1.4. Mesenchymal stem cells (MSCs):
MSCs (or mesenchymal stromal cells) have the potential for self-renewal and differentiation into various cell types [102, 106, 112]. Moreover, MSCs can be involved in many cancer events such as epithelial-mesenchymal transition, angiogenesis, anti-apoptosis, metastasis, immunosuppression, pro-survival, and treatment resistance especially drug resistance [112]. These cells can be inherently resistant to chemotherapy and in various cancer types, they expand this resistance among cancer cells [121-127]. MSCs can contribute to drug resistance and quiescence of cancer cells by creating a pre-metastatic niche for tumor cells [128]. Furthermore, they can move to inflammatory areas, and subsequently, infiltrate the tumor [106]. Indeed, MSCs migrate to the tumor site via the action of factors derived from tumor cells, then, infiltrate the tumor and produce the necessary factors for cancer cells [102]. Mesenchymal stem cells can cause drug resistance through the following actions:
1. Direct cell-to-cell contact between MSCs and cancer cells that triggers multiple signaling cascades in tumors [112, 129].
2. Genetic mutations in MSCs: Genetic changes occur not only in tumor cells but also in non-malignant cells, leading to latent tumor recurrence in radiotherapy- and chemotherapy-treated patients [112, 130].
3. Secretion of soluble factors: MSCs can release a variety of fatty acids, cytokines, and growth factors that result in drug resistance [102, 112, 131, 132].
4. Differentiation of MSCs into CSC or CAF: Some characteristics of CSCs are enhancing colony-forming capacity and pluripotency, obtaining drug resistance along with loss of anchorage dependence, having the capability to promote of metastasis and tumor progression, and inherently resistant to chemotherapy, moreover, CAFs have a key role in drug resistance and CAF-MSC cells (a type of CAF cells possessing resembling function and phenotype of bone marrow-derived mesenchymal stem cell (BM-MSC) in the tumor stroma) are involved in tumor growth, the decline in cell apoptosis, increase in cell proliferation, and resistance to chemotherapy; therefore, by differentiating MSCs into CSC or CAF, they can cause treatment resistance [112].
5. Release of exosomes: According to multiple studies, exosomes released from MSCs promote chemotherapy resistance through mediation in interactions between cancer cells and MSCs, specific mRNA molecules and proteins transportation, and drug sequestration [112, 133].