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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...

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Autores principales: 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.
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
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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.
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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
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