RECENT USSR WORK ON ETIOLOGY AND IMMUNOLOGY OF CANCER

• Document Type: CREST
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): CIA-RDP80-00809A000700200129-5
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 5
• Document Creation Date: December 22, 2016
• Document Release Date: August 31, 2011
• Sequence Number: 129
• Publication Date: October 6, 1954
• Content Type: REPORT

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Vol 17, No 1 12 5'30 Jun 54 Prof L. Zil'ber
Active Member, Academy
of Medical Sciences USSR
RECENT USSR WORK ON ETIOLOGY AND IMMUNOLOGY OF CANCER
Meditsinski Rabotnik
At present, the virus etiology of many tumors has been established with
certainty. These include certain tumors of insects and fish, various types of
sarcoma of chickens and ducks, various forms of leukoses of birds, the carcinoma
of frog kidneys, the papillomas of many animals such as cattle, dogs, and rabbits,
the cancer of the lactic glands of mice, the leukemia of mice, and human warts.
The viruses which cause these diseases have been photographed under an
electron microscope. Some of the largest of them, for instance, the virus of
the cancer of the lactic glands of mice, can be observed under an optical micro-
scope after the preparation has been stained according to M. Morozov's method.
After these viruses have been introduced into the body of a susceptible animal,
they produce tumors identical with those from which they have been isolated.
A very important confirmation of the etiological role played by these
viruses was furnished by the investigations of A. Timofeyevskiy and S. Benevo-
lenskaya, who have shown that the viruses transform normal cells into tumor
cells in tissue cultures. At present, even the most obstinate opponents of the
virus theory do not deny the obvious fact that viruses are the direct cause of
the development of many types of tumors.
In the course of the investigation of tumors produced by viruses a very
curious phenomenon was discovered. It is easy to isolate a virus producing
rabbit papilloma from this type of papilloma. However, as soon as the papilloma
has been transformed into a cancer (analogous to the transformation into cancer
of the papillomas of the throat or of the urinary bladder of humans), the virus
can no longer be isolated from the tumor. Nevertheless, serological investiga-
tion indicates that the virus is still present in the tumor. Such viruses,
which have lost their pathogenicity, are referred to as masked viruses.
On the other hand, it is known that the growth of tumors may be induced
by many factors other than viruses, namely, diverse chemical substances which
are known as cancerogens, various types of radiant energy, and the action of
hormones and of many other substances and inducing effects. Even the repeated
injection of such substances as fructose or chicken protein may result in the
growth of a tumor. When tumors have been induced in this manner, no viruses
can be isolated from them. What is the etiology of these tumors? Do all these
substances and physical effects produce malignant neoplasms, as is believed by
the proponents of the polyetiological theory of the origin of tumors, or do
they function as pathogenic factors which create suitable conditions under which
viruses already present in the organism may unfold their action?
One may assume that in tumors induced by cancerogenic effects the virus
is present in a masked form and for that reason cannot be detected. But can it
be detected prior to the loss of pathogenicity?
The first experimental work on cancer carried out at our laboratory dealt
with an investigation of this problem. We induced tumors in mice by injecting
cancerogenic substances subcutaneously. Six to eight months later, as soon as
a minor hardening was observed under the skin at the site of the injection of
the cancerogenic substance, the tissue was excised and disintegrated and an
extract from it filtered through Berkefeld filters. The filtrate, which was
absolutely free of cells, was injected subcutaneously into mice that had been
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treated prior to that with cancerogenic substances administered in a quantity
which does not produce tumors. We assumed that in the initial stage of develop-
ment of the tumor the virus would not be masked and for that reason would be
capable of being detected on the basis of its pathogenic effect. In view of
the fact that viruses multiply with the greatest facility in young cells which
are in the process of division, and taking into consideration the fact that
introduction of cancerogenic substances creates foci of tissue proliferation,
we took the precaution of introducing extracts of rudimentary tumors to mice
which had been treated prior to that with cancerogenic substances in minimal
doses that do not produce tumors.
Our experiments yielded positive results. In approximately 15% of the
cases, the cell-free filtrates of sarcomas in the initial state of develop-
ment induced the appearance of similar tumors. In some cases these tumors
could be transmitted by the same method to other mice. Similar results were
obtained in analogous experiments on rabbits. These experiments furnished
an experimental basis for the hypothesis that viruses play a role in the
etioi;.-v of tumors that have been induced by cancerogenic substances. How-
ever, our experiments could be reproduced only with difficulty. They gave
positive results in a relatively small number of cases. The attempts to
detect viruses in an analogous manner in the tumors of other animals [besides
rabbits and mice] that have been induced by cancerogenic substances were un-
successful. Under the circumstances we chose other ways of solving the
problem, At present, it is clear that we committed an error in discontinuing
our investigations. Timofeyevskiy and Benevolenskaya have recently reported
that the cell-free extract of rat sarcoma produced malignization of rat
fibroblasts in a tissue culture exposed to the parallel action of a cancero-
genic substance which does not produce malignization alone. In these experi-
ments the same principle of the combined action of a virus and of a cancero-
genic substance was applied that had been applied in our investigation. Here
a process has been reproduced in vitro which we observed in vivo in our experi-
ments. These data and other results indicate the necessity of resuming our
previous experiments and of investigating the role of viruses in the generation
of induced tumors by applying virological methods of investigation.
One of the principal arguments advanced by the opponents of the virus
theory of the generation of tumors was the fact that there are no foreign
proteins in tumors which are not transmitted by filtrates or in human tumors.
However, a virus, whether masked or not masked, consists of protein which is
foreign to the organism. If heterogenous protein is absent in tumors, there
can be no immunity to tumors, because immunity is the reaction of the organism
to heterogenous substances. The problem of the presence or absence of hetero-
genous antigens in tumors is for that reason a cardinal problem, the solution
of which is essential not only for proving the virus theory of the origin of
tumors but also for establishing whether immunological processes in cancer are
possible or not The reason why many investigators were unable to find hetero-
genous proteins possessing antigenic characteristics in tumors is as follows.
One may assume that the failure of some of these attempts was due to the
low concentration of the antigen in the tumors and to the low sensitivity of
the reactions used for the detection of these antigens. For that reason, we
decided to investigate not merely the extracts of tumor tissue
as has been
do
b
,
ne
y many investigators, but protein factions isolated from these extracts.
In doing this, we assumed that the antigen for which we searched will be con-
tained in one of the fractions in a more concentrated form. Originally we
searched for the antigen by using the reaction of complement Fixation carried
out at low temperatures. Subsequently, we developed the highly sensitive
reaction of anaphylaxis accompanied by desensitization, which made it possible
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tissues. By using this reaction inm work rcarried aoutttogether iwith fN.loNartsissov,
Z. Baydakova, and others, we succeedeC: in demonstrating that in tumors of
animals induced by cancerogenic substances there are antigens which are absent
in the tissues of healthy animals and which produce the formation of antibodies
during the process of the development of tumors. Subsequently, our collabo-
rators A. Gardash'yan, D. Levine, V. Gorodilova, L. Shershul'skaya, and others,
isolated specific antigens from all strains of transmissible tumors which were
available to us, as well as from all investigated human tumors.
One may state on the basis of this that tumors contain specific antigens.
The principal objection to the virus theory of the origin of tumors has thus
been eliminated and the study of the immunology of tumors has been given a
sound theoretical basis for the'first time.
After the solution of this problem many other problems arose. Do the
specific antigens of tumors consist of the substance of viruses or perhaps
of the modified protein of normal tissues? Is there only one specific antigen
in tumors or are there several? In what part of the cell are specific antigens
located? Do the specific antigens induce the formation of antibodies and in
this manner create immunity? These and many other problems which were equally
complex had to be solved by us. The persistent work of a large group of in-
vestigators was necessary in order to supply answers to some of the questions
involved..
Z. Baydakova, R. Radzikhovskaya, A. Vadova, and Z. Postnikova proved
that it is possible to induce a high degree of immunity to tumor viruses.
However, the animals which were immunized to these viruses (those of chicken
sarcoma and rabbit papilloma) got sick in 100 percent of cases after the
corresponding tumor tissue was administered to then. It has been known for a
long time that immunity to tumor tissue arises during the natural resorption
of tumors, However, nobody had investigated this phenomenon on tumors the
virus etiology of which was established with certainty. The observations of
R. Radzikhovskaya have shown that chickens with resorbed tumors were in the
majority of cases immune both to the virus and to the tumor tissue.
Thus, immunization with the virus treats immunity to the virus and does
nct produce immunity to transplanted tumor cells, while immunity to the resoibed
tumor creates immunity both to the virus and to tumor cells. One can draw
only one conclusion from these experiments, namely, that the tumor cells con-
tain in addition to the virus another heterogenous protein which brings about
immunization to tumor tissue. How can this be proven by direct experiment?
To obtain this proof, it was necessary to eliminate the virus from tumor
tissue and to investigate the antigenic composition of the proteins remaining
in this tissue. A. Vadova, Z. Postnikova, Ye. Barabadze, and V. Artamonova
had demonstrated that the papilloma virus is adsorbed on erythrocytes a,-,d that
by repeated adsorption one may completely free the tissue of the virus component.
When Artamonova investigated the proteins of the tumor tissue which remained
after elimination of the virus by this method, she found that they contained
an antigen which is absent in normal tissue. Thus, it has been shown for the
first time that tissue protein which is distinct from the protein of normal
tissues is present in tumors induced by viruses. When the protein of a rabbit
carcinoma which had originated from a papillomma and was isolated from the
fraction analogous to serum alpha-globulin and beta-globulin and was mixed with
papilloma virus in a test tube, the papilloma virus lost its pathogenicity in
30 to 60 minutes. In other words, the virus was masked. On the basis of this,
one may conclude that the phenomenon of the masking of tumor viruses which has
been investigated for 20 years, but has not been explained hitherto, consists
in the blocking of the virus by the modified cell protein which develops in the
organism as a result of changes in the synthesis of tissue proteins produced
by the multiplication of the virus. Further investigations are necessary in
order to establish whether the process of blocking takes place in tumors induced
by cancerogenic substances.
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Considerable difficulties were met in connection with the development
of methods for establishing the location of the specific antigen in the cell.
Without solving this question one could not find an effective method for the
concentration and purification of tumor antigens. In connection with this
problem, extensive work was carried out by the Institute of Epidemiology and
Microbiology imeni N. F. Gamaleya in collaboration with machine construction
engineers on the construction of new laboratory equipment. Particularly
active in this work was V. Loskutov, Chief of the Technical Administration,
Ministry of Machine and Instrument Building USSR. Using the new Soviet
rapid separators, it was possible to obtain from the same batch of tumor
tissue a sufficient quantity of nuclei, mitochondria, microsomes, and soluble
proteins. G. Abelev developed a method for the separation of tumor tissue
into all of these components. These components were then investigated by
N. Nartsissov in serological experiments.
The most important result of these investigations was the finding
that the specific serological activity of the tumor cells is associated
with the mitochondria and the first globulin fraction of proteins obtained
on saturation of the tumor extract with ammonium sulfate to the extent of
33 percent. These results, obtained in the investigation of experimental
tumors and human tumors, create a new basis for work on the problem of the
serological diagnosis of cancer,
The extensive experience accumulated by our laboratory in the investiga-
tion of the immunology of tumors has made it possible for us to carry out a
profitable investigation of the problem of specific prophylaxis of tumors.
Hitherto one could not achieve artificial immunization against tumors trans-
mitted by means of material which does not contain living tumor cells, although
many attempts were made to establish such immunity.. In work carried out with
Z. Baydakova and R. Radzikhovskaya, we developed methods whereby we can obtain
from a tumor a mixture of antigens that creates a rather high degree of immunity.
In the procedure in question a suspension of tumor cells is dissolved by a
cancerolytic serum under definite conditions. The cells which remain undissolved
or have been only partly dissolved are removed from the lysate by centrifuging.
By using formalinized lysates of this type, in which the serum stabilizes
the very labile immunizing proteins, one may create immunity to subsequent im-
plantation of tumor tissue in a considerable percentage of cases (up to 80% of
cases in such a severe and metastasiz:.ng tumor as the Brown-Pierce carcinoma).
By using such vaccines it will perhaps be possible to prevent the recurrence
of cancer in patients who have been operated surgically. Clinical observations
which are being conducted at present at Moscow and Leningrad will make it
possible to answer this question,yiirhin.several years.
These are the fundamental lines a.lon:.s which we conduct our work in order
to solve the principal. problems of the etiology., pathogenesis, and immunology
of tumors. Extensive work on cancer is also being conducted at other Soviet
laboratories,
Many questions still remain to be solved, However, we are convinced that
Soviet theoretical oncology is on the right path. Under the circumstances we
wish to express the hope that our efforts will soon liberate from cancer the
Soviet people and the whole of humanity.
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