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Atheroma as a neoplastic disease
ATHEROMA
AS A NEOPLASTIC
DOUGLAS ROTMAN,
DISEASE
156 Woodland Drive, Hartford, Connecticut 06105, U.S.A.
SUMMARY
An hypothesis is proposed that atheroma may be classified as a leiomyosarcoma derived from the tunica media of an artery. The notion that atheroma is a neoplastic disease provides a simple explanation for a highly complex phenomenon; the pathogenesis of atherosclerosis. According to this hypothesis some smooth-muscle cells in the media undergo malignant transformation, which is manifested by excessive production of hyaluronidase and other glycosaminoglycan hydrolases. This enzymic system frees cells from their bonds and allows them to proliferate. The enzymes also evoke a fibroblast hyperplasia which is followed by a protective collagenization producing a local area of increased resistance to the hydrolases. This accounts for the sclerosing aspect of the disease. Several other features of atherosclerosis are a result of the neoplastic nature of the disease.
INTRODUCTION I propose the hypothesis that atheroma is a malignant tumor, consisting of smooth-muscle cells derived from the tunica media of an artery. To demonstrate that this neoplastic classification makes sense, I will briefly review some relevant aspects of neoplasia. McCormick (1) has suggested that normal cells are restrained from proliferation by highly viscous connective tissue elements between the cells. These connective tissue elements are collagen and the various glycosaminoglycans. McCormick suggests that neoplastic cells grow unceasingly because the connective tissues have lost their capacity to hold the cells’ proliferative powers in check. To help understand the malignant transformation of epithelial tissues (carcinoma) it is useful to consider the normal structure of the epithelial tissues. The epithelial tissues include those cells which form the outer surface of the body and line the body cavities and passageways leading to the exterior. They form the secreting portions of glands and their ducts and important parts of certain sense organs. The epithelial cells are arranged in layers, the lower layer of columnar cells, known as the germinal layer, rests on a matrix of connective tissue known as the basement membrane. McCormick (1) proposed that this membrane normally provides a complete and continuous connective tissue barrier underlying the entire epithelium, constituting an inviolate line of demarkation between the epithelial and mesenchymal tissues. Any breach or disarrangement of this structure could lead to a disturbance in the orderly growth pattern of the epithelial cells, resulting potentially in an inward extention of cell growth through the breach, which is an early stage of malignancy. Normally a breach in the basement membrane is repaired by a proliferation of new connective tissue which fills the gap with impervious scar tissue, which prevents an inward growth of disarranged epithelium. Connective tissue tumors (sarcoma) include tumors arising from underlying tissue of muscle, kJOne and other connective tissue. Connective tissue cells themselves are bound together within a collagenous matrix. McCormick (1) suggests that as with epithelial cells, it is an intact inter202
cellular environment that holds the cells in their normal arrangement, and that any breach of this environment may result in malignant proliferation of the cells. Although McCormick stresses the important role of connective tissue in the neoplastic transformation, he does not explain how the neoplastic cell is capable of disintegrating the connective-tissue that normally holds the cells’ proliferative powers in check. Ewan Cameron (2) has suggested that the glycosaminoglycan hydrolases, particularly hyaluronidase, are responsible for initiating cell proliferation. Working with hyaluronidase are other lysosomal enzymes including chondrosulphatase, /I-N-acetylglucosaminidase and /I-glucuronidase. The synergistic effect of these enzymes is the degradation of the various connective-tissue glycosaminoglycans polymers into disaccharides. The principal glycosaminoglycans are hyaluronic acid and various forms of chondritin and its sulfate esters. These polymers are composed of alternating molecules of a uranic acid (glucuronate or iduronate) and an amino sugar (N-acetylglucosamin or N-acetylgalactosamine.) These glycosaminoglycans are responsible for the high viscosity and cohesiveness of the ground substance and the interfibrillary cement which binds the minute collagen fibrills together into the superstructure of larger collagen fibres. By catalyzing the hydrolysis of the glycosaminoglycans, hyaluronidase and its associated enzymes, liquefies the cement substances that hold body cells and collagenous components together. Cameron (2) believes that all tissue cells have an inherent tendency to divide but this tendency is normally restrained by the viscous nature of their intimate extracellular environment of high molecular weight ground substance glycosaminoglycans. Proliferation is initiated by cellular release of hyaluronidase, which permits the cell local freedom to divide and to migrate within the limits of the altered field. Proliferation will continue as long as hyaluronidase is being released; proliferation will cease and normal tissue organization and restraint will be restored when the production of hyaluronidase returns to normal. Under this interpretation cancer is an abnormal persistence of a normal physiological process. The acquisition of this
ability to (continuously) release hyaluronidase by certain cells and all their descendants, permanently isolates them from all the usual environmental proliferative restraints, and by its very persistence accounts for their invasive properties. Continuing exposure to tumor hyaluronidase leads to a fibroblast hyperplasia which is followed by a protective collagenization producing a local area of increased resistance to hyaluronidase. This is the well known scirrhous response to the tumor. McCormick (1) points out that this scirrhous response explains the relatively benign nature of the scirrhous or hard carcinoma@ with the predominant connective-tissue stroma, as contrasted with the medullary or soft variety with predominant cellular composition, and extreme malignancy. Willis (3) has noted that some malignant tumors can invade veins and produce venous thrombosis. His description of the process is cited here: “Purely mural invasion of a large vein may set up a prohferative thickening of its intima which, along with mechanical compression of the vessel, may result in its obliteration without either tumour invasion of the lumen or formation of thrombus. Invasion of the lumen, however, brings the tumour in contact with the bloodstream. Over the invaded area of intima a small thrombus forms. Organization and malignant infiltration of this initial thrombus follow: the thrombus grows steadily until the lumen is occluded, when thrombosis along a section of the vessel takes place.”
Willis’ description of tumor-induced venous thrombosis is very illuminating, if we interpret atheroma as a malignant tumor. This interpretation suggests that atheromas produce thrombosis in arteries in a manner similar to the way other tumors produce thrombosis in veins.
ATHEROMA AS A NEOPLASM Atherosclerosis is a chronic disease. Unger (4) notes that developmental progress of the disease as shown by post mortem examinations is briefly summarized as follows. Musculoelastic thickening is found in the first decade of life with differences noted between the sexes even at this early date, Fatty streaks occur in the second decade; fibrous plaques in the third; complicated lesions in the fourth and clinically manifest disease in the fifth decade. The fibrous plaque in atherosclerosis is composed mainly of smooth-muscle cells surrounded by a dense collagenous stroma. I propose that these muscle cells are those of a tumor (an atheroma) originating from the muscle tissue of the arterial media. In the discussion of tumors above, I noted that the host of the tumor restrained the spread of the tumor, by encapsulating the tumor in a collagenous stroma. This is what oncologists refer to as the tumor’s scirrhous response. The tumor atheroma evokes a scirrhous response. I propose that atherosclerosis is the scirrhous response to an atheroma, since atherosclerosis contains the collagenous stroma characteristic of a scirrhous response. In other words, I propose that atheroma is a leiomyosarcoma derived from the tunica media of an artery and atherosclerosis is the defensive scirrhous response to this tumor. The smooth-muscle cells of atherosclerotic plaque differ 203
in size and other characteristics from cells in normal artery walls. This is consistent with the neoplasm hypothesis for atheroma, since it is a common feature of malignant cells to exhibit imperfect differentiation. This property of neoplastic cells is termed anaplasia. From this point of view, the muscle cells of atherosclerosis are an anaplastic variant of the normal muscle cells of the arterial wall. Benditt and Benditt (5) have found evidence that the smooth-muscle cells found in human atherosclerotic plaque are of monoclonal origin. They suggest that the cellular contents of atherosclerotic plaque are largely growths that originate from a single cell, something like a wart. They suggest that factors that transform cells such as mutagens or viruses may play an important role in the initiation of the disease. The Benditts point out that the regions where atherosclerotic plaque is most likely to occur (for example near branch orifices) are the very sites where there is a high turnover of endothelial cells. And there is evidence for assuming a higher turnover of muscle cells in the underlying wall. The experimental results of the Benditts suggest that atheroma is a cell proliferative disease and offers support for the hypothesis that atheroma is a leiomyosarcoma. Cameron (2) suggests that tumor hyaluronidase plays an important role in the development of cancer. If atheroma is really a leiomyosarcoma as proposed here, then we would expect hyaluronidase to play a role in the development of atheroma. Kasatkina (6) has shown that intravenous administration of hyaluronidase to rabbits which had received cholesterol with their food intensified and accelerated the development of atherosclerosis. This study indicates that if an atheroma produced its own hyaluronidase, then we may consider this hyaluronidase as a factor contributing to the development of atherosclerosis. It is known that hyaluronidase evokes fibroblast hyperplasia, which is followed by a protective collagenization producing a local area of increased resistance to the enzyme. This hyaluronidase induced sclerosis is simply the scirrhous response to an atheroma, which we have justly identified as atherosclerosis. Platt and Luboeinski (7) have measured the enzyme activities of P-glucuronidase and P-N-acetylglucosaminidase in human aortic tissue. The activities of the enzymes were significantly increased in areas with atherosclerotic changes. These investigators concluded that the increase of enzyme activities were actually due to an enhanced enzyme production of the smooth-muscle cells of the atherosclerotic plaque. This increased level of glycosaminoglycan hydrolases is what we would expect from malignant smooth-muscle cells. The glycosaminoglycan hydrolases determine the permeability of the vessel wall. The diamettr of the intermolecular spaces is approximately 50A, hence only substances of a certain molecular dimension are able to penetrate the vessel wall. The glycosaminoglycans act as a sieve that prevents relatively large molecules from penetrating the vessel wall. Since hyaluronidase disintegrates, the glycosaminoglycans, the enzyme tends to increase the permeability of the vessel wall. The increased hyaluronidase activity in the atherosclerotic part of an artery would allow proteins and lipids to permeate the altered part of the artery.
CHOLESTEROL The role of cholesterol in atherosclerosis has received much attention in recent years. Kasatkina and Pozdyunina (8) studied the intluence that cholesterol has on serum hyaluronidase. They found that rabbits fed 0.2g of cholesterol/kg. body weight, exhibited an increase in serum hyaluronidase from 0.85 to 5.45 units within a period of several weeks. The source of this hyaluronidase may be an atheroma. It seems that either cholesterol directly stimulates cellular hyaluronidase production or it contributes to other agents causing an atheroma to secrete extra hyaluronidase. Cameron (2) suggests that it is the release of excess hyaluronidase that sets the stage for cell proliferation. Since cholesterol stimulates the production of extra hyaluronidase, we might expect it to promote smooth-muscle cell proliferation. This has been experimentally verified. Thomas et al. (9) have shown that swine fed an hypercholesterolemic diet exhibited increased proliferation of endothelial and smooth-muscle cells in the arterial wall. Thus the role of cholesterol in the genesis of atheroma is consistent with the neoplasm hypothesis for atheroma.
LIPOPROTEIN LIPASE After ingestion of a fatty meal, triglycerides enter the blood as chylomicrons. Lipoprotein lipase is an enzyme that helps remove the chylomicrons from the plasma, by hydrolysis of the triglycerides in the chylomicrons. Seethanathan and Kurup (10) have presented evidence that lipoprotein lipase is a mucoprotein whose active part contains a heparin-like glycosaminoglycan. The suggest that the decreased concentration of glycosaminoglycans in rats fed a high cholesterpl diet may impair production of lipoprotein lipase. It is plausible to suggest that hyaluronidase from an atheroma may disintegrate the glycosaminoglycan component of lipoprotein lipase and thus inactivate the enzyme or hyaluronidase may make conditions for synthesis of the enzyme less favorable. This could account for the elevated levels of triglycerides in the plasma of hosts subject to atheroma.
atheroma is already inside an artery. It would be relatively easy for such a tumor to develop tentacles that may infiltrate the intima of the artery. Willis (12) has presented evidence that the depolymerization of the glycosaminoglycans of the ground substance of the intima, is the preconditioning factor in the precipitation of thrombosis. Dr. Willis points out that normally the intima receives its nourishment by diffusion from the arterial lumen and from the vasa vasorum. However in atherosclerosis, dilated capillaries invade the intima from the vasa vasorum. These capillaries frequently rupture and produce intimal hemorrhage. The reason that these capillaries rupture is probably due to hyaluronidase from an atheroma. Chambers and Zweifach (13) studied the effect of hyaluronidase on the capillary wall. They observed that the hyaluronidase produced a local area of weakening of the pericapillary sheath which becomes attenuated and eventually disappears, leaving an unsupported endothelial layer which ruptures with local hemorrhage. Samuels and Webster (14) have shown that platelets adhere along lines of inter-endothelial cement when a vessel is injured. From this beginning a thrombus is formed. Thus it seems that coronary thrombosis is precipitated by intimal hemorrhage, and the intimal hemorrhage is in turn caused by the ulcerative effect of hylauronidase produced by an atheroma, Acknowledgement I am grateful to my correspondent Ewan Cameron for many discussions and for his helpful encouragement.
1.
2. 3. 4. 5. 6.
ARTERIAL CALCIFICATION The stroma of tumors can exhibit metaplastic changes (I 1). For example bony metaplasia is frequent in the stroma of bronchial adenomas. The calcification of athersclerotic arteries can similarly be regarded as an example of osseous metaplasia in the fibroblastic stroma of an atheroma. Hence the pathological calcification of atherosclerotic arteries is consistent with the neoplasm hypothesis for atheroma.
I. 8. 9. 10. 11. 12.
THROMBOSIS Thrombosis can be produced in veins when a tumor invades the lumen of the vessel. Most tumors do not invade arteries. In this respect atheroma may be an exceptional tumor, since this tumor originates in the media of an artery. Because of its convenient site of origin, an
204
13. 14.
REFERENCES McCormick WJ. Cancer: The preconditioning factor in pathogenesis. Arch Pediat NY. 71, 313, 1954 Cameron E. Zfyaluronidaseand Cancer, Pergamon Press, Oxford, 1966. Willis RA. Pathology of Turnours, fourth edition, ~156, Butterworths, London, 1967. Unger PN. Coronary proneness; can it be identified? J Florida Med Assn. 51, 579, 1964 Benditt EP, Benditt JM. Evidence for a monoclonal origin of human atherosclerotic ulaaues. Proc Nat Acad Sci USA 70, 1753, 1973 Kasatkina LV.’ Intluence of hyaluronidase on development of exoerimental atherosclerosis. Kardiologiya 4, 30, 1961 P&t D, Luboeinski HP. The activtiiks of glycosaminoglycan hydrolases of normal and atherosclerotic human aorta. Angiologica 6, 19, 1969 Kasatkina LV, Pozdyunina NM. States of the principle components in the earlv staaes of experimental atherosclerosis. Arkh Patol. 31, 53, 1969 Thomas WA, Florentin RA, Nam SC, Kim DM, Jones RM, Lee KT. Preprohferative phase of atherosclerosis in swine fed cholesterol. Arch Path. 86, 621, 1968 Seethanathan P, Kurup PA. Changes in tissue glycosaminoglycans in rats fed a hypercholesterolaemic diet. Atherosclerosis 14, 65, 1971 Willis RA. Pathology of Turnours, fourth edition, plO0, Butterworths, London, 1967. Willis GC. An experimental study of the intimal ground substance on atherosclerosis. Can Med Assoc J. 69, 17, 1953 Chambers R, Zweifach BW. Intercellular cement and capillary ermeability. Physiol Rev. 27, 436, 1947 Gamuels PB, Webster DR. Role of venous endothelium in inception of thrombosis. Ann Surg. 136, 422, 1952
AS A NEOPLASTIC
DOUGLAS ROTMAN,
DISEASE
156 Woodland Drive, Hartford, Connecticut 06105, U.S.A.
SUMMARY
An hypothesis is proposed that atheroma may be classified as a leiomyosarcoma derived from the tunica media of an artery. The notion that atheroma is a neoplastic disease provides a simple explanation for a highly complex phenomenon; the pathogenesis of atherosclerosis. According to this hypothesis some smooth-muscle cells in the media undergo malignant transformation, which is manifested by excessive production of hyaluronidase and other glycosaminoglycan hydrolases. This enzymic system frees cells from their bonds and allows them to proliferate. The enzymes also evoke a fibroblast hyperplasia which is followed by a protective collagenization producing a local area of increased resistance to the hydrolases. This accounts for the sclerosing aspect of the disease. Several other features of atherosclerosis are a result of the neoplastic nature of the disease.
INTRODUCTION I propose the hypothesis that atheroma is a malignant tumor, consisting of smooth-muscle cells derived from the tunica media of an artery. To demonstrate that this neoplastic classification makes sense, I will briefly review some relevant aspects of neoplasia. McCormick (1) has suggested that normal cells are restrained from proliferation by highly viscous connective tissue elements between the cells. These connective tissue elements are collagen and the various glycosaminoglycans. McCormick suggests that neoplastic cells grow unceasingly because the connective tissues have lost their capacity to hold the cells’ proliferative powers in check. To help understand the malignant transformation of epithelial tissues (carcinoma) it is useful to consider the normal structure of the epithelial tissues. The epithelial tissues include those cells which form the outer surface of the body and line the body cavities and passageways leading to the exterior. They form the secreting portions of glands and their ducts and important parts of certain sense organs. The epithelial cells are arranged in layers, the lower layer of columnar cells, known as the germinal layer, rests on a matrix of connective tissue known as the basement membrane. McCormick (1) proposed that this membrane normally provides a complete and continuous connective tissue barrier underlying the entire epithelium, constituting an inviolate line of demarkation between the epithelial and mesenchymal tissues. Any breach or disarrangement of this structure could lead to a disturbance in the orderly growth pattern of the epithelial cells, resulting potentially in an inward extention of cell growth through the breach, which is an early stage of malignancy. Normally a breach in the basement membrane is repaired by a proliferation of new connective tissue which fills the gap with impervious scar tissue, which prevents an inward growth of disarranged epithelium. Connective tissue tumors (sarcoma) include tumors arising from underlying tissue of muscle, kJOne and other connective tissue. Connective tissue cells themselves are bound together within a collagenous matrix. McCormick (1) suggests that as with epithelial cells, it is an intact inter202
cellular environment that holds the cells in their normal arrangement, and that any breach of this environment may result in malignant proliferation of the cells. Although McCormick stresses the important role of connective tissue in the neoplastic transformation, he does not explain how the neoplastic cell is capable of disintegrating the connective-tissue that normally holds the cells’ proliferative powers in check. Ewan Cameron (2) has suggested that the glycosaminoglycan hydrolases, particularly hyaluronidase, are responsible for initiating cell proliferation. Working with hyaluronidase are other lysosomal enzymes including chondrosulphatase, /I-N-acetylglucosaminidase and /I-glucuronidase. The synergistic effect of these enzymes is the degradation of the various connective-tissue glycosaminoglycans polymers into disaccharides. The principal glycosaminoglycans are hyaluronic acid and various forms of chondritin and its sulfate esters. These polymers are composed of alternating molecules of a uranic acid (glucuronate or iduronate) and an amino sugar (N-acetylglucosamin or N-acetylgalactosamine.) These glycosaminoglycans are responsible for the high viscosity and cohesiveness of the ground substance and the interfibrillary cement which binds the minute collagen fibrills together into the superstructure of larger collagen fibres. By catalyzing the hydrolysis of the glycosaminoglycans, hyaluronidase and its associated enzymes, liquefies the cement substances that hold body cells and collagenous components together. Cameron (2) believes that all tissue cells have an inherent tendency to divide but this tendency is normally restrained by the viscous nature of their intimate extracellular environment of high molecular weight ground substance glycosaminoglycans. Proliferation is initiated by cellular release of hyaluronidase, which permits the cell local freedom to divide and to migrate within the limits of the altered field. Proliferation will continue as long as hyaluronidase is being released; proliferation will cease and normal tissue organization and restraint will be restored when the production of hyaluronidase returns to normal. Under this interpretation cancer is an abnormal persistence of a normal physiological process. The acquisition of this
ability to (continuously) release hyaluronidase by certain cells and all their descendants, permanently isolates them from all the usual environmental proliferative restraints, and by its very persistence accounts for their invasive properties. Continuing exposure to tumor hyaluronidase leads to a fibroblast hyperplasia which is followed by a protective collagenization producing a local area of increased resistance to hyaluronidase. This is the well known scirrhous response to the tumor. McCormick (1) points out that this scirrhous response explains the relatively benign nature of the scirrhous or hard carcinoma@ with the predominant connective-tissue stroma, as contrasted with the medullary or soft variety with predominant cellular composition, and extreme malignancy. Willis (3) has noted that some malignant tumors can invade veins and produce venous thrombosis. His description of the process is cited here: “Purely mural invasion of a large vein may set up a prohferative thickening of its intima which, along with mechanical compression of the vessel, may result in its obliteration without either tumour invasion of the lumen or formation of thrombus. Invasion of the lumen, however, brings the tumour in contact with the bloodstream. Over the invaded area of intima a small thrombus forms. Organization and malignant infiltration of this initial thrombus follow: the thrombus grows steadily until the lumen is occluded, when thrombosis along a section of the vessel takes place.”
Willis’ description of tumor-induced venous thrombosis is very illuminating, if we interpret atheroma as a malignant tumor. This interpretation suggests that atheromas produce thrombosis in arteries in a manner similar to the way other tumors produce thrombosis in veins.
ATHEROMA AS A NEOPLASM Atherosclerosis is a chronic disease. Unger (4) notes that developmental progress of the disease as shown by post mortem examinations is briefly summarized as follows. Musculoelastic thickening is found in the first decade of life with differences noted between the sexes even at this early date, Fatty streaks occur in the second decade; fibrous plaques in the third; complicated lesions in the fourth and clinically manifest disease in the fifth decade. The fibrous plaque in atherosclerosis is composed mainly of smooth-muscle cells surrounded by a dense collagenous stroma. I propose that these muscle cells are those of a tumor (an atheroma) originating from the muscle tissue of the arterial media. In the discussion of tumors above, I noted that the host of the tumor restrained the spread of the tumor, by encapsulating the tumor in a collagenous stroma. This is what oncologists refer to as the tumor’s scirrhous response. The tumor atheroma evokes a scirrhous response. I propose that atherosclerosis is the scirrhous response to an atheroma, since atherosclerosis contains the collagenous stroma characteristic of a scirrhous response. In other words, I propose that atheroma is a leiomyosarcoma derived from the tunica media of an artery and atherosclerosis is the defensive scirrhous response to this tumor. The smooth-muscle cells of atherosclerotic plaque differ 203
in size and other characteristics from cells in normal artery walls. This is consistent with the neoplasm hypothesis for atheroma, since it is a common feature of malignant cells to exhibit imperfect differentiation. This property of neoplastic cells is termed anaplasia. From this point of view, the muscle cells of atherosclerosis are an anaplastic variant of the normal muscle cells of the arterial wall. Benditt and Benditt (5) have found evidence that the smooth-muscle cells found in human atherosclerotic plaque are of monoclonal origin. They suggest that the cellular contents of atherosclerotic plaque are largely growths that originate from a single cell, something like a wart. They suggest that factors that transform cells such as mutagens or viruses may play an important role in the initiation of the disease. The Benditts point out that the regions where atherosclerotic plaque is most likely to occur (for example near branch orifices) are the very sites where there is a high turnover of endothelial cells. And there is evidence for assuming a higher turnover of muscle cells in the underlying wall. The experimental results of the Benditts suggest that atheroma is a cell proliferative disease and offers support for the hypothesis that atheroma is a leiomyosarcoma. Cameron (2) suggests that tumor hyaluronidase plays an important role in the development of cancer. If atheroma is really a leiomyosarcoma as proposed here, then we would expect hyaluronidase to play a role in the development of atheroma. Kasatkina (6) has shown that intravenous administration of hyaluronidase to rabbits which had received cholesterol with their food intensified and accelerated the development of atherosclerosis. This study indicates that if an atheroma produced its own hyaluronidase, then we may consider this hyaluronidase as a factor contributing to the development of atherosclerosis. It is known that hyaluronidase evokes fibroblast hyperplasia, which is followed by a protective collagenization producing a local area of increased resistance to the enzyme. This hyaluronidase induced sclerosis is simply the scirrhous response to an atheroma, which we have justly identified as atherosclerosis. Platt and Luboeinski (7) have measured the enzyme activities of P-glucuronidase and P-N-acetylglucosaminidase in human aortic tissue. The activities of the enzymes were significantly increased in areas with atherosclerotic changes. These investigators concluded that the increase of enzyme activities were actually due to an enhanced enzyme production of the smooth-muscle cells of the atherosclerotic plaque. This increased level of glycosaminoglycan hydrolases is what we would expect from malignant smooth-muscle cells. The glycosaminoglycan hydrolases determine the permeability of the vessel wall. The diamettr of the intermolecular spaces is approximately 50A, hence only substances of a certain molecular dimension are able to penetrate the vessel wall. The glycosaminoglycans act as a sieve that prevents relatively large molecules from penetrating the vessel wall. Since hyaluronidase disintegrates, the glycosaminoglycans, the enzyme tends to increase the permeability of the vessel wall. The increased hyaluronidase activity in the atherosclerotic part of an artery would allow proteins and lipids to permeate the altered part of the artery.
CHOLESTEROL The role of cholesterol in atherosclerosis has received much attention in recent years. Kasatkina and Pozdyunina (8) studied the intluence that cholesterol has on serum hyaluronidase. They found that rabbits fed 0.2g of cholesterol/kg. body weight, exhibited an increase in serum hyaluronidase from 0.85 to 5.45 units within a period of several weeks. The source of this hyaluronidase may be an atheroma. It seems that either cholesterol directly stimulates cellular hyaluronidase production or it contributes to other agents causing an atheroma to secrete extra hyaluronidase. Cameron (2) suggests that it is the release of excess hyaluronidase that sets the stage for cell proliferation. Since cholesterol stimulates the production of extra hyaluronidase, we might expect it to promote smooth-muscle cell proliferation. This has been experimentally verified. Thomas et al. (9) have shown that swine fed an hypercholesterolemic diet exhibited increased proliferation of endothelial and smooth-muscle cells in the arterial wall. Thus the role of cholesterol in the genesis of atheroma is consistent with the neoplasm hypothesis for atheroma.
LIPOPROTEIN LIPASE After ingestion of a fatty meal, triglycerides enter the blood as chylomicrons. Lipoprotein lipase is an enzyme that helps remove the chylomicrons from the plasma, by hydrolysis of the triglycerides in the chylomicrons. Seethanathan and Kurup (10) have presented evidence that lipoprotein lipase is a mucoprotein whose active part contains a heparin-like glycosaminoglycan. The suggest that the decreased concentration of glycosaminoglycans in rats fed a high cholesterpl diet may impair production of lipoprotein lipase. It is plausible to suggest that hyaluronidase from an atheroma may disintegrate the glycosaminoglycan component of lipoprotein lipase and thus inactivate the enzyme or hyaluronidase may make conditions for synthesis of the enzyme less favorable. This could account for the elevated levels of triglycerides in the plasma of hosts subject to atheroma.
atheroma is already inside an artery. It would be relatively easy for such a tumor to develop tentacles that may infiltrate the intima of the artery. Willis (12) has presented evidence that the depolymerization of the glycosaminoglycans of the ground substance of the intima, is the preconditioning factor in the precipitation of thrombosis. Dr. Willis points out that normally the intima receives its nourishment by diffusion from the arterial lumen and from the vasa vasorum. However in atherosclerosis, dilated capillaries invade the intima from the vasa vasorum. These capillaries frequently rupture and produce intimal hemorrhage. The reason that these capillaries rupture is probably due to hyaluronidase from an atheroma. Chambers and Zweifach (13) studied the effect of hyaluronidase on the capillary wall. They observed that the hyaluronidase produced a local area of weakening of the pericapillary sheath which becomes attenuated and eventually disappears, leaving an unsupported endothelial layer which ruptures with local hemorrhage. Samuels and Webster (14) have shown that platelets adhere along lines of inter-endothelial cement when a vessel is injured. From this beginning a thrombus is formed. Thus it seems that coronary thrombosis is precipitated by intimal hemorrhage, and the intimal hemorrhage is in turn caused by the ulcerative effect of hylauronidase produced by an atheroma, Acknowledgement I am grateful to my correspondent Ewan Cameron for many discussions and for his helpful encouragement.
1.
2. 3. 4. 5. 6.
ARTERIAL CALCIFICATION The stroma of tumors can exhibit metaplastic changes (I 1). For example bony metaplasia is frequent in the stroma of bronchial adenomas. The calcification of athersclerotic arteries can similarly be regarded as an example of osseous metaplasia in the fibroblastic stroma of an atheroma. Hence the pathological calcification of atherosclerotic arteries is consistent with the neoplasm hypothesis for atheroma.
I. 8. 9. 10. 11. 12.
THROMBOSIS Thrombosis can be produced in veins when a tumor invades the lumen of the vessel. Most tumors do not invade arteries. In this respect atheroma may be an exceptional tumor, since this tumor originates in the media of an artery. Because of its convenient site of origin, an
204
13. 14.
REFERENCES McCormick WJ. Cancer: The preconditioning factor in pathogenesis. Arch Pediat NY. 71, 313, 1954 Cameron E. Zfyaluronidaseand Cancer, Pergamon Press, Oxford, 1966. Willis RA. Pathology of Turnours, fourth edition, ~156, Butterworths, London, 1967. Unger PN. Coronary proneness; can it be identified? J Florida Med Assn. 51, 579, 1964 Benditt EP, Benditt JM. Evidence for a monoclonal origin of human atherosclerotic ulaaues. Proc Nat Acad Sci USA 70, 1753, 1973 Kasatkina LV.’ Intluence of hyaluronidase on development of exoerimental atherosclerosis. Kardiologiya 4, 30, 1961 P&t D, Luboeinski HP. The activtiiks of glycosaminoglycan hydrolases of normal and atherosclerotic human aorta. Angiologica 6, 19, 1969 Kasatkina LV, Pozdyunina NM. States of the principle components in the earlv staaes of experimental atherosclerosis. Arkh Patol. 31, 53, 1969 Thomas WA, Florentin RA, Nam SC, Kim DM, Jones RM, Lee KT. Preprohferative phase of atherosclerosis in swine fed cholesterol. Arch Path. 86, 621, 1968 Seethanathan P, Kurup PA. Changes in tissue glycosaminoglycans in rats fed a hypercholesterolaemic diet. Atherosclerosis 14, 65, 1971 Willis RA. Pathology of Turnours, fourth edition, plO0, Butterworths, London, 1967. Willis GC. An experimental study of the intimal ground substance on atherosclerosis. Can Med Assoc J. 69, 17, 1953 Chambers R, Zweifach BW. Intercellular cement and capillary ermeability. Physiol Rev. 27, 436, 1947 Gamuels PB, Webster DR. Role of venous endothelium in inception of thrombosis. Ann Surg. 136, 422, 1952