Activation of fibroblasts by nicotine promotes the epithelial‐mesenchymal transition and motility of breast cancer cells

The tumor microenvironment plays an important role in tumor initiation and progression. It is well documented that nicotine participates in cigarette smoking‐related malignancies. Previous studies focused on the effects of nicotine on tumor cells; however, the role of the microenvironment in nicotin...

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Bibliographic Details
Published in:Journal of cellular physiology 2018-06, Vol.233 (6), p.4972-4980
Main Authors: Chen, Pin‐Cyuan, Lee, Wen‐Ying, Ling, Hsiang‐Hsi, Cheng, Chia‐Hsiung, Chen, Ku‐Chung, Lin, Cheng‐Wei
Format: Article
Language:English
Subjects:
Acetylcholine receptors (nicotinic)
Activation
AKT protein
alpha7 Nicotinic Acetylcholine Receptor - agonists
alpha7 Nicotinic Acetylcholine Receptor - metabolism
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cancer-Associated Fibroblasts - drug effects
Cancer-Associated Fibroblasts - metabolism
Cancer-Associated Fibroblasts - pathology
Carcinogens - toxicity
Cell migration
Cell Movement - drug effects
Cigarette smoking
Conditioning
Connective tissue growth factor
Connective Tissue Growth Factor - metabolism
Connective tissues
Culture Media, Conditioned - metabolism
EMT
Epithelial-Mesenchymal Transition - drug effects
Female
Fibroblasts
Growth factors
Humans
Intracellular Signaling Peptides and Proteins - metabolism
MCF-7 Cells
Mesenchyme
Motility
Neoplasm Invasiveness
Nicotine
Nicotine - toxicity
Paracrine Communication - drug effects
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - drug effects
Signaling
Smoking
Smoking - adverse effects
Transforming Growth Factor beta - metabolism
Tumor cells
Tumor Microenvironment
Tumorigenesis
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Summary:The tumor microenvironment plays an important role in tumor initiation and progression. It is well documented that nicotine participates in cigarette smoking‐related malignancies. Previous studies focused on the effects of nicotine on tumor cells; however, the role of the microenvironment in nicotine‐mediated tumorigenesis is poorly understood. Herein, we investigated the effect and molecular mechanism of nicotine on fibroblasts and its contribution to breast cancer. We found that nicotine induced the epithelial‐mesenchymal transition (EMT) of breast cancer cells and promoted activation of fibroblasts. Interestingly, conditioned medium from nicotine‐activated fibroblasts (Nic–CM) had a greater impact on promoting the EMT and migratory capability toward cancer cells than did treatment with nicotine alone. Production of connective tissue growth factor (CTGF) and transforming growth factor (TGF)‐β by nicotine‐treated fibroblasts was demonstrated to be crucial for promoting the EMT and cancer cell migration, and blocking of CTGF and TGF‐β in Nic‐CM‐suppressed tumor motility. Moreover, nicotine induced expressions of CTGF, and TGF‐β in fibroblasts as identified through α7 nicotinic acetylcholine receptor (nAChR)‐dependent activation of the AKT/TAZ signaling mechanism. Together, our data showed for the first time that activation of fibroblasts is largely responsible for accelerating smoking‐mediated breast cancer progression. Nicotine mediates production of CTGF and TGFβ in fibroblasts through α7 nAChR‐dependent activation of AKT/TAZ signaling, which further promotes EMT, and motility of breast cancer.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.26334