Abstract
Simple SummaryCancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process.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.
Highlights
Cancer is considered one of the leading causes of death worldwide
One of the most critical cell types is the cancer-associated fibroblasts (CAFs), which play a primary role in maintaining the plasticity of cancer stem cells (CSCs) through the promotion of tumor cell de-differentiation, the construction of a supportive niche for colonization formed by fibrils of collagens, and their ability to escape chemotherapy [43,97]
CSCs induce the synthesis of angiogenetic factors and the formation of new vessels [119], and they are supported by the structures and signals coming from normal tissue, such as the CAF and niche extracellular matrix (ECM) [120–123] (Figure 3)
Summary
Cancer is considered one of the leading causes of death worldwide. Solid tumors are generally treated with surgery or medical approaches [1,2]. Recent research has identified and isolated cancer stem cells (CSCs), which are considered one of the primary causes of resistance to oncological treatments, and contribute to local and distant recurrence [10,11] These CSCs are characterized by their ability to self-renew and their capacity to proliferate and contribute to significant tumor progression. In solid tumors, the biomechanical properties of the microenvironment have recently been discussed for their capacity for inducing cancer stress, of stiffness around the network tissue, and abnormal interstitial fluid pressure (IFP) [23–25] These combinations of factors may contribute to the metastatic process through the formation of “stressor foci,” which, driven by immunological distress associated with cellular collisions, induce the dissemination of tumor cells and CSCs from the vessels to the circulatory system [27,28]. These biological processes are responsible for tumor growth and recurrence, in association with the development of resistance to common cancer treatments
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