title: Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer.
abstract: 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.
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schölch
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sebastián A
authors.initials: SA
authors.lastname: García
authors.affiliation: Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of General, Gastrointestinal and Transplantation Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Niemietz
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Betzler
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Lahiri K
authors.initials: LK
authors.lastname: Nanduri
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bork
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: May-Linn
authors.initials: ML
authors.lastname: Thepkaysone
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Anka
authors.initials: A
authors.lastname: Swiersy
authors.affiliation: Department of General, Gastrointestinal and Transplantation Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reissfelder
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor
keywords: circulating tumor cells; colorectal cancer; metastasis; mouse model; stem cells