ReviewThe roles of small extracellular vesicles in lung cancer: Molecular pathology, mechanisms, diagnostics, and therapeutics
Introduction
Lung cancer remains the most commonly diagnosed cancer, accounting for 13% of all estimated new cancer cases. Lung cancer is also the leading cause of cancer death worldwide. The mortality rate of lung cancer is 24% and 23% for males and females in the United States from 2019 to 2020 [[1], [2], [3], [4]]. Despite the diagnostic and therapeutic advancements over recent decades (e.g.- low-dose computed tomography screening, liquid biopsies in molecular diagnostics, stereotactic body radiation therapy, and immunotherapy), the overall cure and survival rates for lung cancer still remain low, particularly in metastatic stages. Over half of patients die within one year of diagnosis and only 15% of patients can survive over five years. Therefore, investigation of the molecular pathology of lung cancer and development of new technologies for early diagnostics and therapeutics are required to improve overall survival rates of lung cancer.
Extracellular vesicles (EVs) are cell-released, lipid bilayer membrane-enclosed vesicles in submicron size [5,6]. EVs exist in diverse body fluids, such as plasma, pleural effusions, and bronchial lavage [7,8]. Based on their size and release mechanism, EVs generally are divided into three categories: exosomes (30–150 nm), microvesicles (100–1000 nm), and apoptotic bodies (500–2000 nm) [9,10]. Exosomes originate from the endosomal sorting complex required for transport (ESCRT) dependent endocytic pathway, and microvesicles are directly released into the extracellular environment by the outward budding and fission of the plasma membrane. Exosomes and nanoscale microvesicles are collectively referred to as small EVs (sEVs), which have been recently under intense investigation and hold promise for pathophysiologic and translational discoveries. Previous studies demonstrate that sEV intercellular communication messengers can transfer original cell-derived proteins and nucleic acids to recipient cells, and thus influence the phenotype of recipient cells. Regarding tumors, growing evidence reveals tumor-derived sEVs participate in a variety of pathophysiological processes; some of which include tumor microenvironment, angiogenesis, epithelial-to-mesenchymal transition, formation of pre-metastatic niche, immune regulation, organotropic metastasis, and therapeutic resistance [[11], [12], [13]]. The latest studies further validate that sEVs can be used for early cancer diagnostics, staging, and treatment monitoring. Furthermore, sEVs have been used as cancer vaccine and drug delivery nanocarriers, as well as conferrer of cell membrane neoantigens. While still in its infancy, the field of sEV-based fundamental and translational cancer studies has been rapidly increasing. This review mainly discusses the roles of sEVs in the lung cancer development, metastasis, relevant molecular mechanisms, liquid biopsy, and treatment. It is hoped that this review could inspire readers to further investigate molecular pathology of lung cancer, develop new sEV-based diagnostics, and explore relevant sEV-based therapeutics.
Section snippets
sEV contents as diagnostic and prognostic markers of lung cancer
Isolation of sufficient and pure sEVs is the prerequisite for sEV studies. Given various isolation and detection methods of sEVs have been systemically reviewed elsewhere [14,15], in this review we briefly outline and comment on the approaches that utilize sEV density, size, membrane proteins, solubility, surface charge, and lipid membrane. Ultracentrifugation (UC) has been the most frequently used technique for isolation of sEVs over the past four decades. However, inherent disadvantages such
Biofunctions of sEVs in lung cancer
Growing evidence shows that sEVs mediate tumorigenesis and progression, including intercellular communication, pro-inflammatory responses, and the tumor microenvironment in various cancers. However, these functions have not yet been comprehensively reviewed in lung cancer. Here, we systematically introduce the biofunctions of sEVs in lung cancer only (Fig. 1).
Inhibiting biofunctions and eliminating tumor-derived sEVs
Because tumor-derived sEVs are capable of inducing tumor growth, metastasis, and enhancing drug resistance, elimination of sEVs can interrupt the pathology progress of neoplasia [117]. Suppression of sEV secretion, elimination of circulating sEVs, and interruption of cell-cell communication are feasible approaches [[163], [164], [165]]. Multivesicular bodies (MVBs) fusing with lysosomes or plasma membranes determines the amount of circulating sEVs. Many proteins are involved in the fusion
Perspectives
sEVs are considered to be a promising molecule for lung cancer diagnosis due to their distinct expression of markers, which assists in the identification of early lung cancer and high-risk groups. On the basis of their physiological and pathological roles in lung cancer, like intercellular communication, immune activation, high permeability and affinity etc., sEVs also can be used for lung cancer therapy. However, some obstacles remain to be overcome: (1) The isolation technologies of sEVs in a
Conclusion
In summary, sEVs play a significant role in the physiological processes of lung cancer, such as lung cancer angiogenesis, EMT, metastasis, and immune regulation, and possess a strong potential in cancer diagnosis and treatment. For future work, advanced techniques that produce a large sample capacity and can expeditiously isolate sufficient pure sEVs are strongly desired for sEV-centered fundamental and translational studies. Currently, sEV-based clinical trials are being heavily developed for
Authors' contributions
Yi Liu, Yiqiu Xia, Wenjun Mao, and Yuan Wan wrote the manuscript. Jillian Smollar prepared tables and figures. All the authors critically revised the manuscript.
Research involving human participant/animals
No human participant or animal was involved in this study.
Funding and acknowledgments
This work was supported by grants from the Precision Medicine Project of Wuxi Municipal Commission of Health and Family Planning (J201805), the Youth scientific research project of Wuxi Municipal Health Commission (Q201951), and Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (HB2020003).
Declaration of competing interest
All authors declare that they have no conflicts of interest and no competing interest.
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