Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer
Abstract Background Circulating tumour cells (CTCs) and tumour-derived extracellular vesicles (tdEVs) have great potential for monitoring therapy response and early detection of tumour relapse, facilitating personalized adjuvant therapeutic strategies. However, their low abundance in peripheral bloo...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s13046-024-03259-6 |
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| author | Stefan A. Cieslik Andrés G. Zafra Christiane Driemel Monica Sudarsanam Jan-Philipp Cieslik Georg Flügen Levent Dizdar Andreas Krieg Sascha Vaghiri Hany Ashmawy Stephen Fung Miriam Wilms Leon W. M. M. Terstappen Afroditi Nanou Hans Neubauer Nuh N. Rahbari Wolfram T. Knoefel Nikolas H. Stoecklein Rui P. L. Neves |
| author_facet | Stefan A. Cieslik Andrés G. Zafra Christiane Driemel Monica Sudarsanam Jan-Philipp Cieslik Georg Flügen Levent Dizdar Andreas Krieg Sascha Vaghiri Hany Ashmawy Stephen Fung Miriam Wilms Leon W. M. M. Terstappen Afroditi Nanou Hans Neubauer Nuh N. Rahbari Wolfram T. Knoefel Nikolas H. Stoecklein Rui P. L. Neves |
| author_sort | Stefan A. Cieslik |
| collection | DOAJ |
| description | Abstract Background Circulating tumour cells (CTCs) and tumour-derived extracellular vesicles (tdEVs) have great potential for monitoring therapy response and early detection of tumour relapse, facilitating personalized adjuvant therapeutic strategies. However, their low abundance in peripheral blood limits their informative value. In this study, we explored the presence of CTCs and tdEVs collected intraoperatively from a tumour-draining vein (DV) and via a central venous catheter (CVC) prior to tumour resection. Methods CellSearch analyses of 395 blood samples from 306 patients with gastrointestinal tumours and 93 blood samples from healthy donors were used to establish and validate gates for the automated detection of CTCs and tdEVs with ACCEPT software and R scripts. The selected gate settings were applied to 227 samples of 142 patients with colorectal cancer (CRC) from two independent collectives. Phenotypic features were obtained via numeric analysis of their fluorescence signals (e.g. size, shape, and intensity) and were used for calculating diversity using Shannon index (SI) of clusters generated via the k-means algorithm after Uniform Manifold Approximation and Projection (UMAP) pre-processing, and standard deviation (SD). Results CTCs and tdEVs were more abundant in the DV samples compared to CVC samples (p < 0.05). tdEVs were detected in higher numbers than CTCs in both compartments. Importantly, tdEVs in CVCs were associated with tumor spread, whereas CTCs in DVs were linked to tumor size. In both compartments, the prognostic value of tdEVs for overall survival (OS) surpassed that of CTCs, as demonstrated by univariate, multivariate, and Kaplan-Meier analyses. CTCs and tdEVs in DVs were phenotypically distinct, being larger, more eccentric, and displaying stronger cytokeratin intensities (p < 0.05) compared to those in CVC samples. Furthermore, increased diversity in CTC and tdEV phenotypes was significantly associated with shorter survival, validating the prognostic relevance of the SD-diversity metric. Conclusion Our study demonstrates that DV sampling significantly enhances the detection of prognostically relevant CTCs and tdEVs in CRC patients, underscoring the superior prognostic significance of tdEVs compared to CTCs. Importantly, the combined phenotypic diversity of both markers emerges as a more powerful biomarker than their enumeration alone. These findings suggest that comprehensive, automated analysis of CTCs and tdEVs in DVs may open new avenues for tailoring individualized therapies in CRC patients. |
| format | Article |
| id | doaj-art-40f83cdb1d874c10845385203b2ba59e |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-40f83cdb1d874c10845385203b2ba59e2025-01-12T12:44:38ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111110.1186/s13046-024-03259-6Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancerStefan A. Cieslik0Andrés G. Zafra1Christiane Driemel2Monica Sudarsanam3Jan-Philipp Cieslik4Georg Flügen5Levent Dizdar6Andreas Krieg7Sascha Vaghiri8Hany Ashmawy9Stephen Fung10Miriam Wilms11Leon W. M. M. Terstappen12Afroditi Nanou13Hans Neubauer14Nuh N. Rahbari15Wolfram T. Knoefel16Nikolas H. Stoecklein17Rui P. L. Neves18Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of Medical Cell BioPhysics, Faculty of Science and Technology, University of TwenteDepartment of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University DüsseldorfDepartment of General and Visceral Surgery, University Hospital UlmDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfDepartment of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of Heinrich-Heine University DüsseldorfAbstract Background Circulating tumour cells (CTCs) and tumour-derived extracellular vesicles (tdEVs) have great potential for monitoring therapy response and early detection of tumour relapse, facilitating personalized adjuvant therapeutic strategies. However, their low abundance in peripheral blood limits their informative value. In this study, we explored the presence of CTCs and tdEVs collected intraoperatively from a tumour-draining vein (DV) and via a central venous catheter (CVC) prior to tumour resection. Methods CellSearch analyses of 395 blood samples from 306 patients with gastrointestinal tumours and 93 blood samples from healthy donors were used to establish and validate gates for the automated detection of CTCs and tdEVs with ACCEPT software and R scripts. The selected gate settings were applied to 227 samples of 142 patients with colorectal cancer (CRC) from two independent collectives. Phenotypic features were obtained via numeric analysis of their fluorescence signals (e.g. size, shape, and intensity) and were used for calculating diversity using Shannon index (SI) of clusters generated via the k-means algorithm after Uniform Manifold Approximation and Projection (UMAP) pre-processing, and standard deviation (SD). Results CTCs and tdEVs were more abundant in the DV samples compared to CVC samples (p < 0.05). tdEVs were detected in higher numbers than CTCs in both compartments. Importantly, tdEVs in CVCs were associated with tumor spread, whereas CTCs in DVs were linked to tumor size. In both compartments, the prognostic value of tdEVs for overall survival (OS) surpassed that of CTCs, as demonstrated by univariate, multivariate, and Kaplan-Meier analyses. CTCs and tdEVs in DVs were phenotypically distinct, being larger, more eccentric, and displaying stronger cytokeratin intensities (p < 0.05) compared to those in CVC samples. Furthermore, increased diversity in CTC and tdEV phenotypes was significantly associated with shorter survival, validating the prognostic relevance of the SD-diversity metric. Conclusion Our study demonstrates that DV sampling significantly enhances the detection of prognostically relevant CTCs and tdEVs in CRC patients, underscoring the superior prognostic significance of tdEVs compared to CTCs. Importantly, the combined phenotypic diversity of both markers emerges as a more powerful biomarker than their enumeration alone. These findings suggest that comprehensive, automated analysis of CTCs and tdEVs in DVs may open new avenues for tailoring individualized therapies in CRC patients.https://doi.org/10.1186/s13046-024-03259-6Circulating tumour cellsCTCsTumour-derived extracellular vesiclestdEVsColorectal cancerCRC |
| spellingShingle | Stefan A. Cieslik Andrés G. Zafra Christiane Driemel Monica Sudarsanam Jan-Philipp Cieslik Georg Flügen Levent Dizdar Andreas Krieg Sascha Vaghiri Hany Ashmawy Stephen Fung Miriam Wilms Leon W. M. M. Terstappen Afroditi Nanou Hans Neubauer Nuh N. Rahbari Wolfram T. Knoefel Nikolas H. Stoecklein Rui P. L. Neves Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer Journal of Experimental & Clinical Cancer Research Circulating tumour cells CTCs Tumour-derived extracellular vesicles tdEVs Colorectal cancer CRC |
| title | Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer |
| title_full | Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer |
| title_fullStr | Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer |
| title_full_unstemmed | Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer |
| title_short | Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer |
| title_sort | phenotypic diversity of ctcs and tdevs in liquid biopsies of tumour draining veins is linked to poor prognosis in colorectal cancer |
| topic | Circulating tumour cells CTCs Tumour-derived extracellular vesicles tdEVs Colorectal cancer CRC |
| url | https://doi.org/10.1186/s13046-024-03259-6 |
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