Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis.

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 10 Pg. 2370-2382 (05 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29500278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers
• Cytokines
• Receptors, CCR2
• Receptors, Notch

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biomarkers
• Breast Neoplasms (complications, drug therapy, metabolism)
• Cell Line, Tumor
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Humans
• Immunophenotyping
• Leukocytosis (diagnosis, etiology)
• Mice
• Monocytes (pathology)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Receptors, CCR2 (metabolism)
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays