Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema.

Khairunnisa’ Md Yusof,Kira Groen,Kelly A Avery-Kiejda,Rozita Rosli

doi:10.3389/fcell.2021.732415

Abstract

Secondary lymphedema is characterized by lymphatic fluid retention and subsequent tissue swelling in one or both limbs that can lead to decreased quality of life. It often arises after loss, obstruction, or blockage of lymphatic vessels due to multifactorial modalities, such as lymphatic insults after surgery, immune system dysfunction, deposition of fat that compresses the lymphatic capillaries, fibrosis, and inflammation. Although secondary lymphedema is often associated with breast cancer, the condition can occur in patients with any type of cancer that requires lymphadenectomy such as gynecological, genitourinary, or head and neck cancers. MicroRNAs demonstrate pivotal roles in regulating gene expression in biological processes such as lymphangiogenesis, angiogenesis, modulation of the immune system, and oxidative stress. MicroRNA profiling has led to the discovery of the molecular mechanisms involved in the pathophysiology of auto-immune, inflammation-related, and metabolic diseases. Although the role of microRNAs in regulating secondary lymphedema is yet to be elucidated, the crosstalk between microRNAs and molecular factors involved in the pathological features of lymphedema, such as skin fibrosis, inflammation, immune dysregulation, and aberrant lipid metabolism have been demonstrated in several studies. MicroRNAs have the potential to serve as biomarkers for diseases and elucidation of their roles in lymphedema can provide a better understanding or new insights of the mechanisms underlying this debilitating condition.

Highlights

Lymphedema is a serious chronic condition characterized by swelling, resulting from the abnormal accumulation of protein-rich lymph fluid in the interstitial spaces due to an imbalance between lymph fluid production and transport (Greene and Maclellan, 2013; Ducoli and Detmar, 2021)
This review has highlighted several miRNAs that are involved in processes that contribute to secondary lymphedema
Given that secondary lymphedema involves multiple events and has different stages, extensive studies are warranted to refine the characterization of miRNAs in lymphedema patients or animal models to provide new insights into the mechanisms underlying lymphedema and subsequently facilitate the development of molecular-based therapies for this condition

Summary

Introduction

Lymphedema is a serious chronic condition characterized by swelling, resulting from the abnormal accumulation of protein-rich lymph fluid in the interstitial spaces due to an imbalance between lymph fluid production and transport (Greene and Maclellan, 2013; Ducoli and Detmar, 2021). Radiotherapy and surgical excision induce trauma or insults to the lymph nodes and lymphatic structures, leading to the obstruction of lymph flow and the accumulation of protein-rich fluid at the affected area (Cueni and Detmar, 2008; Alitalo, 2011). Prolonged blockage of lymphatic flow and the accumulation of lymph lead to the pathological features of lymphedema, including inflammation, immune dysfunction, tissue microRNA and Secondary Lymphedema remodeling, fibrosis, and aberrant lipid metabolism. There is no molecular-based therapy for secondary lymphedema and the condition is usually treated with massage, manual lymphatic drainage, compression bandages, remedial exercise, and dietary intervention programs (Do et al, 2017; Jung et al, 2020). In the absence of targeted therapies, further investigations into the molecular mechanisms of lymphedema may highlight additional treatment avenues. The aim of this review is to identify the epigenetic mechanisms, including small regulatory RNAs, which are aberrant in the processes that cause this condition, this may highlight dysregulated pathways in lymphedema and reveal novel therapeutic targets

Objectives

Conclusion