Format

Send to

Choose Destination
Clin Cancer Res. 2018 May 15;24(10):2370-2382. doi: 10.1158/1078-0432.CCR-17-2545. Epub 2018 Mar 2.

Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis.

Author information

1
Department of Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
2
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
3
Department of Pathology, University of California, San Diego, La Jolla, California.
4
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
5
Department of Pathology, City of Hope National Medical Center and Comprehensive Cancer Center, Duarte, California.
6
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
7
Department of Medical Oncology, City of Hope National Medical Center and Comprehensive Cancer Center, Duarte, California.
8
Department of Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. emilywang@ucsd.edu.

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 chemotherapy-triggered 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 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.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. Clin Cancer Res; 24(10); 2370-82. ©2018 AACR.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center