VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis

Foersch, Sebastian; Sperka, Tobias; Lindner, Christina; Taut, Astrid; Rudolph, K. Lenhard; Breier, Georg; Boxberger, Frank; Rau, Tilman T.; Hartmann, Arndt; Stürzl, Michael; Wittkopf, Nadine; Haep, Lisa; Wirtz, Stefan; Neurath, Markus F.; Waldner, Maximilian J.

doi:10.1053/j.gastro.2015.03.016

Cited by 47 publications

(32 citation statements)

References 45 publications

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“…The VEGF-VEGFR2 modulates ATOH8 via AKT signalling pathway to sustain CRC m-CTCs survival VEGF exerts its effects by binding to VEGF receptor 2 (VEGFR2) in CRC cells [35]; similarly, the present results show that VEGFR2 was upregulated in CRC m-CTCs exposed to LSS (Fig. 5a).…”

Section: Lss-induced Autocrine Vegf Participates In Atoh8mediated Crcsupporting

confidence: 76%

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

Huang

et al. 2020

J Exp Clin Cancer Res

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Background: 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; however, the underlying mechanisms remain poorly understood. Methods: In 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-anddown mechanisms of m-CTC survival promotion by ATOH8 were explored. Results: The 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. Conclusions:This 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.

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Section: Lss-induced Autocrine Vegf Participates In Atoh8mediated Crcsupporting

confidence: 76%

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

Huang

et al. 2020

J Exp Clin Cancer Res

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“…Related to this, our findings raise key questions about escape from treatment-induced senescence. While we provide critical confirmation of prior studies linking VEGF pathway inhibition to increases in senescence markers (Foersch et al, 2015;Hasan et al, 2011;Zhu et al, 2013;Morelli et al, 2015Morelli et al, , 2017, we used several drugs and cell lines to show these markers are highly varied, model-dependent, and can diminish after long periods of drug withdrawal. These findings are consistent with increasing evidence showing treatmentinduced senescence may be atypical (i.e., non-permanent) in several instances (Saleh et al, 2018).…”

Section: Discussionsupporting

confidence: 61%

“…Recent preclinical studies have shown that disruption of the VEGF pathway by gene knockout (Foersch et al, 2015) or therapeutic inhibition (Hasan et al, 2011;Andrae et al, 2012;Zhu et al, 2013) can induce cellular senescence. Senescence is a stress-induced cellular response typically associated with permanent growth arrest that serves to limit replication of aged/damaged cells and facilitate tissue remodeling/repair (Pé rez-Mancera et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

et al. 2018

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“…Inflammation greatly contributes to CRC development and progression. 20, 35, 36 In the present study, we identified an inflammatory environment-mediated transcriptional programme that controls the metastatic potential of CRC through GFI1, a transcriptional repressor. Curiously, a key cytokine responsible for GFI1 downregulation is TGF β .…”

Section: Discussionmentioning

confidence: 82%

GFI1 downregulation promotes inflammation-linked metastasis of colorectal cancer

Xing

Xiao

et al. 2017

Cell Death Differ

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Inflammation is frequently associated with initiation, progression, and metastasis of colorectal cancer (CRC). Here, we unveil a CRC-specific metastatic programme that is triggered via the transcriptional repressor, GFI1. Using data from a large cohort of clinical samples including inflammatory bowel disease and CRC, and a cellular model of CRC progression mediated by cross-talk between the cancer cell and the inflammatory microenvironment, we identified GFI1 as a gating regulator responsible for a constitutively activated signalling circuit that renders CRC cells competent for metastatic spread. Further analysis of mouse models with metastatic CRC and human clinical specimens reinforced the influence of GFI1 downregulation in promoting CRC metastatic spread. The novel role of GFI1 is uncovered for the first time in a human solid tumour such as CRC. Our results imply that GFI1 is a potential therapeutic target for interfering with inflammation-induced CRC progression and spread.

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VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis

Cited by 47 publications

References 45 publications

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

GFI1 downregulation promotes inflammation-linked metastasis of colorectal cancer

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