Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality mainly due to metastasis via afferent lymphatics and via the blood stream. These trafficking routes are also used by immune cells and it was recently shown that the chemokine as well as the lysophospholipid system is involved in homeostatic trafficking of lymphocytes.

Based on these observations we proposed that both chemokines as well as lysophospholipids participate in the seeding of CRC cells. Using imunohistology, we could demonstrate on 99 CRC samples that the expression of two homeostatic chemokine receptors (CXCR4, CCR7) is highly significantly associated with metastasis of CRC to the draining lymph node. Furthermore micro array analysis on approx. 50 CRC samples lead to the identification of 60 genes including members of the lysophospholipid system (S1P1, LPA1) as well as further chemokine receptors (XCR1) to be highly over expressed in CRC samples. The over expression of these receptors was verified by immunohistology as well as flow cytometry on human colon carcinoma cell lines.

Still the pathophysiological details of the identified receptors (CXCR4, CCR7, XCR1, S1P1, LPA1) in CRC tumor cell migration remain unclear. Therefore, this proposal aims to functionally further analyze the role of the identified receptors in CRC metastasis by in vitro as well as in vivo studies: In vitro/ex vivo, we will determine the intra-tumor distribution of the identified receptors and relate the expression pattern to clinical parameters. In addition the functional contribution of all five receptors to cell migration and the potential effects of receptor antagonists will be analyzed using human CRC cell lines. To test the role of the receptors in vivo animal models (SCID-mice, tumor models for CRC) will also be applied.