Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 254-269 http://medscipublisher.com/index.php/cge 257 cells, including platelets, neutrophils, macrophages, endothelial cells, and T cells. These interactions have been shown to be permissive or even necessary for CTC survival in the blood（Pereira-Veiga T et al., 2022）. CTCs also provide valuable insights into the molecular mechanisms underlying cancer progression. By analyzing the genetic and phenotypic profiles of CTCs, researchers can identify potential therapeutic targets and biomarkers for personalized treatment strategies (Sundling and Lowe, 2019; Liu et al., 2021). Additionally, CTCs can be used to monitor treatment response and detect minimal residual disease, offering a non-invasive approach to cancer management (Yang et al., 2019; Zhang et al., 2020). 3.3 Mechanisms of CTC release and circulation The release of CTCs into the bloodstream involves several mechanisms, including the detachment of cancer cells from the primary tumor, degradation of the extracellular matrix, and intravasation into the blood vessels (Masuda et al., 2016; Pantel and Speicher, 2016). This process is facilitated by various molecular changes, such as the epithelial-to-mesenchymal transition (EMT), which enhances the migratory and invasive capabilities of cancer cells (Masuda et al., 2016; Liu et al., 2021). Once in circulation, CTCs must survive the hostile environment of the bloodstream, which includes shear stress, immune surveillance, and lack of attachment to a substrate(Masuda et al., 2016; Cabel et al., 2017). To evade immune detection, CTCs can form clusters with platelets or express immune checkpoint molecules(Masuda et al., 2016; Liu et al., 2021). These clusters, known as CTC clusters, consist of groups of cancer cells that detach from the primary tumor and travel together through the bloodstream (Fig.1.c). Unlike individual CTCs, these clusters often include non-cancerous stromal and immune cells, enhancing their survival and metastatic potential (Masuda et al., 2016; Pantel and Speicher, 2016). CTC clusters can be broadly categorized into homogeneous and heterogeneous types. Homogeneous clusters contain only tumor cells, typically ranging from 1 to 30 CTCs, while heterogeneous clusters are composed of cancer cells along with non-cancerous stromal or immune cells, such as white blood cells, fibroblasts, endothelial cells, and platelets. These non-cancer cells help CTC clusters evade the immune system by promoting proliferation and resistance to the host immune response（Herath et al., 2020）. Recent studies have shown that CTC clusters have 23-50 times higher metastatic potential compared to single CTCs, primarily due to their multicellular composition and enhanced molecular heterogeneity. Several cell types in the tumor microenvironment, including platelets, enhance the survival of CTC clusters（Herath et al., 2020）. Platelets, for instance, protect CTCs from NK cells and shear stress by coupling with them and transferring major histocompatibility complexes (MHC), allowing CTCs to mimic host cells and evade immune responses. Additionally, CTC clusters undergo reversible metabolic changes that increase their resistance to oxidative stress. The ability of CTCs to extravasate and colonize distant tissues is influenced by interactions with the premetastatic niche, involving various host cells that support proliferation and resistance to the host immune response（Herath et al., 2020）. 4 Detection and Isolation of CTCs 4.1 Techniques for CTC detection 4.1.1 Immunocytochemistry Immunocytochemistry (ICC) is a widely used technique for the detection of circulating tumor cells (CTCs) due to its ability to identify specific cellular markers (Fig.2). This method involves the use of antibodies that bind to antigens expressed on the surface of CTCs, allowing for their visualization and quantification. ICC is particularly useful for distinguishing CTCs from other cells in the blood, such as leukocytes and erythrocytes, by targeting epithelial markers like EpCAM. However, the epithelial to mesenchymal transition (EMT) process can lead to the loss of these markers, complicating the detection of CTCs (Paterlini-Bréchot and Benali, 2007). Despite this challenge, ICC remains a valuable tool in the identification and characterization of CTCs, providing insights into their role in cancer progression and metastasis (Nagrath et al., 2007; Paterlini-Bréchot and Benali, N. 2007).
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