While studies have shown the various roles of MSCs in cellular functions, including the ability to differentiate into various cell types for damaged tissue repair and regeneration, current evidence has also pointed to the paracrine signaling mechanism [4,5] related to the release of several trophic factors including cytokines, chemokines, and extracellular matrix protein as well as exosomal miRNA into the surrounding cell environment. These paracrine signals were reported to be associated with immunomodulatory properties, angiogenesis, anti-apoptosis, anti-oxidation, anti-inflammation, and cell proliferation [4]. However, in the context of cell cancer interaction, paracrine signaling also promotes the migration of MSC to the tumor site [6] and has been known to either exert suppression or promotion of tumors within the tumor microenvironment (TME) [7]. Among the signaling molecules involved with MSC migration to the tumor site are CXCL12/CXCR4 [8], CCL2 in Breast cancer, and SDF-1 in colorectal, prostate, and breast cancers [9]. The recruitment of MSC to the cancer site can also be achieved via the interaction of MSC with certain cytokines responsible for angiogenesis (IL-8, TGF-β, and VEGF) that are secreted by cancer cells [10]. In addition, MMP-1, a component of the extracellular matrix, helps in stimulating MSC homing to the cancer site via PAR-1 cleavage and activation [11].

The dual role of MSC in cancer-related studies, as either promoting or suppressing cancer activities in cancer cells, is a much-accepted fact, with various reports linking MSC as a tumor enhancer via mediating angiogenesis, attenuating immune reactions, initiating epithelial to mesenchymal transition (EMT), and promoting metastatic processes whereas the tumoricidal effect of MSC on cancer cells appears to be more apparent through the induction of apoptosis and signaling pathways alterations [12].

Several studies have revealed that MSCs can support the tumor vasculature via direct differentiation of MSCs into myofibroblasts that are were then transformed into tumor-associated fibroblasts (TAFs) [13] or indirectly via the secretion of several growth factors [14]. MSCs are capable of secreting several angiogenic factors (FGF-2, PDGF, VEGF, TGF-β, IL-6, IL-8, and angiopoietin-1) that facilitate angiogenesis leading to tumor-promoting features [15]. Additionally, the immunosuppressive effect of MSC contributes to cancer cells’ escape from the immune system surveillance. Due to their direct action on immune cells, MSCs are capable of inhibiting apoptosis or inhibition of T cell proliferation which results in a decline of immunogenic activity [16]. Furthermore, MSC has also shown pro-metastatic effects that are mediated via paracrine factors, including TGF-β, CXCR4, and CCL5; chemokines secreted from MSC [10,16,17]. Martin et al. (2010) revealed that the co-culture of bone marrow-derived MSC with breast cancer resulted in the overexpression of EMT-specific genes and a decrease of mesenchymal to epithelial (MET) genes [18]. Similarly, in a co-culture-based interaction study between an adipose-derived MSC (ADSC) and MCF-7 breast cancer and in an in vivo nude mouse model, MCF-7 cells were shown to exert tumor tropism effects on ADSCs, reportedly regulated by chemokines, such as the macrophage inflammatory protein (MIP)-1δ and MIP-3α. This effect was mediated by epithelial–mesenchymal transition, which significantly induced tumor sphere formation in vitro and promoted tumorigenicity in vivo [19]. The interaction of MSC with cancer cells can also result in the differentiation of MSC into carcinoma-associated fibroblasts (CAFs) via TGF- β resulting in stabilizing the tumor tissue at the primary and metastatic site and thus promoting cancer stemness as well as chemoresistance via paracrine factor secretions [20]. MSC-conditioned medium has been shown to upregulate BCl-2, an anti-apoptotic protein, and suppress the expression of P53 and BAX (apoptosis proteins) that resulted in inhibiting apoptosis, which in turn promoted colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation [21].

Mesbah et al. (2021) showed that the cultivation of colorectal cancer cells with MSC inhibited proliferation and induced apoptosis of colorectal cancer cells with increased expressions on P53, Caspase3, and P21. The tumoricidal or pro-neoplastic effect of MSC on cancer can also be attributed to its hypo- or hyper-activation of certain signaling pathways associated with cancer proliferation, survival, and progression [22]. Among the pathways involved are the ERK1/2, Wnt, PI3K/AKT, JAK/STAT, MYC, Hippo, and NF-kB pathways [23]. MSC-conditioned medium when cultured with head and neck squamous cell carcinoma cell lines resulted in enhancing cellular proliferation via the activation of ERK1/2 signaling in vitro [24]. Additionally, MSC administration into U251 glioma cells suppressed tumor growth and induced apoptosis via downregulating PI3K/AKT pathway [25]. Interestingly, a co-culture experiment on adipose-derived MSC (AD-MSC) with MCF7-luminal and MDA-MB-231-basal breast cancer cells demonstrated the possible influence of exosomal miRNA in promoting these cancer cells towards a more dormant-epithelial phenotype associated with lower metastasis potential but higher chemoresistance. The decrease in metabolic and cellular activities of these dormant cells was attributed to a possible form of evasion by the cancer cells from the effects of these drugs, which generally targeted rapidly proliferating cells, as well as the increased expression of drug resistance-related proteins triggered by MSC-exosomes [26].

Another exciting development at the forefront of MSC and cancer therapy is the interaction between exosomal miRNA and cancer cells. The dysregulation of exosomal miRNA was shown to promote tumor growth due to the activation of angiogenic signaling pathways such as VEGF [27], hedgehog signaling pathway [28], and STAT3 [29]. Other studies reported on the effects of exosomal miRNA that decreased tumor growth were associated with NF-κB p65 activation [30], downregulation of VEGF expression [31], inhibition of Galectin-3 [32], regulation of KDM4B/HOXC4/PD-L1 axis [33], down-regulation of mTOR and S6KB1 expression [34], and down-regulation of trefoil factor 3 (TFF3) [35]. Examples of cancer studies involving exosomal miRNA are summarized in Table 1, and a comprehensive list of miRNA shown to be associated with various cancer types was previously reviewed by Galland et al. [7] as well as Dalmizrak and Dalmizrak [36]. Despite the complexities of MSC interaction with cancers in the respective TME, numerous exosomal miRNA were found to be directly associated with major cancer pathways (Table 1) and were shown to be promising anti-cancer delivery agents with potential as non-cell-based cancer therapy (Table 2).

Exosomal miRNA	MSC	Cancer Type	Signaling Pathway	Function	Ref.
mrR-21 miR-34a	Bone marrow	Breast cancer	Activation of (ERK1/2) pathway	Promote tumor growth	[27]
miR-221	Bone marrow	Osteosarcoma (MG63) and gastric cancer (SGC7901) cells	Activation of hedgehog signaling pathway.	Promote tumor growth	[28]
miR-193a-3p miR-210-3p miR-5100	Bone marrow grown under hypoxic condition	Lung cancer cells and an in vivo mouse syngeneic tumor model	STAT3-induced EMT	Promote cancer cell invasion and EMT.	[29]
miR-221	Bone marrow	Gastric cancer BGC-823 and SGC-7901 cells	ND	Proliferation, migration, invasion, and adhesion to the matrix of GC BGC-823 and SGC-7901 cells were significantly enhanced	[37]
miR-100-5p miR-9-5p let-7d-5p	Bone marrow	Glioblastoma	Activation of MSCs into (CAFs)-like cells	Promote tumor growth via a decrease in anti-tumoral miR-100-5p, miR-9-5p, and let-7d-5p	[38]
miR-17-5p miR-615-5p	Human adipose MSCs	Hepatocellular carcinoma cell line (Huh-7 cells)	Generation of cancer-associated phenotype of some CAF-like characteristics	Promote tumor growth via upregulation of miR-17-5p and 615-5p	[39]
miR-16	Bone marrow	Mouse breast cancer cell line (4T1)	Down-regulation of expressed VEGF in tumor cells	Suppress tumor growth via inhibition of angiogenesis	[31]
miRNA-1231	Bone marrow	Pancreatic cancer	ND	Suppress tumor growth	[40]
miRNA-16-5p	Adipose-derived mesenchymal stem cells	Breast cancer	ND	Suppress tumor growth	[41]
miRNA-128-3p	Human umbilical cord mesenchymal stem cell-	Pancreatic ductal cell carcinoma	Inhibiting galectin-3	Suppress pancreatic ductal cell carcinoma	[32]
miR-15a	Adipose-derived mesenchymal stem cells	Colorectal cancer	Restriction of immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis	Suppress tumor growth	[33]
miR-199a-3p	T-MScs	HepG2 cells.	Potentially targeting CD151, integrin α3 and 6	Inhibit tumor growth and HepG2 cell migration	[42]
miR-375	Enriched in bone marrow mesenchymal stem cells (BMSC)	Prostate cancer cell	Down-regulating trefoil factor 3 (TFF3)	Inhibit migration and invasion	[35]

Abbreviation: ERK1/2: extracellular signal-regulated kinase1/2; STAT3: signal transducer and activator of transcription 3; EMT: epithelial to mesenchymal transition; CAFs: cancer-associated fibroblasts; VEGF: vascular endothelial growth factor; KDM4B/HOXC4/PD-L1: lysine demethylase 4B/homeobox C4/programmed death-ligand 1; TFF3: trefoil factor 3; ND: not defined.

Exosomal miRNA	MSC	Cancer Type	Delivery Method	Function/Target	Ref.
miR 222/223	ND	Immunodeficient mouse model of dormant breast cancer	MSC transfected with antagomiR 222/223	ND	[43]
microRNA-584	Human MSC (Origin ND)	U87 human glioma cells	Exosomes derived from microRNA-584 transfected mesenchymal stem cells	Suppression of the expression of CYP2J2; reduced the levels of phosphorylated AKT and MAPK	[44]
miRNA-221	Human cord blood mesenchymal stromal	Colorectal carcinoma	Cell-derived exosomes were used in the delivery of anti-miRNA oligonucleotides	Anti-tumor efficacy	[45]
miR-381-3p Mimic	Adipose-derived mesenchymal stem cells	MDA-MB-231 cells	miR-381 loaded ADMSC-exosomes	Downregulation of expressed related genes and proteins; inhibited proliferation, migration, and invasion capacity	[46]
miR-34a	Dental pulp MSCs (DPSCs)	Breast carcinoma cells.	miR-34a loaded modified dental pulp MSCs (DPSCs) exosomes	Repression of tumor proliferation	[47]
miR-30c-5p	Human umbilical cord mesenchymal stem cells	Papillary thyroid carcinoma (PTC)	miR-30c-5p containing extracellular vesicles	Tumor-suppressive miRNA targeted PELI1 to inhibit PTC cell proliferation and migration via activating PI3K/AKT pathway	[48]
Let-7f miRNA	Bone marrow-derived human mesenchymal stem cells	4T1 breast tumor model	Let-7f miRNA containing extracellular vesicles	Regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells	[49]
MiR-199a-	Adipose tissue-derived mesenchymal stem	Hepatocellular carcinoma	miR-199a-modified exosomes	Improve chemosensitivity through mTOR	[50]
miR-124	BM-MSC		miR-124 derived exosomes	Anti-tumor effects on cell proliferation, epithelial–mesenchymal transition, and chemotherapy sensitivity	[51]

Abbreviation: CYP2J2: cytochrome P450 2J2; AKT: serine/threonine kinase (protein kinase B); MAPK: mitogen-activated protein kinase; PELI1: pellino homolog 1; PI3K: phosphatidylinositol-3-kinase; SDF-1α: human stromal-derived factor 1; ND: not defined.