The Role of Exosomes in Epithelial–to-Mesenchymal Transition and Cell Functional Properties in Head and Neck Cancer

SIMPLE SUMMARY: According to WHO 2018 estimates, cancer is the second leading cause of mortality worldwide after cardiovascular disease, accounting for one in six fatalities. Mortality due to head and neck cancer is also significantly high, making it the seventh most prevalent cancer. Elucidating the mechanisms of action of key regulators, such as bioactive molecules secreted by the cancer cells in exosomes, their interaction with neighboring and distant cells, the extracellular matrix, and the tumor microenvironment, could be a valuable tool for future diagnostic and treatment approaches. Exosomes facilitate several critical functions in cancer cells, such as epithelial-to-mesenchymal transition, which makes head and neck cancer even worse by giving it a metastatic potential to evade the secondary site and spread cancer in the body. Exploring the molecules involved in this process could help targeting specific sites, for instance, by modifying the cell-specific proteins and exosome cargoes. ABSTRACT: Exosomes are nanosized vesicles that are produced in normal and cancer cells, promoting intracellular communication. In head and neck cancer (HNC), exosomes are involved in many undesirable events of cancer development and progression, including angiogenesis, tumor microenvironment (TME) remodeling, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, extracellular matrix (ECM) degradation, and drug resistance. Exosomes are involved in altering the signaling pathways in recipient cells by the cargoes they carry. Proteins, lipids, and nucleic acids such as DNA fragments and RNAs (i.e., mRNAs, miRNAs, and long non-coding RNAs) are carried in the exosomes to promote cell communication. EMT is a critical cellular process in which epithelial cells are forced to become mesenchymal cells by the actions of SNAIL/SLUG, TWIST, and ZEB family transcription factors carried in exosomes that facilitate metastasis. In this critical review, we focused on exosome biogenesis, their cargoes, and their involvement in EMT induction and metastasis during HNC. Insights into exosome isolation and characterization, as well as their key role in ECM remodeling and degradation, are also presented and critically discussed. More importantly, this article addresses the role of exosomes in HNC and drug resistance induced in drug-sensitive cancer cells. In addition, exosomes have a great potential to be used as diagnostic and therapeutic tools. A better understanding on exosome biogenesis, composition, and functions in HNC will aid in developing novel therapeutic strategies to treat HNC, overcome therapy resistance, and avoid metastasis, which is a significant cause of cancer death.