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AiV ESSAY ON BASEMENT MEMBRANES AND THEIR INVOLVEMENT IN CANCER ARNOLD VAN DEN HOOFF* Introduction: Is Lysis of the Basement Membrane a Prerequisite for Tumor Invasion? It is my firm belief that in the living organism even the simplest structures are maintained by mechanisms of the utmost complexity. If such an apparently simple and static structure is involved in a disease process, its role is always a complex one. It then presents problems for which no simple solutions are to be expected because we are never sure that we have an exhaustive knowledge of its functioning in the all-embracing dynamic context of the intact organism. I shall argue in this article that this view applies to one of the simplest structures of the animal body: the basement membrane, the thin layer that separates an epithelium from its supporting connective tissue stroma. It is specifically on its role in malignant growth ofthe epithelium that I want to reflect. Its involvement in invasive tumor growth at first sight seems obvious. The membrane presents the first barrier to the downward infiltrative spread of the epithelium, and a large body of evidence, pointing to lysis ofthe basement membrane and the adjacent stroma, fits into the concept ofbarriers to be breached. But not all data fit. Invasive growth can occur with intact basement membranes. Invasiveness does not always parallel the production of lytic agents. Highly invasive cancers can be attended with an enhanced formation of stroma rather than with lysis. So one has to ask, Do these data disagree with the traditional concept of stromal degradation as a prerequisite for invasive growth? It seems opportune to weigh the evidence pro and contra lysis of the The author gratefully acknowledges the dedicated help of Mrs. T. M. S. Pierik in preparing this manuscript. *Laboratory of Histology and Cell Biology, University ofAmsterdam Academic Medical Centre, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.© 1989 by The University of Chicago. AU rights reserved. 003 1-5982/89/3203-0632$01 .00 Perspectives in Biology and Medicine, 32, 3 ¦ Spring 1989 \ 401 basement membrane and adjacent stroma as essential for invasive growth. 1 shall first outline the current view of the membrane, touching upon its composition and its functioning in the local setting. I then shall sum up data that seem to support the notion of the basement membrane as a barrier to invasive growth. But then I want to bring up data that in my view seem to contradict the traditional and plausible concept of the basement membrane and its adjacent stroma as barriers to invasion. And last, I intend to suggest an alternative interpretation of the microscopic pictures of what so obviously strikes us as invasive growth. Structure and Composition ofBasement Membranes Under the light microscope, a basement membrane is seen as a continuous layer separating the epithelium from the underlying connective tissue stroma. It can be stained by the periodic-acid-Schiff (PAS) method on account of its high content ofglycoproteins. The electron microscope has brought to light that the membrane, as seen under the light microscope , consists of a very thin lamina adjacent to the epithelium plus the top layer of the stroma. It has been agreed upon by histologists to refer to the ultrastructural layer as the basal lamina. All recent studies on the morphology, physiology, and pathology of the basement membrane bear on this thin sheet. This must be remembered since the correct nomenclature is not always strictly adhered to by recent authors. The terms basement membrane and basal lamina are used indiscriminately, both referring to what should strictly be called basal lamina. The ultrastructure of the basal lamina in routine electron microscopy seems simple: a continuous osmiophilic layer, some tens of nanometers thick, separated from the epithelium by a nonosmiophilic layer of about the same width. The basal laminas of some epithelia appear to be anchored to the stroma by short cross-banded fibrils. Chemical constituents of the basal lamina are: a special type of collagen (so-called type IV), certain glycoproteins, and proteoglycans. Type IV collagen has a specific amino acid composition and differs from other collagens by the unusual arrangement of its fibrils, which form a network . The glycoproteins include...

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