The process of angiogenesis requires at least four coordinated steps, each of which may be a target for inhibition. First, tumors must communicate with the endothelial cells that line the inside of nearby blood vessels. This communication takes place, in part, through the secretion of angiogenesis factors such as vascular endothelial growth factor.[14,15,16,17,18] Second, the activated endothelial cells must divide to produce new endothelial cells, which will be used to make the new blood vessels.[15,17,18,19,20] Third, the dividing endothelial cells must migrate toward the tumor.[15,16,17,18,19,20] To accomplish this, they must produce enzymes called matrix metalloproteinases, which will help them carve a pathway through the tissue elements that separate them from the tumor.[18,19,20,21,22] Fourth, the new endothelial cells must form the hollow tubes that will become the new blood vessels.[17,18] Some angiogenesis inhibitors may be able to block more than one step in this process.
Cartilage is relatively resistant to invasion by tumor cells,[23,24,25,26,27,28,29,30] and tumor cells use matrix metalloproteinases when they migrate during the process of metastasis.[21,25,31,32] Therefore, if the angiogenesis inhibitors in cartilage are also inhibitors of matrix metalloproteinases, then the same molecules may be able to block both angiogenesis and metastasis. Shark tissues other than cartilage have also been reported to produce antitumor substances.[33,34,35,36]
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