MSCs are a class of non-hematopoietic stem cells belonging to the mesoderm, with the characteristics of self-renewal, high proliferation, multi-directional differentiation potential. It has been demonstrated that one of the possible sources of MSCs is the blood vessel wall, which is a type of perivascular cells. This provides a great potential for its involvement in tissue regeneration (da Silva Meirelles et al., 2008). Many studies have been conducted to validate the use of MSCs in bone regeneration and nerve regeneration (Liau et al., 2020; Fu et al., 2021). MSCs exhibit chemotactic properties similar to immune cells in response to tissue injury and inflammation. MSCs can release various bioactive factors, such as immunosuppressive molecules, growth factors, chemokines, and complement components to regulate the inflammatory process and create a balanced inflammatory and regenerative microenvironment in damaged tissues, thereby treating various degenerative and inflammatory diseases (Shi et al., 2018). Because of their inherent ability to migrate and colonize into tumor tissues, MSCs were reported to closely interacted with tumor and tumor cells. It was shown that interleukin (IL)-12-expressing MSCs could inhibit the growth of tumor in a model of mouse renal cell carcinoma (Gao et al., 2010), and in a mouse melanoma brain metastasis model, intracarotid administration of oncolytic herpes simplex virus-armed MSCs significantly prolonged the survival of mice (Du et al., 2017). Thus, MSCs are attracting increasing interest in the field of oncology.

Oral cancer is one of the most common malignant tumors of the head and neck, often occurring in the middle-aged and elderly population and more than 90% of oral cancer are oral squamous cell carcinoma (OSCC) (Choi and Myers, 2008). Over the past decades, the incidence of oral cancer has been on a gradual increase. Smoking, excessive alcohol consumption as well as betel nut chewing, are the main causative factors of oral cancer. In addition, it cannot be ignored that the number of young patients suffering oral cancer also has been increasing. According to public reports, the number of new oral cancer cases and patients of new deaths reached 377,000 and 177,000, respectively, worldwide in 2020 (Chai et al., 2020; Grigolato et al., 2021; Sung et al., 2021).

A growing number of studies have demonstrated the beneficial effects of MSCs-based therapies in the treatment of various diseases, including oral cancers. However, some other studies showed that MSCs may enhance the growth and metastasis of oral cancer. The exact role of MSCs’ effects on tumor, i.e., whether MSCs could exert tumor-suppressive effects or, conversely, whether they favor tumor growth, has not been fully elucidated, and some concerns, including the mechanisms responsible for these phenomenons remain to be not yet clear. To better serve the discovery of potential strategies for the treatment of oral cancer, we reviewed the effects of MSCs on oral cancer, the underlying mechanisms, and MSCs’ potential applications in the treatment of oral cancer.

Originated from the mesoderm and firstly found in bone marrow, MSCs can be isolated from multifarious post-natal tissues, including adipose, umbilical cord, umbilical cord blood, amniotic fluid, and other tissues (Whiteside, 2018; Almeida-Porada et al., 2020; Tavakoli et al., 2020). Apart from these tissues, MSCs have also been isolated from dental tissues, including dental pulp, dental follicle, apical papillae, periodontal ligament, and gingiva (Shi and Gronthos, 2003; Pierdomenico et al., 2005; Janjanin et al., 2008; Lindroos et al., 2008; Sonoyama et al., 2008). MSCs are positive for CD105, CD90, CD73, CD146, CD29, STRO-1, but are negative for CD14, CD34, CD45 (Lei et al., 2014; Hung et al., 2015; Ji et al., 2016). Under suitable inductive medium, MSCs are capable of differentiating into osteoblasts, adipocyte, chondrocytes, and many other cells (Whiteside, 2018).

MSCs are localized throughout the adult body as a small population in the stroma of the tissue concerned, and the micro-environment protect their self-renewal potential and undifferentiated state (Urbanek et al., 2006; Wang et al., 2011). Upon tissue injury or inflammation insult, MSCs are activated and leave their ecological niche and migrate to the site of injury, inflammation and tumors, where they are able to secrete various cytokines, chemokines, and growth factors that closely interact with the inflammatory environment and the tumor environment (TME), respectively (Sun et al., 2014).

Compared to embryonic stem cells, MSCs are related with fewer ethical issues, and have emerged as one of the most promising cell therapy tools due to their excellent biological properties, such as relatively simple cell isolation procedure, high potential for expansion, low immunogenicity, pluripotency, and the ability to secrete mediators that support tissue transformation or replacement (McLeod and Baylis, 2006; Caulfield and Ogbogu, 2011; Widdows et al., 2014; Kariminekoo et al., 2016; Musiał-Wysocka et al., 2019). With the accumulation of data about the interaction between MSCs and tumor cells, MSCs have been demonstrated the natural anti-tumor functions, which is the basis for intensive research for new methods using MSCs as a tool to inhibit tumor growth and invasion, although the dualistic role of MSCs on tumors still exists.

The interaction of MSCs and malignant tumors provides new clinical ideas for the treatment of malignant tumors. However, the promotive or inhibitory effects of MSCs on tumors are still inconclusive. It is shown that the normal tissue microenvironment, whose stability is usually maintained by MSCs, is subsequently changed to TME once a tumor develops and the in vivo homeostasis is disrupted, and TME also could be remodeled by MSCs of normal tissue origin (Whiteside, 2018). Interactions between MSCs and tumors in TME are described in Figure 1.

Some chemokines, cytokines and growth factors in TME have strong chemotactic effects on MSCs, such as CC-chemokine ligands 2 and 5, chemokine ligands 12 and 16, platelet-derived growth factor (PDGF)-AB, vascular endothelial growth factor (VEGF), hepatocyte growth factor and tumor necrosis factor (TNF)-α (Ponte et al., 2007; Shi et al., 2017). It is reported that after exposure to tumor cell-conditioned medium (CM), bone marrow derived MSCs (BMSCs) acquired a myofibroblast phenotype, which characterized by increased expression of α-smooth muscle actin, fibroblast surface protein, vimentin and stromal-derived factor 1, thereby promoting the growth of tumor cells (Mishra et al., 2008). After co-culture with VEGF, MSCs acquired a lymphatic phenotype and an endothelial cells phenotype characterized by the expression of von Willebrand factor, VEGF receptors 1 and 2, vascular endothelial-keratin, and vascular cell adhesion molecule-1, which promote vascular and lymphatic angiogenesis, ultimately lead to regional lymph node metastasis (Oswald et al., 2004; Conrad et al., 2009). These effects are also verified by the study that the BMSCs-mediated tumor promotion is associated with enhanced angiogenesis induced by the secretion of pro-angiogenic factors. In a study of colorectal cancer, Huang et al. (2013) found that MSCs-derived IL-6 could activate Akt and ERK pathways in endothelial cells through upregulation of endothelin-1 in cancer cells, which subsequently enhanced tropism and angiogenesis to tumors. Stromal-derived factor-1α secreted by BMSCs promotes the invasion of squamous cell carcinoma by activating nuclear factor-κB (Chung et al., 2006; Rehman and Wang, 2008; Xu et al., 2019). The epithelial-mesenchymal transformation (EMT) is a key factor in the migration and invasion of malignant tumors. The morphology and phenotype of cancer cells post-EMT are altered and acquire the ability to metastasize to distant sites. Tumor-derived MSCs secrete large amounts of IL-6 and IL-8 to stimulate M2 macrophage polarization, which enhances the EMT of gastric cancer, thus promoting migration and invasion of tumor (Dominici et al., 2006; Li et al., 2019b). MSCs have been reported to favor tumor growth due to immunosuppression, and Djouad et al. (2003) demonstrated that soluble factors produced by MSCs exert immunosuppressive effects by mediating the inhibition of lymphocyte proliferation by CD8⁺ regulatory cells, and further identified the tumor growth-promoting effect of MSCs in a study of B16 melanoma.

In contrast with the above results, a growing number of studies have identified a dual role of MSCs for tumor progression. Pakravan et al. (2017) demonstrated that exosomes derived from BMSCs were able to downregulate the expression of VEGF in breast cancer cells, thereby inhibiting vascular growth. It is reported that interferon (IFN)-γ, IFN-γ-inducible protein 10, IFN-1β, IL-6, IL-8, and TNF-α appear to play an important role in the inhibitory effect of MSCs on tumor cells (Tomchuck et al., 2008). MSCs may inhibit tumor progression by means of cell fusion. Wang et al. (2012b) successfully inhibited the progression of esophageal cancer by inhibiting tumor cells growth and increasing apoptosis by fusing human umbilical cord MSCs with esophageal cancer cells. Human BMSCs derived extracellular vesicles can promote apoptosis or necrosis and inhibit the proliferation of tumor cells in hepatocellular carcinoma, ovarian cancer and Kaposi’s sarcoma by activating cell cycle negative regulators (Bruno et al., 2013).

Given the complex interactions between MSCs, tumor cells, and TME, no simple factor by itself can determine the fate of tumor, and further studies are needed to better understand the special functions of MSCs in the TME before these cells become valuable tools in cancer therapy.

In recent years, there have been gradually increasing studies on the relationship between the MSCs and oral cancer, and in these studies, it was found that, on the one hand, MSCs have an inhibitory effect on oral cancer, while on the other hand, MSCs can promote the progression of oral cancer. In addition, the effects of MSCs derived from different sources on oral cancer were not consistent. The effects of different MSCs on oral cancer are shown in Table 1.

Currently, MSCs are used in clinics for anti-inflammatory therapy, tissue regeneration, graft-versus-host response, autoimmune diseases and gene transfection. In addition, MSCs-based tumor therapy is promising, as MSCs can migrate directionally to target tissues to exert their own effects, and can also exert the effects of therapeutic factors by means of gene transfection and secretion of several kinds of factors, presenting the anti-tumor effects.

Under normal conditions, MSCs maintain a stable internal environment in tissues, and once a tumor develops, the normal tissue microenvironment is subsequently changed to a TME. Tumor-secreted cytokines and growth factors, such as PDGF-AB, VEGF, hepatocyte growth factor, IL-8, etc., can recruit local and distant MSCs, and MSCs can also influence tumor progression by affecting angiogenesis, regulating immunity, inducing apoptosis, inhibiting or promoting proliferation, invasion, migration, etc. As mentioned above, MSCs from different tissues have different effects on oral tumors, including those from normal, precancerous and cancerous tissues, which provide a new perspective for further exploration of oral cancer progression and treatment. At the same time, administration of different doses of MSCs may also produce different results. In addition, it seems that different results can be obtained by using different cancer models and by different routes of administration of MSCs at different times of cancer progression. Notably, anticancer treatment can also affect the recruitment of MSCs.

However, since most of the currently available evidence is obtained through non-human xenografts, the literature supporting the direct use of MSCs for the treatment of cancer patients is still insufficient and their safety remains a major consideration, and more research must be conducted to provide evidence and improve the therapeutic efficacy of MSCs in cancer treatment. These cells have great potential to revolutionize existing cancer therapies.