Viruses and Tumors in the Light of Electron Microscope Studies a Review*

Viruses and Tumors in the Light of Electron Microscope Studies A Review* LEON DMOCHOWSKI (Section of Virology and Electron Microscopy, The University of Texas M. D. Anderson Hospital and Tumor Institute, and Department of Microbiology, Baylor University College of Medicine, Texas Medical Center, Houston, Texas) CONTENTS I. Introduction 978 II. General Ultrastructure of Cells 979 A. Normal cells 1 B. Tumor cells J 1. The cell or plasma membrane of normal and tumor cells ~. The cytoplasm of normal cells 3. The cytoplasm of tumor cells 4. The Golgi apparatus of normal and tumor cells 5. The centri01e of normal and tumor cells 6. Mitochondria of normal cells 7. Mitochondria of tumor cells 8. Other cytoplasmic constituents of normal and tumor cells 9. The nuclear membrane of normal and tumor cells 10. The nucleus of normal and tumor cells 11. The nucleolus of normal and tumor cells III. Ultrastructure of Virus-infected Cells and Viruses 984 A. Herpes simplex B. Salivary gland virus C. :Fowl pox D. Vaccinia E. Ectromelia and molluscum contagiosum F. Meningopneumonitis virus G. Influenza H. Anopheles A virus I. Poliomyelitis J. Coxsackie viruses K. Trachoma virus L. Varicella M. Adenoviruses N. Newcastle disease O. Infectious myxomatosis P. Nucleic acid changes in virus-infected cells IV. Ultrastructure of Virus-induced Tumors and Tumor Viruses 988 A. Rous sarcoma B. Chicken leukosis * Presented in part at the Symposium on Contributions of Electron Microscopy of Viruses and Cells to the Problem of Cancer, held during the Seventeenth Annual Meeting of the Electron Microscope Society of America, Ohio State University, Columbus, Ohio, September 9-1e, 1959. Preparation of this paper was aided by Research Grants No. C-8679 and C-4140 from the National Cancer Institute of the National Institutes of Health, U.S. Public Health Service, and by Grant No. 94-B from the American Cancer Society. 977 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1960 American Association for Cancer Research. 978 Cancer Research Vol. ~0, August 1960 1. Visceral lymphomatosis /. Neurolymphomatosis 3. Granuloblastosis (myeloblastosis) 4. Erythroblastosis 5. Adenoeareinolna of the kidney of chickens C. Chemically induced tumors in chickens D. Normal chicken tissues E. The Shope fibroma of rabbits F. The Shope papilloma of rabbits G. Mammary tumors of mice and the Bittner virus H. Leukemia and other neoplastic conditions of mice 1. Spontaneous and induced leukemia ~. Parotid gland tumors 3. Polyoma-induced tumors of mice ~. X-ray-induced leukemia in mice 5. Other tumors of mice and rats I. The Luck6 adenoearcinoma of the frog J. Human tumors of known, suspected, or unknown viral origin V. Future Prospects 1001 VI. References 1003 I. INTRODUCTION viral agents could be detected in the infected The discovery of viruses at the end of the cells and the observation that these agents can 19th and the beginning of the ~0th century has be differentiated from normal cell constituents led to the development of virology as a new branch have led to electron microscope studies of tumors of biological science which has now grown into in the origin of whieh viral agents were either one of the most prolific and stimulating disciplines known or suspected to play a part. Electron micros- of all biological sciences. Soon after the discovery copy has also proved helpful in assessing the of the so-called infectious viruses came the discov- progress of isolation and purifieation procedures ery of the first tumor-inducing viruses. The part of tumor-indueing viruses, and in the study- of played by viruses in the origin of tumors gained the relationship between the isolated viral particles recognition only slowly. Indeed, it came to be and tumors induced by the inoeulation of suspen- fully recognized only during the last 8 years (114). sions eontaining these partieles. Like any other The new interest in viruses as causative agents method, electron mieroseopy has its limitations. in cancer was brought about by the results of the Nevertheless, its applicability to other methods, application of a number of methods, some long whether ehemieal, physical, or biologieal, makes known in virology but with possibilities only re- it not only one of choice but of neeessity in the cently realized, and some entirely new. Among present and future studies of tlle relationship the methods which have proved to be very helpful of viruses to the origin of tumors, both in animals in the study of viruses in relation to tumors is and lnan. electron microscopy of ultrathin sections of normal A discussion of the contributions of electron and tumor cells and of various preparations made microscopy of viruses and cells to the problem of from tumorous tissues. cancer requires, as a first step, an answer to several Following the application of electron micros- questions. These are: (a) what is a virus; (b) what copy to tlle stu(ty of normal cells, the study of is cancer; (c) are viruses the cause of cancer; (d) cells in viral infections was undertaken. It has what is the relationship of viruses which produce led to the visualization of viruses in the infected infection to those known to cause cancer? tissues and has revealed the complicated structure a) Viruses are intracellular, infectious, poten- of these agents and tile behavior of various sub- tially disease-producing nueleoprotein en t it ies, with microscopic cell elements (luring the different only one type of nucleic acid, which reproduce stages of infection. Almost simultaneously with from their own genetic material, are unable to the application of ele(.tron microscopy to the grow and divide, and are devoid of enzymes (0~94). cytology of normal and virus-infected cells, elec- It will be seen later that eleetr()n inicroscopy tron microscopic studies of malignant cells were has confirmed, at least in part, this definition of undertaken. The comparative ease with which a vir/i~. Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1960 American Association for Cancer Research. DMOCHOWSKI---Electron Microscopy of Viruses and Tumors 979 b) There is no sharp distinction between a past and present reviews are of importance in nornlal and a cancer cell. A gradual, progressive this rapidly developing field (216, 250, 251, 329, change from organized to unrestricted behavior 330, 366, 367, 400, 401,420, 424, 443, 474). of cells takes place in cancer, leading to the The development of suitable fixation procedures invasion of surrounding, then gradually more dis- (335, 372, 380, 417, 419), the introduction of taut cells, and to their final destruction (410). plastic as embedding material (70, 71, 326), and Thus, a distinction between a benign and malig- the development of ultrathin sectioning technics nant tumor is at best an arbitrary one. through the introduction of glass knives (282) c) Cancer, no matter of what type or origin, and of special microtomes (239, ~41, 354, 368, is known to be the result of many diverse factors, 418) have made possible a systematic study of such as genetic, hormonal, and environmental. the ultrastructure of cells. In addition, the technic Viruses are known to be one of the factors involved for the separation of cell components by differen- in the origin of tumors. The present-day question tial centrifugation (242, 344, 345), following the is in how many tumors are they one of the causa- original work of Claude (91, 92, 93), has provided tive factors. From the results of electron micro- important information about the chemical con- scope studies, so far obtained, it may be stated stitution and enzymatic activities of some of the that electron microscopy will play an important isolated cell constituents studied in the electron part in answering this question. microscope. A number of cellular components thus d) The essence of viral infection is not the acquired a new" functional and biochemical mean- disease, but the introduction into the host of a ing. These components vary in their appearance foreign entity which is able to multiply in the during different stages of the life of cells and cells of the host and reproduce other foreign in pathological conditions. Thus, gradually, cell entities, which may but do not necessarily have morphology, cell physiology, and biochemistry to produce a particular disease (294). Electron are becoming one integrated science. microscopic, biochemical, and immunological stud- Electron microscopy has contributed greatly ies have so far failed to reveal any essential dif- to our knowledge of the ultrastructure of cell ferences between infectious and tumor-inducing components and has led to a better understanding viruse< They all share a similar requirement for of their functional significance, although it has hving cells. Indeed, the tumor-inducing viruses revealed comparatively few new structural com- produce many symptoms characteristic of an in- ponents of the cell. A great deal more study is fection, and there are recent indications that some required, which should combine electron micros- infectious viruses may participate effectively in copy of the various cell components separated the development of tumors (148). by means of differential centrifugation with a Having thus answered these preliminary ques- biochemical analysis of these constituents derived tions, it is now possible to turn to electron micro- from cells in various stages of activity, in order scope studies of viruses and tumors. A proper to obtain some new basic concepts of normal and assessment of the contribution of these studies tumor cells. The structural components of cells to the part played by viruses in the origin of are not artifacts, because there exists an agreement tumors requires a thorough understanding of the between the structure of cells as seen under the ultrastructure of normal cells and viruses as seen phase-contrast and in the electron microscope. in the electron microscope.

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