Synthesis and degradation of basement membranes and extracellular matrix and their regulation by TGF-beta in invasive carcinomas (Review)

The proper structure of the extracellular matrix, in particular of the base ment membrane and the adjacent interstitial matrix, are essential prerequis its for a proper function of tissues. Invasive growth in malignant tumors i s associated with a destruction of various matrix structures. Due to extens ive recent analyses significant advances have been made in the knowledge of the structure of the extracellular matrix, the composition of its most imp ortant constituents, their metabolism and that of matrix degrading enzymes, This information provides insight into the pathophysiology of malignant gr owth. Thereby, it has been shown that malignant tumor growth is associated with a loss of basement membrane (BM) material which, however, disappears n ot homogeneously, but affects various BM components to different degree. Th e loss of an intact BM as the first barrier is therefore the initial step o f tumor invasion. Despite this loss there is evidence that the ne,novo synt hesis of BM constituents in tumor and adjacent stromal cells is enhanced. T hus, it is obvious that BM material is degraded during the invasion process to significant degree. In addition, since there is a positive correlation between the amount of retained peritumoral BM and a higher degree of tumor cell differentiation the amount of retained BM material seems to represent a marker for the biological behaviour of the tumor cells. The loss of BM ma terial is well explained by a significant expression of major matrix degrad ing enzymes, the matrix metalloproteinases (MMPs) both on the mRNA and prot ein level. Here again, there is considerable data indicating that both tumo r and stroma cells are involved in the MMP synthesis. In addition to the lo ss of BM substances, the interstitial extracellular matrix (ECM) is disarra nged. This disarrangement may comprise enhanced de novo synthesis ('desmopl asia') or dissolution by distinct MMPs (collagenases, such as MMP-1) reflec ting obviously different reaction statuses of the stromal cells. Finally, s ignificant work has been done on the elucidation of the role of regulating cytokine systems. To this regard, particular attention has been paid to the TGF-beta system and it has been shown that the major three isoforms of TGF -betas are upregulated both in tumor and stroma cells. Since the TGF-beta - effect is mainly mediated by a particular signalling system via the TGF-bet a -receptors (TBRs), the investigation of this system has provided consider able insight into the role of TBRs which are now known to represent the mos t potent tumor suppressor genes. Thus frequent mutations in the TBR-II gene , one of the three TBRs, in various carcinomas suggest that these molecular alterations are responsible for both the loss of the control of cellular p roliferation (in tumor cells) and altered matrix metabolism (in tumor and s troma cells). The further analysis of this major cytokine system therefore will provide us with major insights into the molecular abnormalities of inv asive tumor growth.