A Consideration of Virus-Host
Relationship in Virus-induced
Neoplasia at the Cellular Level
RENATODULBECCO
( California Institute of Technology, Pasadena, Calif. )
mosaic virus, probably constituted by a proteinhelix enveloping the RNA placed in its axis
(Brenner, personal communication).
Mediumsized DNA viruses have probably more than one
protein and are usually icosahedral crystals, in
which a protein shell surrounds the DNA; the
will be examined against a double background:
on the one hand, that of cells infected by animal large-sized DNA viruses ( Vaccinia ) are likely to
viruses in general; on the other hand, that of contain many proteins and to be structurally
lysogenic bacterial cells. The latter background
complex.
appears to be useful, since lysogeny is an exten
In the process of infection, after the attach
sively studied and fairly well understood process ment to a susceptible cell, the virus undergoes
which has been, and still is, widely used as a profound changes, as shown by two symptoms:
model for the study of virus-cell interaction in on one hand the loss of infectivity (eclipse pe
neoplastic cells.
riod); on the other hand a marked decrease in
ultraviolet light sensitivity, as observed with poOn the basis of the results obtained, the impli
cations and significance of the virus theory of liovirus—an RNA virus (9)—and with herpes
cancer will be briefly analyzed. Such an analysis simplex—probably a DNA virus (51). The re
seems useful at the present moment, when re
peatedly confirmed occurrence of infection of
search in the field of neoplasia-producing viruses cells by RNA extracted from a number of differ
is flourishing, and therefore hypotheses may have ent animal viruses suggests that release of the
considerable influence.
nucleic acid from the protein coat is a necessary
step in reproduction.
ASPECTSOFTHEINTERACTION
BETWEENANIMAL
The events occurring in the eclipse period are
VIRUSESANDHOST CELLSIN GENERAL
known in some detail mostly on the basis of
Animal viruses appear to fall into broad morphological observations. Since a great deal of
groups, on the basis of their structure and gen
this material has been presented and analyzed by
eral biological properties. A first distinction is Dr. Bernhard, the facts discussed here will be
between DNA-containing viruses and RNA-con- those particularly pertinent to the present review.
taining viruses; furthermore, DNA viruses can
In cells infected by myxovirus, which is a rep
be separated into medium-sized (40-120 m/¿) resentative of the medium-sized RNA viruses,
and large-sized viruses (120-250 m/¿);RNA vi
the protein associated with the nucleic acid (G
ruses into small-sized (up to 40 m/j.) and me
protein) is localized by fluorescent antibodies in
dium-sized (40-120 m/¿) viruses. Viruses of the nucleus about 2 hours after infection (7, 56 ).
mixed composition or of size above 250 m,u are Later this protein is found also in the cytoplasm.
not considered here, their taxonomic position be
In contrast to the G protein, the coat protein is
ing unclear. Small RNA viruses are spherical and always found in the cytoplasm, beginning 1-2
apparently have a single protein, that of the coat hours after the G protein has made its appear
surrounding the centrally located RNA. Medium- ance in the nucleus.
In cells infected by herpes simplex or by papilsized RNA viruses (the myxovirus group) have
at least two proteins; structurally, they are made loma virus (two medium-sized DNA viruses) a
up of a protein-lipide envelope wrapping a folded viral protein was also localized in the nucleus by
rodlike structure similar to a particle of tobacco fluorescent antibodies, in an early phase of in-
The purpose of this review is to investigate the
nature of the host-cell relationship in virusinduced neoplastic cells. To do so, the properties
of cells infected by neoplasia-producing viruses
(which will be referred to as "tumor viruses")
751
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
752
Cancer Research
fection (32, 47). In cells infected by vaccinia
virus (a large DNA virus) the first localization
of a specific protein by fluorescent antibodies oc
curs in the cytoplasm ( 48 ).
Electron microscopic investigations supply in
formation on the assembly of the virus particles.
In cells infected by DNA viruses of medium size
(adenovirus, herpes simplex) either complete or
partly assembled virus particles are first found in
the nucleus (22, 42, 52), the herpes simplex par
ticles are later found in the cytoplasm, where
they appear to be completed by the addition of
another coat. In cells of the Shope papilloma the
first vims particles appear to be localized in the
nucleolus (41) which is also the site of the first
morphological changes in the cells of the virusinduced Lückerenal carcinoma of amphibians
( 13 ). Particles of the large DNA virus Vaccinia
are found only in the cytoplasm ( 43 ). In the case
of small RNA viruses, complete particles are
found in the cytoplasm only (Coxsackie virus
[44], polio virus [27]). In cells infected by a
myxovirus (RNA, medium-sized) complete par
ticles are found only in contact with the cellular
surface, where final assembly takes place (45).
Particles of tumor viruses belonging to this size
class and probably containing RNA may also be
found at the cellular surface, where one can see
pictures suggesting a series of steps in assembly
and release (mouse mammary carcinoma [40]).
Assembly of particles in the cytoplasm takes
place within foci delineated by membranes
which probably belong to pre-existing membra
nous cellular structures, such as the ergastoplasm
or mitochondria. Within these membranes the
particles are probably assembled from precursor
protein units, as suggested particularly by pic
tures seen in poliovirus-infected cells ( 27 ). Thus,
the final assembly is the crystallization of the
protein units around a nucleic acid core; in some
cases empty protein shells can be formed, similar
to virus particles in size and shape, if the protein
alone, without nucleic acid, can crystallize in the
form of the complete virus particle, as seems to
be the case in RNA viruses.
In contrast with the rather abundant informa
tion concerning the late stages of virus develop
ment, which were just described, very glaring is
our ignorance concerning the whereabouts of the
most important part of the virus, its nucleic acid.
The only meager information available concerns
the relationship between the time of formation
within the cells of the newly synthesized nucleic
acid and the time of formation of the complete
particles; this information can be obtained only
for those viruses which yield an infectious nu
Vol. 20, June, 1960
cleic acid, thus only the small RNA viruses. In
one case (poliovirus) all or most infectious nu
cleic acid appears to be found in complete par
ticles (Boeyé,personal communication); in an
other case it is found in an unidentified precursor
of the virus particles, present in the cells around
the middle of the eclipse period ( 26 ).
From the reported findings a certain number
of basic facts emerge. One fact is that the nu
cleus of the cell—andin some cases the nucleolus
—isinvolved in the reproduction of the mediumsized viruses, either DNA- or RNA-containing,
and is the site of the earliest recognizable events.
It is likely that this is also true for the small RNA
viruses, since in poliomyelitis virus infection the
first cellular changes are observed in the nucleus
(63).
From the sequence of events one suspects that
the viral nucleic acid, for all small- and mediumsized viruses, both DNA- and RNA-containing,
either multiplies in the nucleus of the cells, or at
least goes through it as the first step. DNA virus
es of this class may be entirely synthesized in
the nucleus. There is no evidence for a nuclear
phase of the large DNA virus vaccinia; this may
be the consequence either of incomplete obser
vation or of a greater autonomy of viruses of this
class. The cytoplasm is the site of the synthesis
of the coat protein for many viruses.
The interesting phenomenon of the movement
of the infecting nucleic acid from the cell surface
to the nucleus, and of the RNA genomes—prob
ably progeny—back to the cytoplasm may be the
reflection of normal cellular events. Particles free
in the pericellular medium are known to pene
trate the cytoplasm and the nucleus (37), prob
ably via the ergastoplasm, the spaces of which
appear to be in communication with the exterior
on one side (49) and with the nucleus on the
other ( 66 ). The viral nucleic acid may reach the
nucleus by the same mechanism. The synthesis
of the progeny nucleic acid (either RNA or
DNA) in the nucleus again would follow the
accepted physiological patterns, with the impor
tant exception that the multiplication of the viral
DNA is not synchronized to that of the cellular
DNA, as suggested by results obtained with
herpes simplex virus infection of parasynchronized cell cultures ( 59 ). Later on the fates of the
two viral nucleic acids appear to separate and to
follow the normal pattern of the cellular nucleic
acids: the viral DNA remains in the nucleus,
where its dependent protein is synthesized; the
viral RNA, like the normal nuclear RNA, prob
ably migrates to the cytoplasm, enters in connec
tion with the membrane system of the cell (the
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
DuLBECCO—
Vims-Host Relationship at the Cellular Lerei
cellular surface, or the endoplasmic reticulum or
the mitochondria), and there produces its de
pendent protein.
The viral genome, appears, therefore, to per
petuate itself by a clever process by which it in
tegrates itself into the Lifeof the cells, substitutes
itself for the normal nucleic acid of the same
kind, and, by following the general procedures
usually followed by the normal nucleic acid, does
what the normal nucleic acid is supposed to do:
to synthesize protein.
The pathogenicity of the virus for the cell is
probably produced by two main mechanisms,
except for effects caused by high multiplicity of
infection, which may be due to an effect of the
virus on the cell surface. One mechanism could
be the lack of submission of the viral nucleic
acid to the restraints limiting the multiplication
of the normal cellular nucleic acid and of the
dependent protein; thus, the virus-dependent
synthesis may be so extensive as to starve the cell
to death. The other pathogenic factor may be
the information carried by the viral nucleic acid:
this may cause the synthesis of a protein new to
the cell, able to perturb the normal cellular func
tions by virtue of its physical properties or enzy
matic action. It should be emphasized that syn
thesis and release of particles of animal viruses
are not instantaneously fatal to animal cells, as
shown by the fact that many viruses are released
over a fairly long period of time by the infected
cells; moreover, infection with myxovirus and
synthesis of virus-specific protein in the infected
cells do not prevent the cell from undergoing one
additional division (68). Death of the cell in
infection by animal viruses may be considered
as a secondary complication.
It is understandable that as extreme cases of
cellular involvement in virus infection we may
observe either lysis of the cells—cytocidal viruses
—ifthe viral protein is itself lytic or can activate
lytic enzymes of the cell, or simply a change in
some physiological cellular properties—moderate
viruses—if the viral protein is compatible func
tionally and structurally with the cellular pro
teins.
Compatibility between viral protein and pre
existing cellular protein is perhaps more frequent
than one thinks. For instance, an example of
structural compatibility is observed in myxovirusinfected cells. Here the protein of the virus-coat
becomes integrated in the surface of the cell and
confers to the cell the property of hemadsorption
characteristic of the virus (28, 65); it is likely
that this integration between cellular and viral
protein is responsible for the formation of fila
753
ments of influenza virus, cylindrical structures
having the diameter of virus particles, containing
virus-specific protein, but showing uninterrupted
continuity with the cell membrane in thin elec
tron microscope sections.
The question arises whether the viral genome
causes only the synthesis of the proteins entering
into the constitution of the virus, or of other pro
teins as well. There is some evidence suggesting
that other proteins may be synthesized as well:
in a few known cases the infected cells produce
a substance not produced by the normal cells,
and antigenically different from the proteins of
the virus particles. One case is that of a proteincontaining factor produced by adenovirus-infected cells, which causes reversible morphologi
cal changes in HeLa cells (54). Another case is
that of interferon, a protein-containing substance
produced by cells infected by damaged influenza
virus (8, 29) and probably by other viruses. A
third possible case is that of arginase produced
in rabbit papillomas, induced by the Shope virus,
but not in usual skin cells ( 53 ).
PERTINENTPROPERTIES
OF LYSOGENIC
CELLS
Since many excellent reviews of the subject
exist, only some of the points more directly rele
vant to the present topic will be discussed here.
The penetration of the DNA of a temperate
bacteriophage into a bacterial cell of a strain
sensitive to that bacteriophage, instead of causing
the lysis of the cells, leads, in a certain propor
tion of cases, to formation of lysogenic cells, in
which the phage genome enters into a stable re
lationship with the bacterial genome. The prob
ability for the establishment of a lysogenic com
plex depends on a number of experimental var
iables and on the viral and bacterial strains used,
being strongly decreased or abolished for certain
mutants of the phage (clear mutants, virulent
mutants). The lysogenic bacteria have three
characteristic properties: (a) they give rise to
lysogenic bacteria by multiplication; (&) they
have a constant small probability of releasing
active bacteriophage upon lysis; (c) they are
immune to infection by related temperate bacteriophages, except the virulent mutants.
The release of progeny phage from lysogenic
bacteria can occur either spontaneously or as a
consequence of external action (induction).
Spontaneous release occurs in a small fraction
(10~2 to 10~5) of bacteria at every generation.
Release occurs by a burst, as in infection with
virulent phage. Induction of virus release by ex
ternal action occurs in bacteria infected by inducible phages; many temperate phages are non-
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
754
Cancer Research
inducible. Inducing agents are ultraviolet light,
x-rays, and chemicals, such as mustards, perox
ides, and others. Inducing agents have also mutagenic and carcinogenic properties (38), al
though the correlation between these properties
is not too strong. Induction makes the lysogenic
cells equivalent to the cells infected by a viru
lent phage.
The state of the phage genome inside the bac
terial cell is characterized by the following prop
erties: The phage genome, after some prelimi
nary duplication, becomes connected to the bac
terial chromosome in such a way that in bacterial
crosses it can be mapped like a bacterial gene
( prophage ). The nature of this attachment is not
known. The prophage multiplies only in syn
chrony with the bacterial chromosome; after in
duction becomes capable of autonomous, vegeta
tive reproduction. From experimental data, the
results of induction can be described as a shift
from the prophage state to the state of vegetative
virus.
For future comparison with tumor viruses, the
discontinuous, all-or-none nature of the changes
occurring in lysogenic bacteria should be empha
sized. There is no intermediate condition be
tween lysogenization and lytic viral multiplica
tion, between prophage and vegetative phage,
and evolution from one state to the other occurs
by a complete shift. Shifting between two states
appears to be a property of that class of genetic
elements, called episomes, which were discussed
yesterday.
An important class of lysogenic bacteria is con
stituted by those carrying a defective prophage.
Defective prophages are mutants of normal prophages which are unable to produce an infec
tious progeny (30). If the defective prophage is
inducible, the lysogenic cells lyse upon induc
tion, but no infectious virus is released. The lysate may, however, contain parts of phage par
ticles which can be recognized by electron mi
croscopic investigation (1).
The infection of bacteria by temperate phage
causes alterations of the genetic characters of the
cell. This can occur by two distinct mechanisms:
conversion and transduction.
Conversion is a direct consequence of the pene
tration of the phage genome into the ceh", its es
tablishment as prophage being not required; in
fact, with a suitable system conversion can be
detected in bacteria which lyse ( 62 ). Conversion
can be considered as a consequence of the ex
pression of the phage genome in the cells, with
the consequent synthesis of proteins not synthe
sized by the normal cells. Although conversion
Vol. 20, June, 1960
was first recognized in bacteria undergoing lysog
enization, it is a common consequence of infec
tion by bacteriophages, both temperate and viru
lent. A very striking case of conversion by viru
lent phage is the virus-induced synthesis of a
number of enzymes related to synthesis of DNA
in E. coli cells infected by phage T2 (17, 32).
Transduction is a phenomenon by which a
temperate phage can pick up genes from a bac
terium in which it multiplies and carry them into
the bacterium it infects, thus modifying the char
acter of the latter. The modification caused by
transduction can be permanent ( stable transduc
tion) or transient (abortive transduction), de
pending on whether or not the new bacterial
genes become incorporated in the host chromo
some.
VIKUS-CELLINTERACTION
IN TUMORPRODUCING
VIRUSES
Tumor-producing viruses can be divided, like
other animal viruses, into DNA- and RNA-containing viruses. Most of them are of the medium
size; only the rabbit fibroma virus is of larger
size. As representative examples of the two main
classes, the papilloma and possibly the polyoma
virus may be quoted among those containing
DNA, and the group of chicken tumor viruses
among those containing UNA; of these the Rous
sarcoma virus (16) and the myeloblastosis virus
( 5 ) are prototypes.
A large proportion of the experimental work
on which the following analysis is carried out
was done with the Rous sarcoma virus and with
the mouse polyoma virus. Both are experimental
ly useful because they can be grown and assayed
in vitro (12,55, 61,67).
1. Experimental observations.—In the follow
ing analysis the results which set these viruses
aside from other animal viruses will be especially
considered. There are two main aspects of the
interaction between a tumor virus and its host
cell: the multiplication of the virus and the ef
fect of the virus on the host cell.
a ) The multiplication of the virus: The growth
cycle of the Rous virus in chicken embryonic
cells ( 60 ) and of the polyoma virus in mouse em
bryonic cells (Vogt and Dulbecco, unpublished)
is qualitatively similar to that of other animal
viruses, although much slower. In single-cycle
growth curves the eclipse period lasts 14 hours
to a day, in contrast with the few-hours period
for many other viruses; the release period is very
long, being essentially infinite for the Rous virus
and lasting several days for the polyoma virus.
The slow pace cannot be considered an exclusive
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
DuLBECCO—Virus-Host Relationship
feature of these tumor viruses, however, since
it can be found in nontumor viruses, such as the
adenoviruses ( 19 ) and the salivary gland viruses
(57). Although the rate of infectious virus pro
duction per cell per unit time by tumor viruses is
small relative to that of many other viruses, the
total amount produced after several days of re
lease can be quite comparable.
On the basis of the rather limited information
about the synthesis of virus-specific material in
side the cell, we find no important differences be
tween these tumor viruses and most other animal
viruses. Among DNA viruses, polyoma virus, like
papilloma virus, appears to be synthesized in the
nucleus (24). As already mentioned, early nucleolar involvement was found in two cases of
tumor virus infection; whether this is character
istic of tumor viruses is unknown. Among RNA
viruses, particles of the chicken leukemia viruses
and of the Rous sarcoma virus are assembled in
the cytoplasm, in connection with intracellular
membranous structures, possibly the mitochon
dria (2, 4, 6). Similar findings were obtained
with many other tumor viruses. It is believed that
the presence of ATPase in relatively purified
preparations of chicken myeloblastosis virus ( 14 )
also reveals the derivation of the virus particles
from mitochondria. Although several experimen
tal data have been brought in favor of the -hy
pothesis that this enzyme is an integral part of
the virus particles, even more convincing evi
dence could be obtained by new methods for vi
rus purification, such as equilibrium sedimenta
tion in a density gradient ( 39 ).
An important characteristic of many virus-in
duced tumors is that they produce virus all the
time and nevertheless continue to grow; at the
cellular level this may mean either that each cell
always produces virus and divides or that some
cells produce virus and then die, whereas the
others grow without producing virus. The study
of this problem with the Rous virus shows that
the former case is true for at least the majority
of the cells. Two types of evidence are available
(62). One is that most of the cells of a popula
tion derived from the multiplication of a single
vims-infected cell in the presence of a strong
antiviral serum are virus-yielders; moreover,
these populations release virus at nearly the same
rate as an equivalent population of cells directly
infected by the virus. Thus, the ability to release
virus is transmitted intracellularly from the orig
inal virus-infected cell to at least a majority of its
descendants. The second type of evidence is that
single cells obtained from an infected culture
and kept under continuous observation in drops
at the Cellular Lerei
755
of medium under paraffin oil can divide after
they have released virus.
Whereas the capacity of cells infected by the
Rous virus to transmit infection to the progeny
and the compatibility of virus release with divi
sion of the cells are conclusively proved, it is not
known whether all the descendants of a virusinfected cell are virus-releasers. Evidence on this
point would be important to understand the state
of the virus in the cells.
Attempts have been made at inducing an in
creased virus production from virus-induced tu
mor cells, by exposing them to radiation, in anal
ogy to induction of virus production in lysogenic
bacteria. Experiments with Rous sarcoma cells
by using either ultraviolet light or x-rays as in
ducing agent have given negative results (see,
for instance, Table 4 of [62]). In experiments
with the rabbit papilloma and the rabbit fibroma,
x-ray treatment has produced in some cases an
increase in the content of the infectious virus re
coverable from the tumors; this occasional in
crease was detectable almost immediately after
the irradiation (18). It is unlikely that the er
ratic increased virus recoverability is due to a
shift of the virus from a provirus-type state to a
vegetative state, as in lysogenic bacteria, because
it is already present before a single growth cycle
of the virus could have taken place following ir
radiation. It is probable that the radiation only
increases the recoverability of pre-existing virus
from the cells.
The experiments reported above are open to
the general objection that a lysogeny-type induc
tion may not be observable in the systems em
ployed, since most if not all their cells were al
ready virus-producers. It would be interesting to
see these experiments repeated on cells from vi
rus-induced tumors which do not release virus.
For instance, a potentially suitable system may
be the isolated cells of the basal layer of the papillomas, or the layer itself, in which neither in
fectious virus nor viral antigen can be demon
strated.
However, results of importance for under
standing the nature of the virus-cell interaction
in tumor viruses have been obtained studying
other effects of radiations. A striking result is the
great radio-sensitivity of the cell "capacity" for
the Rous virus, the capacity being defined as the
capacity of the normal cell to yield virus upon
subsequent infection. In contrast, the "capacity"
of the same cells for yielding nontumor-producing viruses is much more resistant. The capacity
to yield Rous virus is as sensitive to radiation as
the ability of the cells themselves to make a clone
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
756
Cancer Research
(55). The possible significance of these findings
will be discussed later.
fo) Effect of the virus on the host cells: One
important property of the Rous virus, and per
haps the central one as a tumor-producing virus,
is that of transforming, within a period of time
corresponding to a few cellular division times,
the normal cells, derived from the chicken em
bryo, to cells endowed with different properties.
The virus-transformed cells will be designated as
Rous cells. Under the usual experimental condi
tions the most outstanding difference between a
Rous cell and the normal cell from which it de
rives is a morphological one. The usual virus
strain ("wild type") transforms the elongated
chicken fibroblasts of the cultures into round
cells; mutants of the virus called morph' trans
form the same cells to very thin fusiform cells;
other mutants affect a transformation to other
somewhat different intermediate morphological
types (60). The transformation is hereditary, in
that the descendants of the transformed cell
maintain the acquired morphological type, as
long as complications such as poly- or aneuploidy
do not arise. This is a clear example of conversion
of the cells by the virus genome, analogous to
conversion caused by bacteriophage.
The possible occurrence of another transfor
mation, perhaps of different nature, has been
suggested (10) in cells infected by the Rous vi
rus or by the related Fujinami virus. This sugges
tion was based on a reinterpretation of the data
of Guy and Purdy (21), obtained with the Fu
jinami virus, and of Harris (23), obtained with
the Rous virus. According to this suggestion the
surface of the infected cells would be trans
formed as to become antigenically similar to that
of the cells in which the virus had been grown;
the newly acquired antigen would, however, be
lost during the subsequent multiplication of the
cells.
The occurrence of an antigenic transformation
of this type would be of great interest for under
standing the nature of the virus-cell interaction
in this system, in view of its possible similarity
to abortive transduction in bacteria. Therefore,
it would be desirable to ascertain in suitable sys
tems whether such an antigenic transformation
takes place and, if so, to determine whether it is
due to the virus or to some other component of
the cell extract used as virus source.
The result of the exposure of a susceptible cell
to a tumor virus depends on a number of factors
related both to the nature of the cell and to en
vironmental conditions. One has the impression
that these factors play here a far more important
Vol. 20, June, 1960
role than in the infection with nontumor-producing viruses in general. Some experimental results
showing the importance of these conditions were
obtained with the polyoma virus (Dulbecco,
Vogt, Freeman, unpublished). This virus pro
duces tumors in either mouse or hamster. Where
as in the mouse the tumors develop after a la
tency of 7-10 months (58), in the hamster they
frequently appear within a few weeks after inoc
ulation ( 15 ). In vitro the virus kills a large pro
portion of the cells in cultures of mouse embryo
cells, in a slow way as outlined before, with the
release of large amounts of virus, but does not
kill the cells of the hamster, in which viral repro
duction occurs, but in a more limited way. In the
hamster cultures, however, the virus often causes
proliferation of fusiform cells, which grow to
form heavy strands; a proliferatory stimulation is
absent or limited in the mouse cultures. There is,
therefore, a systematic difference between the
response of the cells of the two species, both in
vitro and in vivo, cell proliferation being more
easily caused in hamster cells, virus multiplica
tion in mouse cells.
The effect of environmental conditions on these
systems is for instance shown by the marked ef
fect of the type of serum present in the culture
medium after infection. Some horse sera used in
ouf laboratory favor the multiplication of the vi
rus in the mouse cells, compared with some calf
sera (12); on the contrary, the calf sera appear
to favor the proliferatory response of the hamster
cells. The concentration of the serum also has a
marked effect on the in vitro multiplication of
the myeloblastosis virus in myeloblasts (6). The
influence of the condition of the cells on the out
come of infection is observable in the cells of the
rabbit papilloma that carry the Shope virus. In
fectious virus and its antigen are detected in the
nuclei of the nonmultiplying cells in the keratohyaline layer of the epidermis, but not in the
multiplying cells of the basal layer (41, 46, 47).
2. Discussion of the experimental observations.
—Tofacilitate the analysis of the various aspects
of virus-cell interaction in tumor viruses, it will
be useful to introduce a descriptive nomencla
ture. We shall assume, for the sake of discussion,
that there are two distinguishable types of inter
action: an integrative one, in which the infected
cells continue to divide, producing little or no
infectious virus, and in which cell conversion by
the virus is the most outstanding phenomenon;
and a nonintegrative one, in which there is an
extensive synthesis of progeny virus, which ulti
mately leads to the death of the infected cells or
of their immediate descendants.
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
DuLBECCO—Virus-Host Relationship
The results obtained with the polyoma and
papilloma virus show that tumor viruses can un
dergo either an integrative or a nonintegrative
interaction, depending on the type and on the
state of the host cells, and that the two types of
interaction can occur in the same virus-cell sys
tem, but with different probabilities.
Nontumor viruses can also undergo an integra
tive and nonintegrative interaction. An excellent
example is found in the CO- sensitivity virus of
Drosophila (35); this virus can produce an inte
grative, "stabilized infection" of female flies,
which is characterized by the low virus content
and the ability to transmit the infection to the
progeny almost without exception. The same vi
rus can also give rise to a "nonstabilized infec
tion," either partially integrative or nonintegra
tive, characterized by a larger virus content of
the flies and by the infrequent transmission of
the virus to the progeny. It is interesting that in
the males of "stabilized" lines the virus is gener
ally lost during spermatogenesis: does this sug
gest that the virus is carried in the cytoplasm?
The radiosensitive capacity of the chicken em
bryo cells in vitro for the Rons virus has been in
terpreted as an expression of the integrative in
teraction this virus undergoes in the cells. The
interesting hypothesis has been presented that
the identity of the radiosensitivity of the capacity
of the cells for the virus and of the radiosensitiv
ity for cell division is due to the existence of a
single cellular center controlling integration of
the virus and cell division (55).
This interpretation of the radiobiological find
ings is, however, not the only possible one. Ac
cording to a more trivial interpretation (Rubin,
personal communication), a highly sensitive ca
pacity might be the consequence of a decreased
virus production in cells irradiated before infec
tion: such a reduction would have a marked ef
fect only on cells infected by viruses which nor
mally cause the release of very little progeny vi
rus, as is the case with the Rous virus. The great
similarity of the radiosensitivities of the capacity
for Rous virus and of cell division would then be
accidental.
A sensitive capacity for virus reproduction is
not a prerogative of cells infected by tumor vi
ruses, since it is shown also, although to a lesser
extent, by cells infected by adenovirus (Pereira,
personal communication ).
Conversion of cells by the Rous virus is a very
striking phenomenon: it is considered as due to
the expression of the viral genome in the cells.
Conversion is not an exclusive attribute of tumor
viruses nor of integrative virus-cell interaction.
at the Cellular Lerei
757
As in the case of bacteriophages, conversion ap
pears to be a common, possibly universal, attri
bute of virus infection: a clear example of con
version in a nonintegrative interaction is that
caused by influenza virus, already reported.
In conclusion, it is impossible to judge whether
the two descriptive types of virus-cell interaction
observed with tumor viruses, the integrative one
and the nonintegrative one, correspond to two
qualitatively different mechanisms of interaction
of the virus with the cells. It is likely that the
integrative type of interaction is generally pres
ent in multiplying virus-induced tumor cells and
that it is not frequent in cells infected by ordinary
viruses; however, it cannot be considered an ex
clusive property of tumor viruses. Thus, the
tumor virus group cannot be sharply defined on
these grounds among the animal viruses and may
therefore represent a quantitatively
extreme
group rather than a qualitatively different one.
Further light on all these problems will be
thrown by the current investigations of several
tumor-virus-cell systems at the cellular level. In
addition, two more specialized approaches could
be followed, as suggested by the preceding anal
ysis: on one hand the determination of the cor
relation between the radiosensitivity of the cell
capacity to reproduce virus and the type of in
teraction, integrative or nonintegrative, for dif
ferent virus-cell systems and, for the same system,
under different conditions; on the other hand, the
study of the effect of abnormally high tempera
tures, which in Drosophila allows a distinction
between the stabilized and the non-stabilized
types of virus-cell interaction. A combination of
these two approaches could also be used.
3. Comparison with temperate bacteriophage.
—Acomparison of tumor-producing viruses with
temperate bacteriophages producing lysogenization shows two main differences. One difference
is that virus-induced tumor cells, in contrast to
lysogenic cells, usually contain either virus-spe
cific protein or morphological virus particles or
infectious virus. An apparent exception are the
proliferating cells of the basal layer of the epi
dermis in the rabbit papilloma, where so far no
virus-specific material has been detected; virusspecific material may, however, also be present
in these cells in an amount too small to be de
tected.
The second difference is the obvious disconti
nuity existing between the prophage state and
the vegetative state in lysogenic cells, as con
trasted to the continuity of the changes in prop
erties in virus-carrying tumor cells.
These differences do not appear to be so sig-
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
758
Cancer Research
nificant, however, as to bar any analogy between
lysogenic bacteria and virus-induced tumor cells,
since they may not depend on the state of the
viral genetic material that perpetuates the infec
tion from cell to progeny, as will be discussed in
the next section.
More relevant information on this topic may
be obtained in the Rous system. The viral mu
tants now available allow a study of the quanti
tative aspects of superinfection; this in turn will
show whether there is a prophage-type immunity
and may solve the important problem of the
number of viral genomes present per cell. The
latter problem can also be approached by deter
mining whether and in what fashion nonviruscarrying cells are segregated in the progeny of
individual virus-carrying cells.
4. Possible states of the virus in virus-induced
neoplastic cells.—Onthe basis of the available
experimental evidence two states are conceiv
able: (a) modified lysogeny-type state. Its essen
tial feature is the existence of one or more viral
genomes dividing synchronously with the cells.
These genomes could be designated as provirus.
The data presented so far on virus-cell interaction
in tumor viruses show that the hypothetical proviruses might differ from prophage in the follow
ing properties : provirus may be RNA. It may not
be associated with the cellular chromosomes but
with some other synchronously dividing struc
ture ( the nucleolus, for instance, may be looked
upon as a possible site). Provirus may give rise
to vegetative genomes—forinstance, in the period
between the synchronized divisions—without los
ing the property of provirus; or provirus may be
one of the states of an episome having the ca
pacity to shift very frequently between this state
and that of vegetative virus.
(b) Kappa-like state. Its essential feature is
that the viral genomes do not divide synchro
nously with the cell; the viral genomes are ex
clusively in the vegetative state. Their number is
statistically distributed around an average, which
results from a balance between the growth rate
of the virus, its rate of maturation, and the
growth rate of the cells; there may be regulatory
mechanisms stabilizing to a certain extent the
number of vegetative genomes per cell.
Both states could give rise to the type of viruscell interaction described as integrative. The as
sumption that provirus is compatible with vege
tative multiplication of the viral genomes allows
for continuous transitions between the two states
and between integrative and nonintegrative viruscell interaction.
The experimental evidence does not show
Vol. 20, June, 1960
which state occurs in the various investigated
cases, since the number, location, and state of
the multiplying viral genomes in the tumor cells
are unknown. Clearly, on the basis of the general
picture of virus reproduction outlined in another
section of this review, the numerous more or less
complete particles found at some sites in the cells
represent only a consequence of the multiplica
tion of the viral genomes and do not clarify the
characteristic of this multiplication.
MECHANISMOF VIRUS-INDUCED
TUMOR
FORMATION
Tumor formation induced by a virus may be
considered as a type of virus-dependent conver
sion, deriving from the expression of the genetic
potency of the virus in the cells, and of the con
sequent synthesis of new, active proteins. The
information carried by the virus genome into the
cell is in many cases small: for instance, the RNA
introduced by a particle of an RNA-containing
tumor virus is likely to have 5-10,000 nucleotides,
a number of the order of magnitude of that of
the nucleotide pairs of the rn cistrons in phage
T4 (3).
The transformation of a normal cell to a tumor
cell by a virus could then be due to a single new
protein synthesized in the cell. The release of the
cell from the block to multiplication existing in
the organism caused by the new protein could
be, for instance, conceived of either as the supply
of an alternative biochemical pathway to the
blocked one or as a change of the specific per
meability of the cell. It will be recalled that the
cells transformed by the Rous virus undergo a
morphological change, which can be different
depending on the virus genome: this may sug
gest that the converting proteins operate, through
a common mechanism, a series of changes of
morphological, functional, and perhaps antigenic
nature.
The role of virus infection in the causation of
neoplasia may be limited to the transformation
of a normal cell into a cell capable of uncon
trolled multiplication, which need not necessarily
be malignant. In some cases malignancy may be
a secondary phenomenon caused by other
changes, probably of cell-genetic nature, which
could be independent of the virus. Experimental
evidence for this succession is found in the rabbit
papilloma, from which cancer develops later. Cytological studies have shown that these cancers
are aneuploid, whereas the papillomas are euploid (50). In this case the superimposed event
starting the malignant growth may be the aneuploidization, although the converse may be true,
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
DuLBECco—Virus-Host Relationship at the Cellular Lerei
i.e., that aneuploidization is the consequence of
cancerization. In other cases of virus-induced
tumors ( the Rous sarcoma, the mouse and chick
en leukemias) the growth appears to be malig
nant from the start. However, apart from the fact
that it is difficult to define malignancy of cells
releasing continuously highly infectious virus, it
is difficult to exclude the presence of an initial
and transient benign phase in these cases. This
point may be clarified by transplantations of cells
transformed in vitro by the virus into immunologically nonreactive hosts and under conditions
where infection of cells by the virus cannot take
place.
The concept that malignancy is not a necessary
property of cells transformed by tumor viruses
raises the question of the role of the virus in the
formation of malignant cells which arise second
arily in virus-induced tumors. This question has
been extensively discussed in the past for the
carcinomas deriving from papillomas. It is found
experimentally that, whereas the papillomas al
ways contain virus—although in very different
amount depending on the host (see [11] for a
discussion of these findings)—the derived carci
nomas contain virus in much smaller amounts
(Rous, personal communication). On the basis
of these observations many researchers take the
position that the virus is not etiologically related
to the carcinoma. In this respect it should, how
ever, be observed that the virus may persist in
the rapidly dividing carcinoma cells in an undetectable state, perhaps by a mechanism similar
to that operating in the basal cells of the papilloma, where the virus is also undetectable.
The role of the virus as an etiological agent,
even of the carcinomas from which virus cannot
be recovered, can hardly be doubted, since the
viral origin of the papilloma is clear and the car
cinoma would not occur without the papilloma.
The connection of the events can also be logically
understood, and in different ways.
According to one interpretation, the virus re
leases the basal cells of the epidermis from the
regulatory controls. The proliferation of the cells,
possibly in conjunction with the alteration of the
cells by the virus, increases the probability of
chromosomal alterations, which cause genie un
balance (the "accelerated evolution" of Lederberg [34]). At a certain point there arises a cell
genetically so unbalanced ( aneuploid? ) as to be
capable of unchecked and aggressive multiplica
tion: this cell begins the malignant growth. Dur
ing the growth as papilloma the neoplasia was
probably virus-dependent,
the independence
from the regulatory controls being maintained by
759
the continued synthesis of the virus-induced con
verting protein; the progeny of the unbalanced
cell may be released from the organism control
by the genie unbalance itself and may be conse
quently independent of the virus. The virus, be
ing now unnecessary, could be outgrown if the
virus-cell interaction is of the Kappa type. In
view of the progression in cancer development,
the final neoplasia may be very different in char
acter from the original one and nevertheless rep
resent its necessary evolution.
According to another interpretation, the transi
tion of papilloma to carcinoma is caused by a
change of state of the virus within the cell.
POSSIBLERELATIONOF VIRUS-INDUCED
TUMORS
TOOTHEREXPERIMENTALLY
INDUCED
TUMORS
The fact that tumors with similar properties
can be induced by viruses or by other carcino
genic agents, such as radiations, carcinogenic
chemicals, or hormones, raises the question of
the relationship between the various mechanisms
of induction. One question is whether all these
tumors are possibly virus-induced, the other
agents having only the function of changing the
state of the virus or of the cells. This hypothesis
seems supported by the finding of virus in cells
of mouse lymphocytic leukemia induced by ra
diation (20, 31). This, however, may be a very
special case, since the leukemia virus appears to
be very widespread in mice; a few per cent inci
dence of spontaneous leukemia is found in many
"low leukemia" strains—avery high incidence if
one compares it with that of spontaneous human
leukemia ( 0.005 per cent in the same time span ).
It is probable that the virus is present and occult
in the animals and that irradiation of the bone
marrow produced its activation in the thymic
cells through an obscure humoral mechanism.
In other systems no evidence for activation of
a latent virus exists. The occasional findings of
virus particles in sections of cells derived from
spontaneous tumors do not provide enough evi
dence for the conclusion that they are the etio
logical agent of the neoplasia.
A basic unity in the mechanism of formation
of neoplasia by the various carcinogenic agents
can, however, be recognized without making vi
ruses the connecting link. Ultimately, the virus
induces neoplasia by introducing a new genetic
function into the cell, which causes a genie im
balance in the cell. All the other tumor-inducing
agents may also lead to genie imbalance, by
causing either somatic mutations, chromosomal
aberrations, or heteroploidy. Whereas radiations
and certain chemicals may do so by acting on
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
760
Cancer Research
the cellular nucleic acids, other carcinogens, hav
ing no action on nucleic acids, may act on the
protein of the mitotic spindle. By similar mech
anisms also spontaneous neoplasia may conceiv
ably arise.
On the basis of the experimental evidence and
of these considerations, a theory according to
which all cancers are produced by viruses ap
pears to be, at the present time, experimentally
unsupported and theoretically unnecessary. Nei
ther experiment nor theory disproves it, but
widespread acceptance of this hypothesis can
rest only on its experimental verification. The
opposite trend, of propounding a "genetic theo
ry" of cancer, which makes somatic mutation the
universal cancer-producing event, appears equal
ly unjustifiable, since it would deny to the virus
carried intracellularly a genie function control
ling cellular properties.
REFERENCES
1. AHBEH,W., and KELLENBEHGER,
G. Study of the Prop
erties of Seven Defective-Lysogenic Strains Derived
from E. coli K12 (X). Virol., 5:458-75, 1958.
2. BENEDETTI,E. L., and BERNHARD,W. Recherches ul
trastructurales sur le virus de la leucémieérytroblastique du poulet. J. Ultrastr. Research, 1:309-36, 1958.
3. BENZER, S. Fine Structure of a Genetic Region in
Bacteriophage. Proc. Nat. Acad. Se., 41:344-54, 1955.
4. BERNHARD,W., and OBEHLINC,C. Electron Microscopy
of the Malignant Cell with Special Reference to Vi
ruses. Canadian Cancer Conf., 2:59-82, 1957.
5. BONAR,R. A., and BEARD,J. W. Virus of Avian Myeloblastosis. XII. Chemical Constitution. J. Nat. Cancer
Inst., 23:183-95, 1959.
6. BONAH, R. A.; PARSONS,D. F.; BEAUDREAU,G. S.;
BECKER,C.; and BEARD,J. W. Ultrastructure of Avian
Myeloblasts in Tissue Culture. J. Nat. Cancer Inst.,
23:199-255, 1959.
7. BREITENFELD,P. M., and SCHÄFER,
W. The Formation
of Fowl Plague Virus Antigen in Infected Cells, as
Studied with Fluorescent Antibodies. Virol., 4:32845, 1957.
8. BURKE,D. C., and ISAACS,A. Some Factors Affecting
the Production of Interferon. Brit. J. Exper. Path.,
39:452-58, 1958.
9. DULBECCO,R. Quantitative Aspects of Virus Growth
in Cultivated Animal Cells. Ciba Found. Symp. on the
Nature of Viruses, pp. 147-54, 1956.
10.
. Virus-Cell Interactions in Latent Infections.
Symposium on Latency and Masking in Viral and
Rickettsial Infections, pp. 43-50. Burgess Publishing
Co., 1957.
11.
. Interaction of Viruses and Animal Cells. Physiol.
Rev., 35:301-35, 1955.
12. DULBECCO,R., and FREEMAN, G. Plaque Production
by the Polyoma Virus. Virol., 8:396-97, 1959.
13. DURYEE, W. R. Precancerous Cells in Amphibian
Adenocarcinoma. Ann. New York Acad. Sc., 63:12801302, 1956.
14. ECKERT, A. A.; SHARP, D. G.; MOMMAERTS,E. B.;
REEVE, R. H.; BEARD,E.; and BEARD,J. W. Virus of
Avian Erythromyeloblastic Leukosis. III. Interrelation
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Vol. 20, June, 1960
of Plasma Particles, Infectivity, and the Enzyme Dephosphorylating Adenosine Triphosphate. J. Nat. Can
cer Inst, 14:1039-53, 1954.
EDDY, B. E.; STEWART,S. E.; YOUNG,R.; and BUR
ROUGHS,G. Kidney-Neoplasms in Hamster Induced by
Mouse Tumor Agent Passed in Tissue Culture. J. Nat.
Cancer Inst., 20:747-62, 1958.
EPSTEIN, M. A., and HOLT, S. J. Observations on the
Rous Virus: Integrated Electron Microscopical and
Cytochemical Studies of Fluorocarbon Purified Prep
arations. Brit. J. Cancer, 12:363-69, 1958.
FLAKS, J. G., and COHEN, J. S. The Enzymic Syn
thesis of 5-hydroxymethyldeoxycytidyIic
Acid. Biochim. et Biophys. acta, 25:667-68, 1957.
FRIEDWALD,W. F., and ANDERSON,R. S. The Effects
of Roentgen Rays on Cell-Virus Associations. Findings
with Virus-Induced Rabbit Papillomas and Fibromas.
J. Exper. Med., 78:285-304, 1943.
GINSBERG,H. S. Characteristics of the Adenoviruses.
III. Reproductive Cycle of Types 1 to 4. J. Exper.
Med., 107:133-52, 1958.
GROSS, L. Serial Cell-Free Passage of a Radiation
Activated Mouse Leukemia Agent. Proc. Soc. Exper.
Biol. & Med., 100:102-5, 1959.
GYE, W. E., and PURDY,W. J. The Infective Agent
of Tumor Filtrates: A Further Investigation by Means
of Antisera to Normal Tissue. Brit. J. Exper. Path.,
14:250-59, 1933.
HARFORD,C. G.; HAMLIN, A.; PARKER,E.; and VAN
RAVENSWAAG,
T. Electron Microscopy of HeLa Cells
Infected with Adenoviruses. J. Exper. Med., 104:44354, 1956.
HARRIS, R. J. C. Acquired Tolerance of Turkeys to
Rous Sarcoma Agent. Proc. Royal Soc., s.B, 146:5966, 1956.
HENLE, G.; DEINHARDT,F.; and RODRIGUEZ,J. The
Development of Polyoma Virus in Mouse Embryo
Cells as Revealed by Fluorescent Antibody Staining.
Virol., 8:388-91, 1959.
HOLLAND,J. H.; MCLAREN,L. D.; and SYVERTON,J. T.
Mammalian Cell-Virus Relationships. III. Poliovirus
Production by Non-Primate Cells Exposed to Poliovirus Ribonucleic Acid. Proc. Soc. Exper. Biol. &
Med., 100:843-45, 1959.
HOPPERT,J., and SANDERS,F. K. An Infective Ribonu
cleic Acid Component from Tumour Cells Infected
with Encephalomyocarditis
Virus. Nature, 182:51517, 1958.
HORNE, R. W., and NAGINCTON,J. Electron Micro
scope Studies of the Development and Structure of
Poliomyelitis Virus. J. Mol. Biol., 1:333-38, 1959.
HOTCHIN,J. E.; COHEN, S. M.; RUSKA,H.; and RUSKA,
C. Electron Microscopia! Aspects of Hemadsorption in
Tissue Cultures Infected with Influenza Virus. Virol.,
6:689-701, 1958.
ISAACS,A., and LINDENMANN,J. Virus Interference.
I. The Interferon. Proc. Roy. Soc., s.B, 147:258-67,
1957.
JACOB,F., and WOLLMAN,E. Recherches sur les bac
teria lysogènes defectives. I. Déterminismegénétique
de la morphogenèse chez un bactériophage tempéré.
Ann. Inst. Pasteur, 90:282-302, 1956.
KAPLAN,H. J. Indirect Induction Mechanisms in Carcinogenesis: A Review. Cancer Research, 19:791803, 1959.
KORNBERG,A.; ZIMMERMAN,S. B.; KORNBERC,S. R.;
and JOSSE, J. Eurymatic Synthesis of Deoxyribonu-
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
DuLBECco—Virus-Host Relationship at the Cellular Level
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
761
cleic Acid. VI. The Influence of Bacteriophage T, on
50. PALMER,C. G. The Cytology of Rabbit Papilloma and
the Derived Carcinomas. J. Nat. Cancer Inst., 23:241the Synthetic Pathway in Host Cells. Proc. Nat. Acad.
Sc., 45:772-85, 1959.
48, 1959.
LEBRUN, J. Cellular Localization of Herpes Simplex
51. POWELL,W. S. Radiosensitivity as an Index of Herpes
Simplex Virus Development. Virol., 9:1-19, 1959.
Virus by Means of Fluorescent Antibody. Virol., 2:
496-510, 1956.
52. REISSIG,M., and MELWICK,J. L. The Cellular Changes
LEDEHBERC,J. Genetic Approaches to Somatic Cell
Produced in Tissue Cultures by Herpes B. Virus Cor
Variation: Summary Comment. J. Cell. & Comp.
related with the Concurrent Multiplication of the
Physiol., 52 (Suppl. 1):383-401, 1958.
Virus. J. Exper. Med., 101:341-52, 1955.
L'HERITIER, P. The Heredity Virus of Drosophila.
53. ROGERS,S. Induction of Arginine in Rabbit Epithelium
Adv. Virus Research, 5:195-245, 1958.
by the Shope Rabbit Papilloma Virus. Nature, 183:
1815-16, 1959.
Liu, C. S. Studies on Influenza Infection in Ferrets by
Means of Fluorescein-labeled
Antibodies. I and II.
54. ROSE, W. R.; HARTLEY, J. W.; ROIZMAN, B.; and
J. Exper. Med., 101:665-76, 677-85, 1955.
LEVY, H. B. Characterization of a Factor Formed in
the Course of Adenovirus Infection of Tissue Cultures
LUSE, S. A., and SMITH, M. G. Electron Microscope
Causing Detachment of Cells from Glass. J. Exper.
Studies of Cells Infected with the Salivary Gland Vi
Med., 108:713-29, 1958.
ruses. Ann. N. Y. Acad. Sc., 81:133-44, 1959.
55. RUBIN, H., and TEMIN, H. M. A Radiological Study
LWOFF, A. Lysogeny. Bacteriol. Rev., 17:269-337,
of Cell-Virus Interaction in the Rous Sarcoma. Virol.,
1953.
7:75-91,1959.
MESELSON, M.; STAHL, F. W.; and VINOGRAD,J.
Equilibrium
Sedimentation
of Macromolecules in 56. SACHS, L.; FOGEL, M.; and WINOCOUH,E. In Vitro
Analysis of a Mammalian Tumor Virus. Nature, 183:
Density Gradient. Proc. Nat. Acad. Sc., 43:581-88,
663-64, 1959.
1957.
57. SMITH, H. G. Preparation in Tissue Culture of a CyMOORE, D. H.; LASFAHGUES,E. Y.; MURRAY,M. R.;
topathogenic Virus from Human Salivary Gland Virus
HAAGENSEN,C. D.; and POLLARD,E. C. Correlation
(SGV) Disease. Proc. Soc. Exper. Biol. & Med., 92:
of Physical and Biological Properties of Mouse Mam
424-30, 1956.
mary Tumor Agent. J. Biophys. & Biochem. Cytol.,
58. STEWART,S. E.; EDDY, B. E.; and BORGESE,N. G.
5:85-92, 1959.
Neoplasms in Mice Inoculated with a Tumor Agent
MOORE,D. H.; STONE,R. S.; SHOPE, R. E.; and GEL
Carried in Tissue Cultures. J. Nat. Cancer Inst., 20:
BER, D. Ultrastructure and Site of Formation of Rab
1223-43, 1956.
bit Papilloma Virus. Proc. Soc. Exper. Biol. & Med.,
59. STOKER,M. G. P., and NEWTON, A. The Effect of
101:575-78, 1959.
Herpes Virus on HeLa Cells Dividing ParasynchroMORGAN,C.; ELLISON,S. A.; ROSE,H. M.; and MOORE,
nously. Virol., 7:438-48, 1959.
D. H. Structure and Development of Viruses as Ob
60. TEMIN, H. M. The Control of Cellular Morphology in
served in the Electron Microscope. I. Herpes Simplex
Embryonic Cells Infected with Rous Sarcoma Virus.
Virus. J. Exper. Med., 100:195-202, 1954.
Virol., 10:182-97, 1960.
. II. Vaccinia and Fowl Pox Viruses. J. Exper.
61. TEMIN, H. M., and RUBIN, H. Characteristics of an
Med., 100:301-10, 1954.
Assay System for Rous Sarcoma Virus and Rous Sar
MORGAN,C., HOWE, C., and ROSE,H. M. Intracellular
coma Cells in Tissue Culture. Virol., 6:669-88, 1958.
Crystals of Coxsackie Virus Viewed in the Electron
62.
. A Kinetic Study of Infection of Chick Embryo
Microscope. Virol., 9:145-49, 1959.
Cells in Vitro by Rous Sarcoma Virus. Ibid., 8:209-22,
MORGAN,C.; ROSE, H. M.; and MOORE,D. H. Struc
1959.
ture and Development of Viruses as Observed in the
63. TENNENBAUM,E. Changes in Cellular Nucleic Acids
Electron Microscope. III. Influenza Virus. J. Exper.
during Infection with Poliomyelitis Virus as Studied
Med., 104:171-83, 1956.
by Fluorescence Microscopy. Nature, 180:1044, 1957.
NOYES,W. F. Studies on the Shope Rabbit Papilloma.
64. UETAKE,H.; LURIA, S. E.; and BURROWS,J. W. Con
II. The Creation of Infective Virus in Papillomas of
version of Somatic Antigens in Salmonella by Phage
the Cottontail Rabbit. J. Exper. Med., 109:423-28,
Infection Leading to Lysis or Lysogeny. Virol., 5:681959.
91, 1958.
NOYES,W. F., and MELLORS,R. C. Fluorescent Anti
65. VOGEL, J., and SHELOKOV,A. Adsorption-Hemagglubody Detection of the Antigen of the Shope Papilloma
tination Test for Influenza Virus in Monkey Kidney
Virus in Papillomas of the Wild and Domestic Rabbit.
Tissue Culture. Science, 126:358-59, 1957.
J. Exper. Med., 106:555-61, 1957.
66. WATSON, M. L. The Nuclear Envelope: Its Structure
NOYES,W. F., and WATSON,B. K. Studies on the In
and Relationship to Cytoplasmic Membranes. J. Bio
crease of Vaccinia Virus in Cultured Human Cells by
phys. & Biochem. Cytol., 1:257-70, 1955.
Means of Fluorescent Antibody Techniques. J. Exper.
67. WINOCOUR,E., and SACHS,L. A Plaque Assay for the
Med., 102:237-61, 1955.
Polyoma Virus. Virol., 8:397-400, 1959.
PALADE, G. E. Relations between the Endoplasmic
68. WHEELOCK,E. F., and TAMM, I. Mitosis and Division
Reticulum and the Plasma Membrane in Macrophages.
in HeLa Cells Infected with Influenza or Newcastle
Anat. Ree., 121:445, 1955.
Disease Virus. Virol., 8:532-36, 1959.
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.
A Consideration of Virus-Host Relationship in Virus-induced
Neoplasia at the Cellular Level
Renato Dulbecco
Cancer Res 1960;20:751-761.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/20/5_Part_1/751.citation
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1960 American Association for Cancer Research.