Hypoxia-induced epithelial-mesenchymal transition and fibrosis for the development of breast capsular contracture

Yao-Lung Kuo,Jian-An Chen,Ting-Mao Chou,Chun-Hui Chu,I-Ming Jou,Tai-I Hsu,Po-Wei Huang,Seng-Feng Jeng,Li-Ren Chang,Jhy-Shrian Huang

doi:10.1038/s41598-019-46439-7

Abstract

Fibrosis has been considered as a major cause of capsular contracture. Hypoxia has widely emerged as one of the driving factors for fibrotic diseases. The aim of this study was to examine the association between hypoxia-induced fibrosis and breast capsular contracture formation. Fibrosis, epithelial-mesenchymal transition (EMT), expression levels of hypoxia-inducible factor-1α (HIF-1α), vimentin, fibronectin, and matrix metalloproteinase-9 (MMP-9) in tissues from patients with capsular contracture were determined according to the Baker classification system. Normal breast skin cells in patients with capsular contracture after implant-based breast surgery and NIH3T3 mouse fibroblasts were cultured with cobalt chloride (CoCl2) to mimic hypoxic conditions. Treatment responses were determined by detecting the expression of HIF-1α, vimentin, fibronectin, N-cadherin, snail, twist, occludin, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and -2, as well as phosphorylated ERK. The expression levels of HIF-1α, vimentin, fibronectin, and fibrosis as well as EMT were positively correlated with the severity of capsular contracture. MMP-9 expression was negatively correlated the Baker score. Hypoxia up-regulated the expression of HIF-1α, vimentin, fibronectin, N-cadherin, snail, twist, TIMP-1 and -2, as well as phosphorylated ERK in normal breast skin cells and NIH3T3. Nonetheless, the expression levels of MMP-9 and occludin were down-regulated in response to CoCl2 treatment. This study is the first to demonstrate the association of hypoxia-induced fibrosis and capsular contracture.

Highlights

Among all cosmetic procedures, implant-based breast surgery is one of the most commonly performed ones[1]
Further in vitro experiments reveal that hypoxia drives the fibrotic process in primary breast skin cells and NIH3T3 mouse fibroblasts by determining the levels of mesenchymal markers, including vimentin, fibronectin, and N-cadherin in response to cobalt chloride (CoCl2) stimulation
Fibronectin expression was down-regulated in the loose region, but up-regulated in the dense region (Fig. 2c, asterisk). These results suggest that hypoxia-inducible factor-1α (HIF-1α) and its downstream regulators are responsible for the fibrotic process and extracellular matrix (ECM) remodeling in the development of breast capsular contracture

Summary

Introduction

Implant-based breast surgery is one of the most commonly performed ones[1]. No matter what kind of implant is inserted into patient’s breast, it inevitably induces a foreign body reaction This reaction will lead to an excessive fibrotic process, which eventually results in a common complication following implant-based breast surgeries, designated capsular contracture[4]. This complication causes painful and deformed breasts. Further in vitro experiments reveal that hypoxia drives the fibrotic process in primary breast skin cells and NIH3T3 mouse fibroblasts by determining the levels of mesenchymal markers, including vimentin, fibronectin, and N-cadherin in response to cobalt chloride (CoCl2) stimulation. Cytoskeletal disorganization can be observed in tissues and cells under hypoxic conditions, implicating that hypoxia may drive fibrosis, but disturb the homeostasis of ECM in capsular contracture

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Conclusion