap...
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Published in | Clinical cancer research Vol. 24; no. 10; pp. 2370 - 2382 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research Inc
15.05.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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 chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem-like cell (CSC) phenotype and contributing to tumor relapse.
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.
In human patients and mice, we detected a therapy-induced 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.
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.
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-senior authors |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-17-2545 |