Abstract

Introduction: Oral cancer is the sixteenth most prevalent cancer globally, with Asian countries accounting for two-thirds of cases. Despite advancements in surgery, chemotherapy, and radiotherapy, late diagnosis, the absence of specific biomarkers, and the high cost of treatment result in poor outcomes. Tumor recurrence remains a significant challenge, highlighting the need for innovative therapeutic strategies. One promising avenue is the study of exosomes, which carry biomolecules like proteins, lipids, DNA, RNA, and microRNA, playing a key role in intercellular communication and the tumor microenvironment. Stem-cell-derived exosomes could revolutionize cancer therapy by targeting tumors and modulating immune responses. MicroRNAs within these exosomes are crucial in cancer progression, metastasis, and aggressiveness, contributing to high recurrence rates in oral cancer.

Methods: This review followed PRISMA-ScR guidelines to explore the therapeutic potential of stem cell-derived exosomes in oral cancer. A literature search in PubMed and Web of Science used terms related to "exosomes," "stem cells," and "oral cancer," including studies in English published before March 1, 2024. Original research, clinical trials, in vitro, and in vivo studies were selected; reviews and conference abstracts were excluded. Two reviewers independently screened and reviewed studies. Data extraction included study characteristics such as exosome origin, cargo, target cells, animal species, sample size, pathways, and primary outcomes.

Results: This review included nine studies, all conducted in vitro, with six also encompassing in vivo experiments. Notably, four of these studies were conducted in China. Findings suggest that stem cell-derived exosomes are promising candidates for oral cancer therapy, playing key roles in reducing pro-inflammatory cytokines, inducing apoptosis, enhancing cytotoxicity, inhibiting angiogenesis, and reducing oral cancer cell proliferation. The studies examined various types of exosomes derived from different stem cell sources, including umbilical cord mesenchymal stem cells, cancer stem cells, and other relevant tumor-related cells.

Conclusions: This review unravels the therapeutic potential of stem cell-derived exosomes as promising tools for oral cancer therapy. Exosomes derived from UC-MSCs, SHED, MenSCs, and hBMSCs reduce inflammation, induce apoptosis, and modulate angiogenesis and metastasis. Offering advantages over conventional treatments, such as low immunogenicity and targeted delivery, further research and clinical trials are essential to validate their safety, efficacy, and mechanisms.

Introduction

Malignant diseases pose a significant challenge to modern medical science1. Despite continuous efforts to develop novel treatment modalities, malignant diseases persist as a significant challenge for researchers owing to their multifaceted nature, genetic heterogeneity, and ability to adapt2. According to GLOBOCAN 2022 statistics, around 9.7 million cancer-related deaths were reported in 2022 alone, emphasizing the ongoing battle against this formidable clinical adversary3.

Malignant tumors of the mouth that affect the lip and oral cavity are known as oral cancers4. They can originate from salivary glands or lymphoid tissues, and the most common subtype arises from squamous cells in the oral mucosa5. The diverse etiology of this genetic and epigenomic disorder includes tobacco smoking, alcohol consumption, human papillomavirus (HPV) infection, nutritional deficiency, radiation exposure, hereditary predisposition, and the presence of pre-malignant oral lesions6, 7. Notably, the consumption of alcohol and tobacco stands out as major risk factors for oral cancer8. Oral carcinogenesis is characterized by heterogeneity, which is essential in forming the tumor microenvironment (TME), impacting interactions between tumor and non-tumor cells, and providing resistance to conventional therapies9. According to GLOBOCAN 2022, oral cancer ranked as the 16th most prevalent form of cancer globally, with a recorded incidence of approximately 389,495 new cases and 188,230 deaths in the year 2022. The incidence rates for lip and oral cavity cancer among males in South and Southeast Asia were highest in Taiwan, followed by Sri Lanka, India, and Pakistan10. The incidence and mortality rates of oral cavity cancer in this region are among the highest globally, contributing nearly two-thirds (66%) of all newly reported cases worldwide3. This significant incidence rate, especially in this region, underscores an urgent need for innovative therapeutic approaches beyond the current limitations of conventional treatments.

While surgical interventions, chemotherapy, and radiotherapy continue to serve as primary modalities for managing malignant diseases, the persistence of tumor recurrence remains a major challenge, further heightened by the adverse effects associated with therapeutic interventions11, 12. Hence, there is a paramount interest in identifying novel, reliable therapeutic options capable of early detection of neoplastic events. These therapeutic options will offer significant advantages in combating this life-threatening malignancy and ultimately enhance individual health outcomes and survival13.

One promising avenue is the study of exosomes, which play a crucial role in intercellular communication and shaping the TME. Exosomes have recently received considerable attention as a novel nano-platform for drug delivery14. Their established function as carriers of various cargoes, including proteins, lipids, DNA, messenger RNA, non-coding RNA, and microRNA (miRNA), serves as a crucial mechanism for intercellular exchange of information and signal transduction15. Due to their intrinsic ability to interact with the TME, exosomes present a unique solution to overcoming resistance and recurrence in oral cancer, bridging gaps in current therapeutic approaches16. This phenomenon significantly impacts the TME, profoundly affecting immune system evasion, metastasis, angiogenesis, tumor development, and treatment resistance17. Consequently, exosomes hold promise as prognostic and diagnostic biomarkers, as well as therapeutic agents. By enabling targeted drug delivery, exosomes could provide a pathway to overcome current treatment resistance and recurrence challenges, especially in oral cancer treatment18.

Characteristics of stem cells include the ability to differentiate into several cell types, self-renewal, and pluripotency. They can be derived from a variety of vascularized tissues and organs, including the liver, adipose tissue, bone marrow, umbilical cord, cancer cells, and dental tissues, exhibiting migratory and regenerative potentials. Utilizing stem cell-derived exosomes as a targeted medication delivery system presents the promising potential for enhancing drug absorption and distribution within tumor sites19. This novel approach could significantly advance anticancer therapy, particularly in resistant forms of oral cancer. This review aims to unravel the therapeutic potential of stem cell-derived exosomes, introducing novel concepts for clinical management and therapeutic options for oral cancer.

Methods

The review was carried out following the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Scoping Reviews (PRISMA-ScR)20.

Search Strategy

A comprehensive literature search was performed using PubMed and Web of Science databases to identify pertinent studies. The search strategy employed a combination of terms related to “exosomes”, “stem cells”, and “oral cancer”. An English language restriction was applied, and articles published before 1 March 2024 were included in the search.

Study Selection

The search aimed to identify pertinent research that explores the therapeutic potential of stem cell-derived exosomes in oral cancer.

Inclusion and Exclusion Criteria

This review included original research articles, clinical trials, in vitro studies, and animal model studies that investigated stem cell-derived exosomes as a potential therapeutic approach for oral cancer. Only studies published in English were included.

Studies were excluded if they did not focus specifically on oral cancer. Additionally, studies that did not involve stem cell-derived exosomes or focused on non-exosomal approaches were excluded. Reviews, meta-analyses, and conference abstracts were excluded due to a lack of original data.

The EndNote citation software was utilised to conduct a three-phase examination process on the articles acquired from the databases. Duplicate files were removed in Phase I. Phase II involved analysing the titles and abstracts. Phase III involved a thorough examination of articles from the selected abstracts. Two reviewers, MAM and WNS, conducted separate evaluations of the titles and abstracts of all identified studies. To ensure consistency and minimise bias, the reviewers adhered to a predefined process for article selection and data extraction, which included detailed discussions to resolve any discrepancies. Any disagreements were resolved through consultation with a third reviewer (RM).

Data Extraction and Analysis

For each study included, we utilised a structured data extraction process to gather relevant information, including the location, publication year, exosome origin, exosomal cargo, target cell (for in vitro studies), and animal species and sample size (for in vivo studies), pathway involved, and primary outcome. The reviewers jointly reviewed the extracted data to ensure accuracy and consistency in interpretation, thereby reducing variability. This review presents its findings through a narrative synthesis methodology adhering to the PRISMA-ScR guidelines20. Additionally, no quality assessment was performed, as scoping reviews aim to inclusively identify all accessible evidence and underscore their primary attributes, irrespective of their quality. Figure 1 illustrates the literature search process.

× Figure 1 . Study selection flowchart through literature search. Figure 1 . Study selection flowchart through literature search.

Table 1.

Characteristics of included in vitro studies

Study Country Origin of exosomes Exosomal cargo Target cells Pathway involved Outcome Abdelwhab et al ., 2023 21 Egypt UC-MSCs-exos HOTAIR Oral squamous cell carcinoma (OSCC) cell line (SCC-25) UC-MSCs-exos downregulated the expression of HOTAIR UC-MSCs-exos exhibits therapeutic potential against OSCC in vitro by modulating inflammation, apoptosis, and HOTAIR expression. Capik et al ., 2023 22 Turkey hiTDEs miR-1825 SCC-9 (human tongue squamous carcinoma) and FaDu (human hypopharyngeal carcinoma) cell lines TSC2/mTOR pathway, which was deregulated by miR-1825 Promotes endothelial cell viability, migration, invasion, and angiogenesis. Chen et al ., 2019 23 Taiwan CSC_EVs miR-21-5p Human OSCC cell lines, SCC-15 and CAL27, and primary NGFs (PCS-201-018) β-catenin, PI3K, STAT3, mTOR, and TGF-β1 pathways CSC_EVs boost cisplatin resistance, clonogenicity, and tumorsphere formation in OSCC cells, while OSCC_EVs heighten metastasis, stemness, and chemoresistance, and worsen survival. OV treatment decreases EV cargo, hampers self-renewal, blocks NGF-CAF transformation, making CSCs sensitive to CDDP. Liu et al. , 2022 24 China SHED-Exo miR-100-5p and miR-1246 HUVECs were the target cells used in the in vitro assays. A tube formation assay involving endothelial cells SHED-Exos show potential as a novel therapeutic approach for anti-angiogenic treatment, inhibiting angiogenesis. Wu et al ., 2022 25 China OSCC-CSC-sEVs lncRNA UCA1, which acts as a ceRNA for miR-134. The OSCC cell line Cal27 (CL-0265, human oral epithelial cells (HOEC, and HEK-293T cells. The PI3K/AKT pathway was implicated in the mechanism by which lncRNA UCA1 modulates M2 macrophage polarization by targeting LAMC2. In vitro : OSCC-CSC-sEV UCA1 transfer induces M2 macrophage polarization via LAMC2-mediated PI3K/AKT, aiding tumour progression and immunosuppression. In vivo : M2-TAMs enhance OSCC cell migration, invasion, and tumorigenicity by transferring exosomal UCA1 targeting LAMC2. Rosenberger et al ., 2019 26 Chile MenSC and UCMSC *Unclear HUVEC and human microvascular endothelial cell line *Unclear In vitro : Treatment of endothelial cells with exosomes leads to increased cytotoxicity, reduced VEGF secretion, and inhibited angiogenesis in a dose-dependent manner. In viv