Cancer stem cells: advances in knowledge and implications for cancer therapy

Abstract

Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.

Fig. 1

The Development of the CSC Theory. As early as 1855, in the discourse on the origins of tumors, Cohnheim posited that tumors stemmed from embryonic cells. Subsequent decades of genetic research concluded that tumor formation necessitates the accumulation of susceptibility genes, implying that the cells causing tumors must possess self-renewal capabilities. It wasn’t until 1937 that Furth demonstrated the potential of single malignant cells to induce tumors. This revelation spurred researchers to delve into the characteristics of such cells, encompassing self-renewal, aberrant differentiation, interaction with the microenvironment, and heightened plasticity. In 1997, John Dick identified leukemia stem cells. Since then, the theory of CSCs has basically taken shape. And people have begun to continuously isolate and prove CSCs from different tumor types

Fig. 2

Origin, formation and/or maintenance of CSCs. CSCs originate from differentiated normal/cancer cells, stem/progenitor cells, or cell-cell fusion of cancer cells with stem cells or cancer cells with differentiated cells. The microenvironment of the CSC niche plays an essential role in the formation and maintenance of CSCs. MSCs, TAMs, MDSCs, and CAFs can secrete cytokines and chemokines that induce and/or maintain stem-like properties of cancer cells. Besides, CAFs can also modulate stemness by secreting EVs, and MSCs can regulate stemness through direct contact with CSCs. Finally, hypoxia and high nitric oxide (NO) concentration also support the CSC niche

Fig. 3

Biomarkers for CSCs in solid tumors and hematopoietic malignancies. Biomarkers for CSCs in solid tumors (left), hematopoietic malignancies (right), or both (center). The biomarkers can be classified into cell-surface markers and intracellular markers. Intracellular markers can be further classified into transcription factors that function in the nucleus and molecules that are found in the cytoplasm. Cell-surface markers make up the main differences between markers of solid tumors and those of hematopoietic malignancies

Fig. 4

Crosstalk of signaling pathways in CSCs. a, b The Notch pathway can be activated by the NF-κB pathway while activating the NF-κB pathway. c PPARγ inhibits the STAT5 pathway to downregulate the expression of HIF2α and CITED2, ultimately attenuating the stemness characteristics of CSCs. d BRAP inhibits the TGF-β/PI3K/AKT/mTOR axis to reduce the stemness of CSCs. e LncROPM upregulates PLA2G16 expression to facilitate phospholipid metabolism, which subsequently activates the PI3K/AKT, WNT/β-Catenin, and Hippo/YAP pathways to maintain the stemness of CSCs. f Amplified miR-139 through the miR-139/PDE2A/Notch1 loop, inhibits the WNT pathway to attenuate the tumorigenicity of CSCs. g LINC00115, upregulated by the TGF-β pathway, sponges miR-200s to activate the ZNF596/EZH2/STAT3 axis to promote the stemness and tumorigenesis of CSCs. h Activation of the TLR4/NANOG axis subsequently upregulates the YAP1/SMAD3 and IGF2BP3/AKT/mTOR/SMAD3 pathways to inhibit the nuclear transfer and phosphorylation of SMAD3, ultimately attenuating the tumorigenicity of CSCs. i WNT/β-Catenin pathway downstream effector PROX1 inhibits each other with Notch1, thereby elevating the stemness of CSCs and hindering their differentiation. j PROX1, which can be activated by the WNT/β-catenin pathway, inhibits each other with Notch1, thereby enhancing the stemness of tumor cells and hindering their differentiation. k SOX9/PROM1 positive feedback loop in inhibits differentiation by activating the CSC program, which positively correlates with WNT pathway and negatively correlates with TGF-β pathway. l The PI3K/AKT pathway, activated by CBX7, further stimulating the NF-κB/miR-21 axis, and ultimately promoting the stemness characteristics and metastasis of tumor cells

Fig. 5

Mechanism of resistance of CSCs to chemotherapy. CSCs possess the ability to maintain a quiescent state and reduce metabolic activity, thereby exhibiting resistance to chemotherapy. Furthermore, CSCs are capable of metabolic reprogramming, utilization of ABC transport proteins, and activation of DNA repair pathways, which allows them to evade chemotherapy. Additionally, the microenvironment plays a crucial role in supporting CSC survival. The balance between ROS and anti-apoptotic versus pro-apoptotic signals, along with exosomes secreted by tumor-associated fibroblasts, dynamically regulates CSCs

Fig. 6

Immunotherapy targets CSCs. a Targeted therapy using antigens of CSCs, such as CAR-T and monoclonal antibodies, etc. b Leverage the innate immune cells’ natural cytotoxic activity to circumvent antigen presentation and nonspecifically target CSCs, such as NK cells or CIK cells. c Active immunization strategies involve the use of DC vaccines loaded with CSC lysates, or the reinvigoration of T cells through targeting immune checkpoints. d γδ T cells exhibit the dual capacity to directly attack CSCs and indirectly stimulate NK cells or DCs to target CSCs

Fig. 7

Radioresistance induced by CSCs. a As for radiosensitive cancer cells, radiation can induce the production of ROS, which subsequently leads to the accumulation of cytochrome C and apoptosis, and DNA damage that causes various types of cell death. b CSCs can be radioresistant due to their high expression of DNA damage repair-associated molecules and powerful radical scavenging system

Fig. 8

Targeted drug resistance of CSCs (except liver cancer). (a, k) gefitinib resistance (b) osimertinib resistance (c, d, j) erlotinib resistance (e) palbociclib resistance (f) capmatinib resistance (g, h) vemurafenib resistance (i) sunitinib resistance

Fig. 9

Targeted drug resistance of liver CSCs. a IFNGR stimulation of the JAK2/STAT1/PARP1 pathway is responsible for stemness maintenance and sorafenib resistance, and can be reversed by the JAK2 inhibitor momelotinib. b MSI2 binds LFNG to stimulate the Notch1 pathway to upregulate tumor cell’ stemness and sorafenib resistance. c Wortmannin inactivates the TROY/PI3K/AKT axis triggered by CAFs to inhibit the stemness of tumor cells and restore their sensitivity to sorafenib. d FZD10 contributes to stemness maintenance and lenvatinib resistance by activating the β-Catenin/c-Jun/MEK/ERK axis. e CD73 upregulates the c-Myc/SOX9 axis and inhibits GSK3β to hinder the ubiquitination and degradation of SOX9, ultimately maintaining the stemness characteristics and lenvatinib resistance of tumor cells. f CSCs release exosomes to upregulate Nanog expression in a RAB27A-dependent manner, promoting stemness characteristics and regorafenib resistance of tumor cells

Fig. 10

Targeting CSCs through classical signaling pathways. a WNT/β-Catenin pathway. Commonly developed targets include WNT/Frizzled complex, β-Catenin/TCF, CK1α, tankyrase, and COX. b Hedgehog pathway. Commonly developed targets include SHH-PTCH interaction, SMO, and GLI. c Notch pathway. Commonly developed targets include Notch, Dll3/4, γ-secretase, ADAM. d NF-κB pathway. Commonly developed targets include NF-κB complex, IκB, IKKα/β/γ, NF-κB inducing kinase (NIK). e JAK/STAT pathway. Commonly developed targets include JAK1/2/3, STAT1/2/3/4/5. f TGF-β pathway. Commonly developed targets include TGF-β1/β2/β3, TβRI/II, Smad3/4/5. g PI3K/AKT pathway. Commonly developed targets include PI3K complex, AKT1/2/3, mTORC1/2. h PPAR pathway. Common targets that have been developed include PPARα/γ/δ

Fig. 11

Drug delivery systems in targeting CSCs therapy. The utilization of drug delivery systems, predominantly nanomaterials, plays a pivotal role in targeting CSCs therapy. Traditional passive targeting relies on the leakage of immature blood vessels. However, advancements in technology have enabled the attainment of active targeting of nanoparticles through surface modifications. Nanomaterials, serving as carriers, offer the capacity to encapsulate therapeutic agents such as small interfering RNA (siRNA) and drugs, thus safeguarding against drug degradation. Moreover, active targeting facilitated by nanomaterials enhances drug concentration and enables precise identification of CSCs. Furthermore, nanoparticles can be stimulated both internally and externally to trigger drug release, with these triggering factors potentially doubling as therapeutic strategies