Better together: circulating tumor cell clustering in metastatic cancer

Abstract

Circulating tumor cells (CTCs) are vital components of liquid biopsies for diagnosis of residual cancer, monitoring of therapy response, and prognosis of recurrence. Scientific dogma focuses on metastasis mediated by single CTCs, but advancement of CTC detection technologies has elucidated multicellular CTC clusters, which are associated with unfavorable clinical outcomes and a 20-to 100-fold greater metastatic potential than single CTCs. While the mechanistic understanding of CTC cluster formation is still in its infancy, multiple cell adhesion molecules and tight junction proteins have been identified that underlie the outperforming attributes of homotypic and heterotypic CTC clusters, such as cell survival, cancer stemness, and immune evasion. Future directions include high-resolution characterization of CTCs at multiomic levels for diagnostic/prognostic evaluations and targeted therapies. Circulating tumor cells form clusters that enhance breast cancer metastasisAlthough metastasis accounts for 90% of solid tumor-related mortality, it currently evades targeted treatments and demands a better understanding. Metastasis is a multistep process during which cancer cells spread from the primary tumor site to distant organs, starting with the primary tumor formation, where tumor cells gradually expand and locally invade the surrounding stroma and tissues, including the blood and lymphatic vessels. At this point, the intravasated tumor cells, now called 'circulating tumor cells' (CTCs) and a vital component of liquid biopsy [1,2], develop adaptive mechanisms that favor their survival in the harsh microenvironment of the circulatory system. CTCs may disseminate to distant parts of the body before they finally extravasate or get trapped within the capillaries in certain organs, form metastatic niches, and regenerate secondary tumors [3][4][5].The presence of CTCs in the blood of patients with cancer was first detected in 1869 by Thomas Ashworth [6], but, because of advances in technology, CTCs have only recently attracted great attention for their key role in tumor metastasis [6,7]. Many studies have shown that CTCs may be used to predict disease progression and prognosis in patients with metastatic cancer [4]. In metastatic cancers such as breast cancer, the currently accepted level of CTCs that correlates with worse overall survival and progression-free survival is five or more CTCs in 7.5 mL of blood [8]. CTC enumeration can be used to better stratify patients with stage IV breast cancer as stage IV aggressive, with more than five CTCs, and stage IV indolent, with fewer than five CTCs [8]. Stage IV indolent disease is associated with significantly longer overall survival, regardless of disease subtype and prior treatment [8]. The presence of CTCs in early breast cancer was also demonstrated to have prognostic impact [9,10]. Thus, CTC analysis in patients with cancer is a minimally invasive, clinically informative method of predicting disease stage and survival that is not dependent on cancer subtype or previous trea...

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design

“…CTCs, even obtained from a single patient at the same time, may show strong heterogeneity (see Section 3) and thereby varied metastatic potential. In addition, CTCs can exist in clusters (very strong metastatic factors) that can significantly influence cancer development [24].…”

“…On the other hand, Illie et al found that CTC-positive patients with tobacco-induced chronic obstructive pulmonary disease may have developed lung cancer [23]. This suggests that cancer patients in the early stages of lung cancer could display high metastatic activity, such as higher CTC counts and formation of CTC clusters (a highly metastatic and aggressive form of CTC) [24][25][26].…”

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

“…In this context, it is notable that circulating tumour cell (CTC) clusters exhibit altered adhesion molecule profiles and ICAM-1 is one of the adhesion molecules that mediates aggregation of CTCs. The significance of multicellular CTC clusters for cancer patients was recently reviewed [177]. It should also be noted that the heterotypic CTC clusters include immune cells and CAFs and that their escape from the primary tumour site is enabled by leaky vasculature [177].…”

“…The significance of multicellular CTC clusters for cancer patients was recently reviewed [177]. It should also be noted that the heterotypic CTC clusters include immune cells and CAFs and that their escape from the primary tumour site is enabled by leaky vasculature [177]. Finally, DNA methylation is an essential factor for stemness (re-)programming of CTCs [178].…”

Quantitative Analysis of Cell Aggregation Dynamics Identifies HDAC Inhibitors as Potential Regulators of Cancer Cell Clustering

“…Furthermore, in patients with breast or prostate cancer, overexpression of the JUP gene that encodes plakoglobin has been associated with poor prognosis [ 4 ]. Other cell adhesion molecules, such as CD44 or ICAM1, have also been shown to be involved in the clustering of cancer cells [ 11 ].…”