Cancer-Derived Extracellular Vesicles as Biomarkers for Cutaneous Squamous Cell Carcinoma: A Systematic Review

SIMPLE SUMMARY: Biomarkers including DNA, RNA, and surface-associated proteins in tumor-derived extracellular vesicles promote accurate clinical diagnosis and indicate the prognosis of cancer. In this systematic review, pre-clinical and clinical studies on extracellular vesicles derived from cutaneous squamous cell carcinoma (cSCC-derived EVs) were summarized, for which studies on the genomics, transcriptomics, and proteomics of cSCC-derived EVs were highlighted. The contents in cSCC-derived EVs may reflect the mutational landscape of the original cancer cells or be selectively enriched in extracellular vesicles, as provided by the significant role of target molecules including desmoglein 2 protein (Dsg2), Ct-SLCO1B3 mRNA, CYP24A1 circular RNA (circRNA), long intergenic non-coding RNA (linc-PICSAR) and DNA Copy Number Alteration (CNA). Evidence of these studies implied the diagnostic and therapeutic potential of cSCC-derived EVs for cutaneous squamous cell carcinoma. ABSTRACT: Cutaneous squamous cell carcinoma (cSCC) as one of the most prevalent cancers worldwide is associated with significant morbidity and mortality. Full-body skin exam and biopsy is the gold standard for cSCC diagnosis, but it is not always feasible given constraints on time and costs. Furthermore, biopsy fails to reflect the dynamic changes in tumor genomes, which challenges long-term medical treatment in patients with advanced diseases. Extracellular vesicle (EV) is an emerging biological entity in oncology with versatile clinical applications from screening to treatment. In this systematic review, pre-clinical and clinical studies on cSCC-derived EVs were summarized. Seven studies on the genomics, transcriptomics, and proteomics of cSCC-derived EVs were identified. The contents in cSCC-derived EVs may reflect the mutational landscape of the original cancer cells or be selectively enriched in EVs. Desmoglein 2 protein (Dsg2) is an important molecule in the biogenesis of cSCC-derived EVs. Ct-SLCO1B3 mRNA, and CYP24A1 circular RNA (circRNA) are enriched in cSCC-derived EVs, suggesting potentials in cSCC screening and diagnosis. p38 inhibited cSCC-associated long intergenic non-coding RNA (linc-PICSAR) and Dsg2 involved in EV-mediated tumor invasion and drug resistance served as prognostic and therapeutic predictors. We also proposed future directions to devise EV-based cSCC treatment based on these molecules and preliminary studies in other cancers.