Res Proj 2: Development of PET Imaging Probes for Chemokine Receptors for Head...

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Head and neck cancer mortality would be greatly diminished if it were possible to non-invasively detect small foci of head and neck cancer or micrometastases early on. It would also be of great interest if the same technology could be used to detect (or predict) the metastatic potential of primary tumors in the early stages of disease progression. This would provide the opportunity to prevent further malignant progression of head and neck cancer. Metastasis is the result of several sequential steps and represents an organ-selective process (5). Although a number of mechanisms have been implicated in the metastasis of head and neck cancer, the precise mechanisms determining the directional migration and invasion of tumor cells into specific organs remain elusive. Chemokines are secreted proteins that act in a coordinated fashion with cell-surface proteins, including integrins, to direct the homing of various subsets of hematopoietic cells to specific anatomical sites (6-9). CXCR4 mediates the migration of cancer cells to the lymph nodes, lungs, liver, and bones whereas CCR7 mediates the migration of cancer cells to the lymph nodes exclusively. This migration is mediated through the binding of CXCR4 to its ligand, stromal cell-derived factor 1 (SDF-1) and that of CCR7 to its ligand, CCL7. While the levels of SDF-1 are high at the common destinations of cancer metastasis including the lymph node, lung, liver, and the bone marrow and those of CCL7 are particularly high in the lymph nodes, the expression of CXCR4 and CCR7 is significantly elevated in malignant tumors compared to their normal tissue counterparts. The interactions between SDF-1 and CXCR4 and between CCL7 and CCR7 have been shown to direct cells to organ sites that have high levels of SDF-1 and CCL7 expression, suggesting that these interactions play a key role in the chemotaxis and homing of these metastatic cells. When SDF-1 binds to CXCR4 or CCL7 binds to CCR7, the complex activates the pertussis toxin-sensitive Garprotein-mediated signaling (10). The inhibition of both interactions between CXCR4 and SDF-1 and between CCR7 and CCL7 may therefore provide a means of inhibiting the metastatic process.