Abstract
BackgroundMetastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; however, the underlying mechanisms remain poorly understood.MethodsIn view of the scarcity of CTCs in the bloodstream, suspended colorectal cancer cells were flowed into the cyclic laminar shear stress (LSS) according to previous studies. Then, we detected these suspended cells with a CK8+/CD45−/DAPI+ phenotype and named them mimic circulating tumour cells (m-CTCs) for subsequent CTCs related researches. Quantitative polymerase chain reaction, western blotting, and immunofluorescence were utilised to analyse gene expression change of m-CTCs sensitive to LSS stimulation. Additionally, we examined atonal bHLH transcription factor 8 (ATOH8) expressions in CTCs among 156 CRC patients and mice by fluorescence in situ hybridisation and flow cytometry. The pro-metabolic and pro-survival functions of ATOH8 were determined by glycolysis assay, live/dead cell vitality assay, anoikis assay, and immunohistochemistry. Further, the concrete up-and-down mechanisms of m-CTC survival promotion by ATOH8 were explored.ResultsThe m-CTCs actively responded to LSS by triggering the expression of ATOH8, a fluid mechanosensor, with executive roles in intravascular survival and metabolism plasticity. Specifically, ATOH8 was upregulated via activation of VEGFR2/AKT signalling pathway mediated by LSS induced VEGF release. ATOH8 then transcriptionally activated HK2-mediated glycolysis, thus promoting the intravascular survival of colorectal cancer cells in the circulation.ConclusionsThis study elucidates a novel mechanism that an LSS triggered VEGF-VEGFR2-AKT-ATOH8 signal axis mediates m-CTCs survival, thus providing a potential target for the prevention and treatment of hematogenous metastasis in CRC.
Highlights
Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC)
atonal bHLH transcription factor 8 (ATOH8) is a shear stress response molecule and is associated with metastasis and poor prognosis in CRC CTCs are vital to tumour metastasis, while the number of CTCs is sparse
In the clinical cohort 1, we found that the proportion of ATOH8 (+) CTCs was higher in the subgroup with high metastatic mesenchymal CTCs or a total CTC number ≥ 5 cells/5 mL (HP group) (Additional file 3: Figure S2 h), suggesting that ATOH8 (+) CTCs are potentially associated with a high risk of metastasis
Summary
Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; the underlying mechanisms remain poorly understood. Most CTCs perish in circulation, facing obstacles including physical stress, anoikis, and immune response [4], approximately 0.1% of CTCs manage to survive as disseminated seeds for eventual relapse [5]. Living cells continue to perceive and respond to mechanical forces, which are important regulators of cell survival and function [6]. A study indicated that mechanically sensitive PANX1 channels on the surface of breast cancer cells could respond to LSS stimuli and facilitate the survival of CTCs [13]. More research is needed owing to the scarcity and contradictions in data regarding LSS and CTC survival
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