Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

Hurtado, Pablo; Martínez-Pena, Inés; Piñeiro, Roberto

doi:10.3390/cancers12102861

Cited by 56 publications

(49 citation statements)

References 142 publications

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“…Additional studies reveal that CTC clusters can be heterogeneous, meaning that CTCs are capable of forming clusters with other cell types, such as WBCs, including neutrophils and myeloid-derived suppressor cells [50][51][52][53][54], as well as cancer-associated fibroblasts (CAFs) (Figure 3). Based on a single-cell RNA-sequencing analysis of CTC-WBC clusters from patients with breast cancer, most CTC-WBC clusters form with neutrophils [50].…”

Section: Heterotypic Ctc Clustersmentioning

confidence: 99%

Better together: circulating tumor cell clustering in metastatic cancer

et al. 2021

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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...

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Section: Heterotypic Ctc Clustersmentioning

confidence: 99%

Better together: circulating tumor cell clustering in metastatic cancer

et al. 2021

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“…Indeed, circulating tumor cells (CTCs) do not act independently and they are assisted by stromal and immune cells, which alter their metastatic potential. CAFs, which were reported to be associated with CTCs in heterotypic CTC clusters, seem to increase the metastatic efficiency (330). Interestingly, CAFs were found to be present in the brain metastases from lung carcinoma and other carcinomas, in contrast to primary brain tumors or normal brain tissue (107).…”

Section: The Effects On Tumor Progressionmentioning

confidence: 99%

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Günaydın

2021

Front. Oncol.

103

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Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

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“…Moreover, Heeke et al, 2019 mentioned that the CTC clusters have a clear advantage because they ‘never travel alone’ and they have close crosstalk with the circulating microenvironment. Indeed, cancer-associated fibroblasts and CTCs are considered as ‘dangerous liaisons’ ( Hurtado et al, 2020 ), since cancer-associated fibroblasts (CAFs) secrete different proteins (cytokines, chemokines, growth factors) that promote invasion and angiogenesis, induce migration of tumor cells, and even confer evasion of the immune system. In conclusion, different types of clusters exist; the very rare and most aggressive ones are the heterotypic CTC clusters compared to the homotypic clusters and single CTCs ( Castro-Giner and Aceto, 2020 ; Duda et al, 2010 ).…”

Section: Group Phenotypic Composition In the Context Of Cancermentioning

confidence: 99%

Group phenotypic composition in cancer

Capp

DeGregori

Nedelcu

et al. 2021

eLife

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Although individual cancer cells are generally considered the Darwinian units of selection in malignant populations, they frequently act as members of groups where fitness of the group cannot be reduced to the average fitness of individual group members. A growing body of studies reveals limitations of reductionist approaches to explaining biological and clinical observations. For example, induction of angiogenesis, inhibition of the immune system, and niche engineering through environmental acidification and/or remodeling of extracellular matrix cannot be achieved by single tumor cells and require collective actions of groups of cells. Success or failure of such group activities depends on the phenotypic makeup of the individual group members. Conversely, these group activities affect the fitness of individual members of the group, ultimately affecting the composition of the group. This phenomenon, where phenotypic makeup of individual group members impacts the fitness of both members and groups, has been captured in the term ‘group phenotypic composition’ (GPC). We provide examples where considerations of GPC could help in understanding the evolution and clinical progression of cancers and argue that use of the GPC framework can facilitate new insights into cancer biology and assist with the development of new therapeutic strategies.

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Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

Cited by 56 publications

References 142 publications

Better together: circulating tumor cell clustering in metastatic cancer

Better together: circulating tumor cell clustering in metastatic cancer

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Group phenotypic composition in cancer

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