KFO 227:  Colorectal Cancer: From Primary Tumour Progression towards Metastases

• Subject Area: Medicine
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101804013

Metastases remain the main cause of death for colorectal cancer (CRC) patients. Successful metastasis requires the potential and ability of various tumour cells to enter the circulation, to attach and to invade the target organ as well as subsequent formation of metastases. The various mechanisms and aspects of primary tumour progression via circulating tumour cells (CTC) towards a metastasis are still poorly understood. Furthermore, the exact role of the immunological host anti-tumour response has to be defined more closely in CRC.
The Clinical Research Unit aims to examine (in seven different subprojects) various biological and potential therapeutic aspects underlying the stepwise progression from a primary tumour via tumour cell dissemination towards metastases in colorectal cancer. Subproject (SP) 1 aims to isolate and further characterise CTC and disseminated tumour cells (DTC) and focusses on the prognostic role of circulating endothelial cells and various angiogenic factors. SP 2 analyses and further characterises the transplantable colon cancer-initiating cell compartment. SP 3 aims to identify genes with a pathogenic role in colorectal tumour progression and metastasis. SP 4 elucidates the molecular pathways leading to transcriptional up-regulation of ß-catenin in the invasion front of CRC liver metastases. SP 5 will apply microsatellite instability typing to all human colorectal tumour samples examined in the other subprojects. SP 6 deals with changes in the cellular host immune response during the metastatic cascade. SP 7 deals with hypoxia and angiogenesis in CRC.
All seven subprojects rely on the same set of clinical samples and tissues provided by the C-project. This will generate a more comprehensive biological and translational understanding of this complex process for the single patient.

• DFG Programme: Clinical Research Units

Projects

• Clinical significance of the local and systemic immunologic microenvironment in patients with colorectal cancer liver metastases (Applicants Halama, Niels ;  Zörnig, Ph.D., Inka )
• Coordination and administration of the Clinical Research Unit KFO 227/2 and centralized tissue sampling and CTC detection service for all subprojects (Applicant Schneider, Martin A. )
• Enrichment and molecular characterization of single disseminated tumor cells (DTCs) and proof of circulating tumor cell (CTC)- and DTC-mediated tumorigenicity in vitro and in vivo (Applicant Weitz, Jürgen )
• Genetic and functional heterogeneity within the tumor-initiating cell compartment of human colon cancer (Applicant Ball, Claudia )
• Molecular analysis of intestinal stem cell associated genes in colorectal cancer (CRC) (Applicant Lichter, Peter )
• Molecular oxygen sensing and PHD-inhibition: implications for colorectal cancer growth (Applicant Schneider, Martin A. )
• The clinical impact of microsatellite instability in colorectal cancer (Applicant Kloor, Matthias )
• The role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression (Applicant Schulze-Bergkamen, Henning )
• The role of host cell-tumor cell interaction for beta-catenin mediated tumor cell invasion in colorectal liver metastases (Applicant Brand, Karsten )
• Therapeutic potential of T cell responses against tumor initiating cell-associated antigens in CRC (Applicant Beckhove, Philipp )

• Spokesperson: Professor Dr. Markus W. Büchler
• Leader: Professor Dr. Martin A. Schneider, since 10/2012