Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

Abstract

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs' self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.

Keywords: cancer; cancer stem cells; drug resistance; metastasis; microenvironment; stem cells; tumorigenesis.

Figure 1

Quiescence in cancer stem cells. CSCs have the unique capacity to undergo a dormant state, making them invincible to external attack and preserving a reservoir of highly proliferative cells, which can recreate the entire tumor, if necessary.

Figure 2

The role of stiffness in cancer. Stiffness triggers the differentiation process of CSCs, allowing the tumor to constantly reconstitute itself. A stiff matrix fosters CSC dissemination in the bloodstream, responsible for metastatic dissemination.

Figure 3

The tumor microenvironment supports CSCs. The tumor microenvironment is primarily responsible for the regulation of CSC plasticity, activating stemness pathways and promoting immune escape through cytokine release and inactivation of the T-lymphocytes, thereby inducing a tumor cell to acquire the CSC phenotype or a mesenchymal stroma cell to complete the epithelial mesenchymal transition towards cancer phenotype. TME prompts the angiogenetic de novo formation via CSC spread in the bloodstream for metastatic dissemination.

Figure 4

Signaling pathway regulating self-renewal in CSCs. Notch signaling, like the Wnt and Hedgehog pathways, is a highly evolutionarily conserved pathway of cell fate determination, with major relevance across multiple aspects of cancer biology, from angiogenesis and tumor immunity to the regulation of CSCs’ self-renewal ability.

Figure 5

Challenging cancer drug resistance. A novel approach to cancer therapy focused on CSCs to break through the mechanism of drug resistance in cancer.

Figure 6

Target therapy specific to quiescent cells. CSCs are protected inside the niche in a dormant scheme. These different synthetic nanoparticles (NPs), such as liposomes, micelles, polymers, and gold nanoparticles, have been shown to successfully deliver anticancer drugs to the targeted CSCs by using CSC-specific markers, such as CD44, CD90, and CD133.