Cargando…
Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer
The prognosis of colorectal cancer (CRC) is closely linked to the occurrence of distant metastases, which putatively develop from circulating tumor cells (CTCs) shed into circulation by the tumor. As far more CTCs are shed than eventually metastases develop, only a small subfraction of CTCs harbor f...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053645/ https://www.ncbi.nlm.nih.gov/pubmed/27029058 http://dx.doi.org/10.18632/oncotarget.8373 |
_version_ | 1782458452298170368 |
---|---|
author | Schölch, Sebastian García, Sebastián A. Iwata, Naoki Niemietz, Thomas Betzler, Alexander M. Nanduri, Lahiri K. Bork, Ulrich Kahlert, Christoph Thepkaysone, May-Linn Swiersy, Anka Büchler, Markus W. Reissfelder, Christoph Weitz, Jürgen Rahbari, Nuh N. |
author_facet | Schölch, Sebastian García, Sebastián A. Iwata, Naoki Niemietz, Thomas Betzler, Alexander M. Nanduri, Lahiri K. Bork, Ulrich Kahlert, Christoph Thepkaysone, May-Linn Swiersy, Anka Büchler, Markus W. Reissfelder, Christoph Weitz, Jürgen Rahbari, Nuh N. |
author_sort | Schölch, Sebastian |
collection | PubMed |
description | The prognosis of colorectal cancer (CRC) is closely linked to the occurrence of distant metastases, which putatively develop from circulating tumor cells (CTCs) shed into circulation by the tumor. As far more CTCs are shed than eventually metastases develop, only a small subfraction of CTCs harbor full tumorigenic potential. The aim of this study was to further characterize CRC-derived CTCs to eventually identify the clinically relevant subfraction of CTCs. We established an orthotopic mouse model of CRC which reliably develops metastases and CTCs. We were able to culture the resulting CTCs in vitro, and demonstrated their tumor-forming capacity when re-injected into mice. The CTCs were then subjected to qPCR expression profiling, revealing downregulation of epithelial and proliferation markers. Genes associated with cell-cell adhesion (claudin-7, CD166) were significantly downregulated, indicating a more metastatic phenotype of CTCs compared to bulk tumor cells derived from hepatic metastases. The stem cell markers DLG7 and BMI1 were significantly upregulated in CTC, indicating a stem cell-like phenotype and increased capacity of tumor formation and self-renewal. In concert with their in vitro and in vivo tumorigenicity, these findings indicate stem cell properties of mouse-derived CTCs. In conclusion, we developed an orthotopic mouse model of CRC recapitulating the process of CRC dissemination. CTCs derived from this model exhibit stem-cell like characteristics and are able to form colonies in vitro and tumors in vivo. Our results provide new insight into the biology of CRC-derived CTCs and may provide new therapeutic targets in the metastatic cascade of CRC. |
format | Online Article Text |
id | pubmed-5053645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50536452016-10-12 Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer Schölch, Sebastian García, Sebastián A. Iwata, Naoki Niemietz, Thomas Betzler, Alexander M. Nanduri, Lahiri K. Bork, Ulrich Kahlert, Christoph Thepkaysone, May-Linn Swiersy, Anka Büchler, Markus W. Reissfelder, Christoph Weitz, Jürgen Rahbari, Nuh N. Oncotarget Research Paper The prognosis of colorectal cancer (CRC) is closely linked to the occurrence of distant metastases, which putatively develop from circulating tumor cells (CTCs) shed into circulation by the tumor. As far more CTCs are shed than eventually metastases develop, only a small subfraction of CTCs harbor full tumorigenic potential. The aim of this study was to further characterize CRC-derived CTCs to eventually identify the clinically relevant subfraction of CTCs. We established an orthotopic mouse model of CRC which reliably develops metastases and CTCs. We were able to culture the resulting CTCs in vitro, and demonstrated their tumor-forming capacity when re-injected into mice. The CTCs were then subjected to qPCR expression profiling, revealing downregulation of epithelial and proliferation markers. Genes associated with cell-cell adhesion (claudin-7, CD166) were significantly downregulated, indicating a more metastatic phenotype of CTCs compared to bulk tumor cells derived from hepatic metastases. The stem cell markers DLG7 and BMI1 were significantly upregulated in CTC, indicating a stem cell-like phenotype and increased capacity of tumor formation and self-renewal. In concert with their in vitro and in vivo tumorigenicity, these findings indicate stem cell properties of mouse-derived CTCs. In conclusion, we developed an orthotopic mouse model of CRC recapitulating the process of CRC dissemination. CTCs derived from this model exhibit stem-cell like characteristics and are able to form colonies in vitro and tumors in vivo. Our results provide new insight into the biology of CRC-derived CTCs and may provide new therapeutic targets in the metastatic cascade of CRC. Impact Journals LLC 2016-03-25 /pmc/articles/PMC5053645/ /pubmed/27029058 http://dx.doi.org/10.18632/oncotarget.8373 Text en Copyright: © 2016 Schölch et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Schölch, Sebastian García, Sebastián A. Iwata, Naoki Niemietz, Thomas Betzler, Alexander M. Nanduri, Lahiri K. Bork, Ulrich Kahlert, Christoph Thepkaysone, May-Linn Swiersy, Anka Büchler, Markus W. Reissfelder, Christoph Weitz, Jürgen Rahbari, Nuh N. Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
title | Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
title_full | Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
title_fullStr | Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
title_full_unstemmed | Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
title_short | Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
title_sort | circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053645/ https://www.ncbi.nlm.nih.gov/pubmed/27029058 http://dx.doi.org/10.18632/oncotarget.8373 |
work_keys_str_mv | AT scholchsebastian circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT garciasebastiana circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT iwatanaoki circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT niemietzthomas circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT betzleralexanderm circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT nandurilahirik circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT borkulrich circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT kahlertchristoph circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT thepkaysonemaylinn circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT swiersyanka circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT buchlermarkusw circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT reissfelderchristoph circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT weitzjurgen circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer AT rahbarinuhn circulatingtumorcellsexhibitstemcellcharacteristicsinanorthotopicmousemodelofcolorectalcancer |