Tumor–endothelial cell interactions: Therapeutic potential

Metastasis is the primary cause of death in cancer patients. However, the molecular mechanism of the metastatic process is poorly understood because it involves multiple steps with a high degree of complexity. A critical step for successful establishment of secondary colonization is the hematogenous dissemination of malignant cells. During this process, the attachment of cancer cells to the endothelial cells on microvasculature is considered to be an essential step and many adhesion molecules as well as chemokines have been found to be involved in this process. This interaction of cancer–endothelial cell is considered not only to determine the physical site of metastasis, but also to provide the necessary anchorage to facilitate tumor cell extravasation. However, recent evidence indicates that this interaction also serves as a host defense mechanism and hinders the process of metastasis. The tumor metastases suppressor gene, KAI1, has been known to block metastatic process without affecting the primary tumor growth, and this protein has been found to be able to bind to the chemokine receptor, Duffy antigen receptor for chemokines (DARC), which is expressed on endothelial cells. Importantly, this interaction markedly induces senescence of tumor cells. This novel finding is not only significant in the context of molecular dissection of metastatic process but also in the therapeutic implication to develop drugs inhibiting metastasis.