Steffi Treitschke, Kathrin Weidele, Adithi Ravikumar Varadarajan, Giancarlo Feliciello, Jens Warfsmann, Sybille Vorbeck, Bernhard Polzer, Catherine Botteron, Martin Hoffmann, Vadim Dechand, Tobias Mederer, Florian Weber, Melanie Werner-Klein, Tobias Robold, Hans-Stefan Hofmann, Christian Werno, Christoph A. Klein
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引用次数: 1
Abstract
The cellular basis of the apparent aggressiveness in lung cancer is poorly understood but likely associated with functional or molecular features of disseminated cancer cells (DCCs). DCCs from epithelial cancers are mostly detected by antibodies directed against histogenetic markers such as cytokeratin or EpCAM. It has been argued that marker-negative metastatic founder cells might escape detection. We therefore used ex vivo sphere formation for functional detection of candidate metastasis founders. We generated cell suspensions from 199 LN samples of 131 lung cancer patients and placed them into non-adherent cell culture. Sphere formation was associated with detection of DCCs using EpCAM immunocytology and with significantly poorer prognosis. The prognostic impact of sphere formation was strongly associated with high numbers of EpCAM-positive DCCs and aberrant genotypes of expanded spheres. We also noted sphere formation in patients with no evidence of lymphatic spread, however such spheres showed infrequent expression of signature genes associated with spheres from EpCAM-positive samples and displayed neither typical lung cancer mutations (KRAS, TP53, ERBB1) nor copy number variations, but might be linked to disease progression >5 years post curative surgery. We conclude that EpCAM identifies relevant disease-driving DCCs, that such cells can be expanded for model generation and that further research is needed to clarify the functional and prognostic role of rare EpCAM-negative sphere forming cells.
期刊介绍:
The International Journal of Cancer (IJC) is the official journal of the Union for International Cancer Control—UICC; it appears twice a month. IJC invites submission of manuscripts under a broad scope of topics relevant to experimental and clinical cancer research and publishes original Research Articles and Short Reports under the following categories:
-Cancer Epidemiology-
Cancer Genetics and Epigenetics-
Infectious Causes of Cancer-
Innovative Tools and Methods-
Molecular Cancer Biology-
Tumor Immunology and Microenvironment-
Tumor Markers and Signatures-
Cancer Therapy and Prevention