Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting

Figure 2

Crosstalk between CSCs and their niches. Cells present in the CSC niche produce some factors that stimulate self-renewal and angiogenesis and secrete factors involved in tumor cell invasion and metastasis. MSCs secrete CXCL12, IL-6, and IL-8 (the black arrows indicate the expression promotion) which promote CSC stemness via upregulating NF-κB. To attract more MSCs towards CSCs, the latter also secretes IL-6. Gremlin 1 is an antagonist produced by MSCs to boost up the undifferentiated state. The tumor cells present around the CSC produce IL-4 which stimulates T_H² and further produce TNF-α for upregulating the NF-κB signaling. GM-CSF, G-CSF, and M-CSF are also produced by the same tumor cell to induce the expansion of some immune cells such as TAMs, TANs, MDSCs, and DCs. To enhance the plasticity of CSCs, TNF-α and TGF-β are produced by TAM to promote the NF-κB-dependent or TGF-β-dependent EMT. TGF-β is also being produced by TAMs to stimulate the T_reg cells. TAM, T_reg, and hypoxic microenvironment also inhibit CD8⁺ T cell, NK cell cytotoxicity, and phagocytosis of macrophages thus inhibiting immunosurveillance (red arrows depicting inhibition). Hypoxic microenvironment increases the concentration of ROS, promotes cell survival, and induces EMT via the TGF-β signaling pathway. The downregulated c-Myc expression inhibits cell proliferation under hypoxia and enhances stemness. CXCL12 is produced by CAF to promote angiogenesis. Under hypoxic microenvironment, CSCs and ECs produce VEGF, which further induces angiogenesis. Nitric oxide production via the Notch signaling pathways leads to the self-renewal of CSCs. CAFs also produce TNC, HGF, and MMP2/3/9, which help in the enhancement of the Wnt and Notch signaling. It also produces MMP10 which promotes ECM degradation and remodeling thus enhances the CSC’s stemness.