Fig. 1

Cancer stem cells targeting. There are Different approaches for targeting cancer stem cells that can be used in a variety of cancers such as: (A) CSC niches: various types of cells and growth factors involving endothelial cells, immune cells, cancer associated fibroblasts (CAFs), various growth factors, and cytokines can be contained in the niche which provide a suitable microenvironment for tumor growth. Severe hypoxia and increased angiogenesis in the tumor microenvironment would cause a CSC niche to be formed near blood vessels. Along with these components, environment shifts, such as hypoxia, and pH have been introduced to contribute to the CSC niche. One of the important features of TME is low oxygen levels, referred to as hypoxia which turns out to maintain the stemness and thus malignancy of CSCs and finally promote tumor survival and metastasis. in response to hypoxia, the expression of the hypoxia-inducible factors (HIF1α, HIF-2α) are increased which can result in tumor malignancy. B Signaling pathways: One of the emerging targets for cancer treatment is the signaling pathways that regulate CSCs maintenance and survival. At present the Wnt, Notch, and Hh signaling pathways, as well as the TGF-β, JAK-STAT, PI3K, and NF-κB signaling pathways are the main signaling pathways which often interact with each other in CSCs during tumor development. Targeting the Wnt pathway has been proved to be difficult but noticeable progress has been made in early clinical trials of Notch and Hh pathway inhibitors. C Cell surface markers: targeting CSC surface markers is a potential CSC therapeutics approach and CD44 is one of the most commonly used and established CSC biomarkers which is a cell-surface extracellular matrix receptor. Many studies have introduced CD44 antibody therapy as the major anti-CSC approach. Another well-known CSC marker in several tumors such as glioblastoma, hepatocellular and colon cancers is CD133 which is a transmembrane glycoprotein. CD133 + CSCs have been proved to be resistant to chemotherapy and radiotherapy due to their lower proliferation, slower cell cycle, anti-apoptotic genes and higher expression of DNA repair. EpCAM has been discovered to be a CSC marker in solid tumors and is correlated with all CSCs characteristics. There is a significantly high frequency of tumor-initiating cells in EpCAM + /CD44 + /CD24− population in breast cancer. D Therapeutics molecules and (E) differentiation therapy: Metformin, salinomycin, DECA-14, rapamycin, Oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, All-trans retinoic acid (ATRA) and monoclonal antibodies have recently been shown to suppress CSCs self-renewal in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can be used to dramatically hinder tumor growth, metastasis and recurrence; and (F) overcoming drug resistance in CSCs: Drug efflux leads to decreased intracellular drug concentration in CSCs through multi-drug resistance (MDR) transporters. Overexpression of ABCG2 which is one of the subfamilies of the ATP-binding cassette (ABCA-G) transporters is a major mechanism of chemoresistance in CSCs cells. The fourth generation of inhibitor drugs is in progress [4, 9,10,11,12,13]. CSCs cancer stem cells, DLL delta‑like ligand, ATRA all‑trans retinoic acid, OSM oncostatin M, BMPs bone morphogenetic proteins, CDF difluorinated curcumin, ALDHs aldehyde dehydrogenases, DEAB diethylaminobenzaldehyde, HIF hypoxia‑inducible factors