Section 2.1: Biological characteristics of CSCs (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 2.1: Biological characteristics of CSCs
With the deepening of tumor biology research, clinical diagnosis and cancer treatment have significantly improved in recent years. However, the high recurrence rate and high mortality rate are still unresolved and are closely related to the biological characteristics of CSCs. With further understanding of CSC characteristics, research on tumor biology has entered a new era. Therefore, understanding the biological properties of CSCs is of great significance in the diagnosis and treatment of tumors.
CSCs have a strong self-renewal ability, which is the direct cause of tumorigenesis. CSCs can symmetrically divide into two CSCs or into one CSC and one daughter cell. CSCs expand in a symmetrical splitting manner to excessively increase cell growth, ultimately leading to tumor formation. CSCs isolated from original tumor tissue that were transplanted into severe combined immunodeficiency disease (SCID) mice then formed new tumors. CSCs and normal stem cells also share some of the same regulatory signaling pathways, such as the Wnt/beta-catenin, Sonic Hedgehog (Hh), and Notch pathways, which are involved in the self-renewal process. In addition, other signaling molecules, such as PTEN and the polycomb family, also play important roles in the regulation of CSC growth. The regulation of CSC self-renewal is the key link to understanding tumorigenesis. These studies will provide a clear target for cancer treatment.
In addition to their self-renewal ability, CSCs also have the ability to differentiate into different cell types. Bonnet and Dick demonstrated in 1997 that CD34+/CD38- leukemia stem cells (LSCs) have the ability to differentiate and proliferate in SCID mice. Brain CSCs isolated from patients are positive for the markers CD133 and nestin, which are the same markers as those of normal neuronal stem cells, but some cells lack surface markers for differentiation. Generally, various signaling pathways regulate the self-renewal and differentiation of normal stem cells to promote their proliferation and differentiation in a relatively balanced manner. Once the regulatory balance is destroyed, uncontrolled CSCs ultimately lead to tumorigenesis. CSCs also transdifferentiate into other multilineage cells to regulate tumorigenesis. Bussolati et al. found that renal CSCs differentiated into vascular endothelial cells (ECs) in the bulk of tumors formed in SCID mice after injection of human renal CSCs. Additionally, CSCs that differentiate into vascular ECs and promote angiogenesis have been found in a variety of cancers, such as glioblastoma and liver cancer.
Metastasis refers to the process by which cancer cells travel from the primary site through lymphatic vessels, blood vessels, or the body cavity. Since stromal cells (such as granulocytes and macrophages) secrete signaling molecules in the tumor microenvironment (TME), these cells stimulate epithelial-mesenchymal transformation (EMT) to promote the invasion of tumor cells, which induce differentiated human mammary epithelial cells to form mammary glands. Activation of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway transforms nontumorigenic CD44-/CD24+ breast cancer cells into tumorigenic CD44+/CD24- breast cancer cells. A study showed that CSCs are closely related to EMT, and EMT is likely to be the basis for tumor invasion and metastasis. In addition, CD133+/CXCR4+ pancreatic cancer cells and CD44+/alpha2betahi1/CD133+ prostate cancer cells are also tumorigenic. Therefore, these studies indicate that CSCs play a crucial role in tumor metastasis and development.
Furthermore, understanding the mechanism of CSC drug resistance is vital for cancer treatment and preventing recurrence. CSCs efficiently express ATP-binding cassette (ABC) transporters (including MDR1 (ABCB1), MRP1 (ABCC1), and (ABCG2)), which are multidrug resistance proteins, and these proteins protect leukemia and some solid tumor cells from drug damage and induce drug resistance. According to previous studies, aldehyde dehydrogenase (ALDH), a marker in many CSCs, eliminates oxidative stress and enhances resistance to chemotherapeutic drugs, such as oxazolidine, taxanes, and platinum drugs. ALDH also removes free radicals induced by radiation and stimulates resistance to radiation. Inducing DNA damage and apoptosis through chemotherapy and radiotherapy are commonly used cancer treatments. However, CSCs can effectively protect cancer cells from apoptosis by activating DNA repair abilities.
It is currently believed that CSCs are the key "seeds" for tumor initiation and development, metastasis, and recurrence. CSCs have evolved and are highly heterogeneous. Breast CSCs have different expression patterns of surface biomarkers, such as CD44+, CD24-, SP, and ALDH+. CD271- or CD271+ melanoma stem cells can form tumors in SCID mice. The heterogeneity of CSCs has also been found in other cancers, including glioblastoma, prostate cancer, and lung cancer. The heterogeneity of CSCs is so complex that more effective biomarkers are needed to identify CSCs or distinguish the heterogeneity of CSCs.
