Extracellular Matrix Degradation And Pufas

Matrix degradation and invasion by cancer cells represent one of the key events in the metastatic cascade (figure 2). After tumour cells have adhered to the extracellular matrix, proteolytic enzymes, either secreted from the tumour cells, bound to the tumour cell membrane or from other sources will degrade the matrix to clear the way for tumour cells to migrate. Proteolytic enzymes involved in this matrix degradation mainly include metallo-proteinases (collagenases, and stromelysins) and serine proteinases (plasmin, trypsin, thrombin, urokinase-plasminogen activator (uPA). Their activities are controlled by their activation from pro-enzyme forms and deactivation by the relevant enzyme inhibitors. Thus, the balance of degradation is maintained by the participation of proteolytic enzyme inhibitors, including plasminogen activator inhibitors (PAIs), tissue inhibitor of metalloproteinases (TIMPs), and antiplasmin. The effects of experimentally modulating the level or function of these endogenous proteolytic inhibitors in tumours may assist to reduce invasion and metastasis.

Both proteolytic enzymes and their inhibitors can be regulated by PUFAs. It has been shown that the level of plasminogen activator inhibitor I, a member of the serpin class of protease inhibitors, was enhanced by DGLA and DHA (33). This enhancement further inhibited the activity of both tissue type and urokinase type plasminogen activators (tPA and uPA). EPA, GLA, and AA have been shown to inhibit uPA and collagenase IV production from cancer cells (34,35). Such regulation occurred at a transcriptional level (33). Other unsaturated fatty acids, such as 9-octadecenoic acid, have also been shown to influene MMP-2 expression (36). Interestingly, this appeared to be the response of another recently identified tumour suppressor and member of the serpin family, maspin (37-39). GLA and EPA selectively increased the protein and mRNA level of maspin in a range of cancer cells (40). It has been reported that LA stimulated tumour cell invasion and 92-kDa type IV collagenase production in vitro; GLA however inhibited invasion and did not induce activity of the proteolytic enzyme (17,19,41,42). In vivo, such an effect was not seen in terms of the tumour growth and metastasis formation, which may be due to the metabolism of the fatty acid in vivo to arachidonate-derived eicosanoids that may be involved in the metastatic process.

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