Shope Virus Research Articles

A COMPARISON OF VIRUS-INDUCED RABBIT TUMORS WITH THE TUMORS OF UNKNOWN CAUSE ELICITED BY TARRING

Tarring the ears of rabbits of one sort with a single kind of tar evoked epidermal tumors of a few sharply defined types, namely ordinary papillomas, carcinoids, carcinomas, and "frill horns." These last, relatively infrequent, are now recognized for the first time. The carcinoids have proved to be the expression of a spurious malignancy of papillomas, resulting from intercurrent influences, and they were wholly dependent upon these for their threatening aspect and behavior. Chief amongst such influences was continued tarring. It had the effect of establishing the papillomas, stimulated their proliferation, complicated their morphology, and rendered some of them disorderly, aggressive, and anaplastic. It brought all of the tissues of the ears into an excitable state, and often this state endured long after the skin had apparently returned to normal. The characters of the papilloma-carcinoids and of the frill horns were so different and distinctive as to imply the action of differing, specific causes. The papillomas were very like those induced with the Shope virus, and hence a point-to-point comparison was made of their manifestations, including the derivation of carcinomas from them. This comparison demonstrated that the unknown cause of the tar papillomas provoked neoplastic phenomena which were identical in all essential respects with those due to the virus. To suppose, for experimental purposes, that the papillomas which tarring elicits are caused by a virus rendered pathogenic by this procedure, is to demand least of the unknown. Yet it does not follow that they must be due to a virus.

Studies in Carcinogenesis: V. Methyl Derivatives of 1:2-Benzanthracene

During the last decade a considerable amount of information has been accumulated regarding the experimental production of malignant tumors in laboratory animals. Several widely different types of agents are now known to be capable of inciting malignant growth. In addition to the well known carcinogenic action of x-rays and of radioactive substances, it is now clear, from the results obtained in a number of independent laboratories, that prolonged exposure to ultraviolet light2 gives rise to malignant tumors in the exposed tissues. As to biological agents, it has been recognized for some time that certain worm parasites are responsible for the genesis of malignant tumors of the urinary bladder and of the liver in man, and of the liver in the rat. Although Rous (1911) had discovered many years ago that fowl sarcoma could be transmitted by cell-free filtrates, and although Gye (1925) had been emphasizing the significance of this approach to the cancer problem, yet “the work of Peyton Rous and his collaborators has not met with its just recognition” according to Gye and Purdy (1931). The demonstration by Rous and Beard (1934) that carcinoma may be induced in rabbits with the Shope virus has, however, resulted in a revival of interest in the question of the role of viruses in the genesis of tumors generally. According to Rowntree, Steinberg, Dorrance and Ciccone (1937), crude wheat germ oil, given orally, produces sarcoma in rats in a very short time.

Antigenicity and Infectivity of Extracts of Virus-Induced Rabbit Papillomas

The antigen which binds complement when mixed with sera neutralizing the Shope papilloma-virus bears an evident relation to the virus itself; for it is present in high titer in virus-containing extracts of papillomas, it is retained by filters which hold back the virus, and its effectiveness is destroyed by the same amount of heating which renders the virus non-pathogenic.1 The experiments now to be reported throw further light on this relation.Tests with Extracts of Non-Infectious Papillomas and of Normal Skin. On inoculation the Shope virus gives rise to papillomas in both domestic and cottontail rabbits; yet only infrequently can it be extracted in active state from the domestic-rabbit growths, and occasionally those of cottontails fail to yield it. Papillomas from 6 cottontail and 8 domestic rabbits, which were produced by the virus yet from which it could not be recovered, have been extracted as usual and tested repeatedly for capacity to bind complement under optimal conditions. Most of these non-in...

A Complement-Fixation Reaction Involving the Rabbit Papilloma Virus (Shope)

SummaryA coniplernent-fixation reaction is described, with extracts or filtrates of papillonias containing infective Shope virus and antisera effective against the latter. The implications of the work are being studied.

OBSERVATIONS ON THE RELATION OF THE VIRUS CAUSING RABBIT PAPILLOMAS TO THE CANCERS DERIVING THEREFROM

The papillomas caused by the Shope virus sometimes grow down spontaneously into the subcutaneous tissue and extend along the lymphatics in the same way as do many cancers of the human breast. They may even invade the voluntary muscle under such circumstances, taking on an aspect suggestive of squamous cell carcinomatosis, but ultimately they differentiate in the way characteristic of the papilloma. Slight operative interferences with papillomas may be followed by a development of secondary nodules in the lungs. These result from cell emboli, and the same local conditions determine their fate as are effective in the case of emboli composed of human cancer cells. The virus-induced papilloma is not only a neoplasm in its immediate aspect and habit but sometimes one that verges upon malignancy. The tumors, including the cancers, which eventually derive from it in favorable hosts, are representative of more than a mere enhancement of the activity of the growth. They develop within a relatively brief period of time but only after the papilloma has grown for a long while; and they are morphologically various whereas the parent tumor is remarkably constant in its form. Some of the new growths differ but little from the papilloma, however, even when possessed of the ability to metastasize, and many continue to be influenced by the virus. The Shope virus is heavily conditioned in its carcinogenic activity, yet it is the nearest cause for cancer now known.

OBSERVATIONS ON THE RELATION OF THE VIRUS CAUSING RABBIT PAPILLOMAS TO THE CANCERS DERIVING THEREFROM

All the strains of the Shope virus thus far tested which give rise to vigorous, progressively enlarging papillomas in domestic rabbits, function as carcinogenic agents by way of these growths. The more pathogenic the virus as evidenced by the brevity of its incubation period and the vigor of the papillomas produced, the sooner and oftener does cancer occur. The number of virus entities contained in the inoculum notably influences the outcome, cancer appearing most frequently in those confluent, papillomatous masses which have resulted from the greatest concentration of the virus material under test. The papillomas experimentally induced by the ordinary inoculation methods are essentially aggregates of proliferating cell families, each the outcome of some primary cell-virus association. Some of these associations are followed more frequently by cancer than others are in the same animal. Cottontail rabbits, the natural hosts of the virus, are notably resistant to its sustained activity, as compared with domestic rabbits. Though often growing rapidly at first, the papillomas of cottontails soon become relatively inert in most cases, and they usually retrogress, and rarely undergo malignant change. In an instance here reported both a squamous cell carcinoma and a metastasizing sarcoma appeared at the base of some papillomas due to experimental inoculation, which had existed on the ears of a cottontail for nearly 2 years. The meaning of the phenomena is discussed.

A Comparison of the Tar Tumors of Rabbits and the Virus-Induced Tumors

By tarring the ears of domestic and cottontail rabbits tumors have been procured for comparison with others experimentally induced with the Shope virus.1 The tarred rabbits were strictly isolated.The growths caused by virus regularly developed from the surface epidermis and were papillomas varying little in structure, whereas not a few of those consequent on tarring originated from the skin appendages, with result in a wider morphological variety. The tar papillomas were scattered, discrete and often punctate in origin; so too were the papillomas due to virus when this had been appropriately inoculated. The growths due to tarring appeared only after it had been repeated often enough to cause general hyperplasia of the epithelium, together with complex connective tissue alterations; and many of them retrogressed after tarring was stopped. The virus tumors, on the other hand, arose on the basis of the slight epidermal trauma incident to inoculation, and their progression was followed, not preceded, by conne...