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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer.
Cancer Res. 74, 1694-1704 (2014)
The prognosis of colorectal cancer is closely linked to the occurrence of distant metastases. Systemic dissemination is most likely caused by circulating tumor cells (CTC). Despite the fundamental role of CTC within the metastatic cascade, technical obstacles have so far prevented detailed genomic and, in particular, phenotypic analyses of CTC, which may provide molecular targets to delay or prevent distant metastases. We show here a detailed genomic analysis of single colorectal cancer-derived CTC by array comparative genomic hybridization (aCGH), mutational profiling, and microsatellite instability (MSI) analysis. Furthermore, we report the first gene expression analysis of manually selected colorectal cancer-derived CTC by quantitative real-time PCR (qRT-PCR) to investigate transcriptional changes, enabling CTC to survive in circulation and form distant metastases. aCGH confirmed the tumor cell identity of CellSearch-isolated colorectal cancer-derived CTC. Mutational and MSI analyses revealed mutational profiles of CTC to be similar, but not identical to the corresponding tumor tissue. Several CTC exhibited mutations in key genes such as KRAS or TP53 that could not be detected in the tumor. Gene expression analyses revealed both a pronounced upregulation of CD47 as a potential immune-escape mechanism and a significant downregulation of several other pathways, suggesting a dormant state of viable CTC. Our results suggest mutational heterogeneity between tumor tissue and CTC that should be considered in future trials on targeted therapy and monitoring of response. The finding of upregulated immune-escape pathways, which may be responsible for survival of CTC in circulation, could provide a promising target to disrupt the metastatic cascade in colorectal cancer.
Impact Factor
Scopus SNIP
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0.000
2.090
163
Anmerkungen
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Sprache
englisch
Veröffentlichungsjahr
2014
HGF-Berichtsjahr
0
ISSN (print) / ISBN
0008-5472
e-ISSN
1538-7445
Zeitschrift
Cancer Research
Quellenangaben
Band: 74,
Heft: 6,
Seiten: 1694-1704
Verlag
American Association for Cancer Research (AACR)
Verlagsort
Philadelphia, Pa.
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Pancreatic Islet Research (IPI)
PubMed ID
24599131
Erfassungsdatum
2014-12-31