Role of cancer stem cell-derived extracellular vesicles in cancer progression and metastasis

Cancer is a multifactorial disease and one of the leading causes of morbidity and mortality worldwide [1]. Therefore, it is crucial to promptly identify, prevent, and treat all potential causes of cancer in order to minimize its impact on individuals and society. Various factors, such as environmental exposures, lifestyle choices, and genetics, can contribute to its development [2]. Early detection and treatment play a key role in improving outcomes and reducing mortality rates among cancer patients [3]. The occurrence of cancer is accompanied by changes in the adjacent tissue stroma [4]. Several strategies, including chemotherapy, radiotherapy, targeted therapy, and surgery, have been devised to treat cancer [1]. However, these treatments are effective only for certain types of malignancies [5]. Metastasis, heterogeneity, chemotherapy resistance, recurrence, and evasion of immune surveillance are the primary reasons for the failure of cancer treatment [6].

Despite early detection and treatment, some residual cells may persist, which can eventually lead to tumor recurrences and the progression of more aggressive cancer, ultimately resulting in metastasis These residual cells are known as cancer stem cells (CSCs) or tumor-initiating cells (TICs) [7]. CSCs are subpopulations of proliferating tumor cells that contribute to tumor initiation, progression, metastasis, cancer relapse, and drug resistance. They possess the ability to self-renew and differentiate into various types of cancer cells in response to chemotherapy [8]. Due to their greater plasticity and adaptability within tumors, CSCs have a higher potential to form tumors compared to regular cancer cells. CSCs can efficiently transition between epithelial and mesenchymal-like states, and this plasticity enhances tumor resistance and the risk of relapse. In a study of leukemia cells conducted by Bonnet and Dick in 1997, a subpopulation of cells expressing the CD34 surface marker but not the CD38 marker was identified. This CD34+/CD38− subpopulation was found to initiate tumor development in NOD/SCID recipient mice after transplantation. CSCs have also been detected in solid tumors in addition to blood cancers. The presence of CSCs in solid cancers was first observed in 2003 when human breast cancer cells were transplanted into immunocompromised mice. Over time, CSCs have been documented in various other solid cancers, including melanoma, brain, lung, liver, pancreas, colon, breast, and ovarian cancer [7].

CSCs have three potential origins: (a) epigenetic changes occurring in stem/progenitor cells (niche) or even differentiated cells, such as methylation, demethylation, mutation, and rearrangements; (b) spontaneous oncogenic reprogramming in somatic cells; and (c) activation of the tumor microenvironment (TME) through extracellular cues [8]. Theoretically, CSCs have the capacity to rebuild an entire tumor even if only one CSC exists. Successful cancer-targeted therapy requires the elimination of CSCs. As highly plastic cells originating from diverse sources, CSCs are often considered the main contributors to the failure of chemotherapy and radiotherapy. Therefore, targeting CSCs represents one of the most promising approaches for cancer treatment. A deeper understanding of the characteristics and signaling pathways of CSCs is necessary to develop more effective therapeutic strategies aimed at eradicating these cells [8], [9].

Extracellular vesicles (EVs) are pivotal, heterogeneous cell-mimetic vesicles secreted by almost all types of cells in biological fluids such as blood, urine, breast milk, saliva, semen, inter-articular fluid, cerebrospinal fluid, and amniotic fluid [10]. They are composed of a bilayered lipid membrane and are responsible for delivering a broad spectrum of pre-arranged signals (e.g., specific biomolecules) from sender cells to receiver cell(s) [11]. EVs play a crucial role in maintaining tissue homeostasis and responding to pathogenic factors in the extracellular space They serve as an alternative mechanism for cell-to-cell communication, transmitting different messages to recipient cells [12]. The cell machinery has its own mechanism to interpret these signals, which can induce various actions upon encountering the target cell. Depending on the nature of the body fluids, the type of cell, and the contents carried by the vesicles, EVs can perform actions such as immunomodulation, angiogenesis, increased coagulation, induction of programmed cell death, control of neurogenesis, as well as cell division and cell differentiation [13]. While the exact reasons for their secretion from source cells are not fully understood, strong evidence has revealed the diverse roles and functions they carry out in the body [14]. Although the presence of EVs in human peripheral blood has been known for some time, they were first introduced in 1996 as a mechanism for exchanging information between different cells, highlighting their irreplaceable role in antigen presentation. Recent studies have focused on classifying cell-derived vesicles based on size and cellular origin. Based on size, the four main types of extracellular vesicles are microvesicles (MVs) (100–1000 nm in diameter), apoptotic bodies (5000–1000 nm in diameter), exosomes (20–150 nm), and multivesicular bodies (MVBs). Microvesicles and apoptotic bodies originate from the outer protrusion of the plasma membrane, while exosomes and MVBs originate from the indentation of the plasma membrane [15].

Every living cell constantly strives to survive and maintain homeostasis, and cancer cells, especially CSCs, are no exception. These cells employ different complex mechanisms to survive and invade organs or tissues. One of the most effective ways for cancer to spread and grow is by producing anti-inflammatory factors and suppressing the immune system [16]. Utilizing healthy cells to support their growth and dissemination represents a highly intricate strategy. Over the past decade, extensive studies have demonstrated the fundamental potential of extracellular vesicles in controlling the immune system, angiogenesis, and cancer metastasis. Like other cells in the body, CSCs secrete EVs to communicate with other cells and create a suitable environment for the migration and metastasis of cancer cells to other organs or tissues [17]. Researchers studying cancer and cancer stem cells are eager to uncover communication mechanisms, such as extracellular vesicles, that can influence patterns of growth, proliferation, angiogenesis, invasion of other tissues, and cancer metastasis. Understanding these mechanisms could lead to significant advancements in cancer research in the coming years. Therefore, this review article aims to provide a detailed discussion on the role of CSC-EVs in cancer progression and metastasis.

The study of CSCs originated in 1994 with a focus on acute myeloid leukemia. It was revealed that CD34+ and CD38− cells are the stem cells responsible for this type of leukemia [18], [19]. Furthermore, CSCs express different surface markers such as CD44, CD133, and nestin, which have been identified in various tumors and constitute a major component of the tumor mass [20], [21]. Through self-renewal and differentiation into multiple cell types (Fig. 1), CSCs are capable of initiating tumor formation. In light of this, numerous cellular factors regulate the activities of CSCs, making them promising targets for cancer therapeutic strategies [22].

Further investigations have demonstrated that CSCs also arise from solid cancer cells. These cells exhibit characteristics such as self-renewal, differentiation potential, infinite proliferation abilities, and the ability to initiate tumors. Additionally, CSCs display resistance to chemotherapy and radiotherapy, as well as a high capacity for invasion and metastasis. Despite constituting only a small fraction of cancer cells, CSCs possess remarkable tumor-forming potential [8]. This has been consistently observed in both in vitro and in vivo experiments conducted on mice [12]. The aforementioned studies provide a more comprehensive understanding of the invasion, development, and drug resistance of CSCs in cancers, thereby offering novel therapeutic avenues for cancer treatment.

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