2020
DOI: 10.1016/j.celrep.2020.108105
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Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells

Abstract: Summary Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingl… Show more

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Cited by 161 publications
(143 citation statements)
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“…Several combinations of Axitinib and Bevacizumab with other targeted agents, checkpoint inhibitors or cytotoxic agents are presently approved for treatment of various cancers since they offer varying levels of improvement over existing monotherapy options. In a recent study 51 it was observed that VEGF blockade, though effective in suppressing the primary tumour, could present hypoxic conditions conducive to release and survival of CTC clusters with metastatic potential. It follows that a combination regimen that targets angiogenesis as well as other activated pathways or cellular mechanisms (such as e.g., DNA replication, DNA synthesis, or mitosis) in tandem could avoid such potential pitfalls by acting on CTCs or clusters released from the tumor and are no longer susceptible to inhibition of angiogenesis.…”
Section: Discussionmentioning
confidence: 99%
“…Several combinations of Axitinib and Bevacizumab with other targeted agents, checkpoint inhibitors or cytotoxic agents are presently approved for treatment of various cancers since they offer varying levels of improvement over existing monotherapy options. In a recent study 51 it was observed that VEGF blockade, though effective in suppressing the primary tumour, could present hypoxic conditions conducive to release and survival of CTC clusters with metastatic potential. It follows that a combination regimen that targets angiogenesis as well as other activated pathways or cellular mechanisms (such as e.g., DNA replication, DNA synthesis, or mitosis) in tandem could avoid such potential pitfalls by acting on CTCs or clusters released from the tumor and are no longer susceptible to inhibition of angiogenesis.…”
Section: Discussionmentioning
confidence: 99%
“…The differential labeling of the MDA-MB-231 LM2 cell line with eGFP and mCherry fluorescence enabled the detection of multicolor CTC clusters in circulation, which were later shown to be oligoclonal precursors of metastasis to the lung requiring plakoglobin for collective tumor cell transit ( 52 ). Interestingly, such CTC collectives preferentially arose in hypoxic areas of the tumor, as demonstrated in patient and cell line specimens ( 53 ). Similar studies using MDA-MB-231 or murine 4T1 cell lines further demonstrated the requirement of neutrophils to facilitate CTC cluster cell cycle entry, heightening metastatic conditioning in the circulation ( 54 ).…”
Section: Models Of Metastasismentioning
confidence: 98%
“…In patients with HNSCC, one of the decisive parameters influencing the prognosis is the condition of the lymph nodes [ 176 ]. Hypoxia within the tumor tissues has been recently reported as the main cause for the shedding of larger numbers of CTC clusters, resulting in increasingly successful distant metastases [ 177 ]. This is in contrast to other studies showing that angiogenesis increases the metastatic process.…”
Section: Notch Signaling In (Neo-)angiogenesismentioning
confidence: 99%