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Colorectal cancer: from primary tumor progression towards metastases

Curative treatment of colorectal cancer (CRC) is frequently hindered by the occurrence of remote metastases. A decent understanding of the processes underlying metastatic progression of colorectal cancer would therefore provide a scientific basis for a major advancement in the treatment of this widespread disease.

The Clinical Research Unit KFO 227 aims at delineating the mechanisms underlying the formation of distant metastases from tumor cells originating in the colon and rectum. This complex process can be dismantled into several key events, each of which is quintessential for the occurrence of distant colorectal cancer metastases. First, promoted by lack of oxygen and other environmental factors, tumor cells undergo gene expression changes associated with a pro-metastatic phenotype and the ability to invade adjacent tissues and vessels at the primary tumor site. Subsequently, circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) occur in the blood circulation or at remote areas such as the bone marrow, where they may rest in quiescence, while still retaining their metastatic potential. Eventually, CTCs extravasate from blood vessels at the metastatic site. Here, they rely on their capacity of survival and self-renewal – properties that are characteristic of tumor initiating cells (TIC). Importantly, during the entire process of metastatic progression, tumor cells need to escape the host immune response.

Within the KFO 227, clinicians from the fields of surgery and medical oncology have joined forces with expert scientists from the fields of pathology, translational oncology, stem cell biology, molecular genetics, tumor biology and immunology. Altogether, eight subprojects (SP1-8) have been devised to tackle relevant scientific questions related to key events in the metastatic cascade. Which tumor cell-specific genetic and epigenetic alterations predispose to metastasis formation (SP3, SP4), and which genetic properties are peculiar to tumor initiating cells (SP2)? Which molecular mechanisms regulate cancer cell invasiveness and survival (SP8); and how are they affected by the tumor-specific microenvironment (SP6)? What are the sophisticated biologic properties underlying the tumorigenicity of CTCs and DTCs (SP1), and does the bone marrow represent a specific reservoir for TIC (SP2)? Finally, how do the local and systemic immune responses interact in the tumor defense (SP7), and how do cancer cells manage to evade immune surveillance (SP4, SP5)? Which mechanisms are suited to efficiently boost the tumor-specific immune response (SP5)?

All subprojects are closely linked by a common C-project. The C-project provides the opportunity to continuously synchronize the accomplishments provided by the individual subprojects with a growing database of clinical features from CRC patients and, thus, to outline their clinical relevance, with the long-term goal to devise novel diagnostic tools and individualized treatment protocols for successful clinical application in CRC patients.

University Hospital Heidelberg
Department of General, Visceral and Transplantation Surgery
Im Neuenheimer Feld 110
69120 Heidelberg