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].