CANCER RESEARCH
VOLUME
21
NOVEMBER 1961
NUMBER
10
Transplantable Animal Cancer, the Primary Standard
Guest Editorial*
VAN R. POTTER
(McArdle Memorial Laboratory, The Medical School, Unh,ersity of Wisconsin, Madison, Wisconsin)
T w o previous editorials h a v e a p p e a r e d u n d e r
the titles " I I u m a n Cancer, the P r i m a r y T a r g e t "
(3) a n d " A n i m a l Cancer, the P r i m a r y T o o l " (1).
These essays r e p r e s e n t c o m m e n d a b l e contributions in the a r e a of critical writing in the field of
cancer research. W e need m u c h m o r e discussion
on the relative m e r i t s of the different a p p r o a c h e s
to the cancer p r o b l e m simply because the n u m b e r
of possible c o m b i n a t i o n s of m e a s u r e m e n t s a n d
m a t e r i a l s is for all practical purposes infinite 9
I believe t h a t emphasis on h u m a n cancer (3)
or on p r i m a r y a n i m a l cancer (1) w i t h o u t vigorous
parallel d e v e l o p m e n t s in the field of t r a n s p l a n t able a n i m a l cancer would be a mistake. This view
is in c o n t r a s t to t h a t of the previous a u t h o r s , since
D a y (1) believes t h a t " w e should begin limiting
the use of the troear, n o t e x p a n d i n g it. T h e foreignness of the t u m o r explant superimposes such a
nmltitu(te of e x t r a n e o u s features u p o n the ' t u m o r ness' of the tissue a n d wrests such a m u l t i t u d e of
p e r t i n e n t f e a t u r e s f r o m it t h a t it can serve only
poorly as a physiological model for eaneer in m a n .
9 . . Those subtleties inherent in cancer which distingafish it f r o m n o r m a l tissue m a y emerge clearly
a n d simply once we r e v e r t to s y s t e m a t i c studies
with a u t o e h t h o n o u s t u m o r s in our l a b o r a t o r y
a n i m a l s . " H o l l a n d a n d Heidelberger (3) are n o t
explicitly opposed to the use of t r a n s p l a n t e d tumors, b u t t h e y " d o u b t the wisdom of aeeepting
biochemical information derived f r o m t r a n s p l a n t able t u m o r s w h e n the d a t a a p p a r e n t l y are n o t
consistently applicable to s p o n t a n e o u s neoplasms
* Supported in part by a grant (No. C-646) from the National Cancer Institute, National Institutes of Health, U.S.
Public Health Service.
in the same species" a n d suggest t h a t " t h e convcnience of these t u m o r s as research tools tends
to obscure t h e need for cancer research in m a n . "
t l e p a t o m a s t u d i e s . - - O n the basis of recent
studies on r a t h e p a t o m a s in cooperation w i t h D r .
I I a r o l d M o r r i s a n d D r . I I e n r y P i t o t (5, 7-9) it is
not surprising t h a t m a n y t r a n s p l a n t a b l e t u m o r s
are n o t idcntical w i t h s p o n t a n e o u s or p r i m a r y induced t u m o r s in the same species (3), a n d it is no
longer possible to affirm categorically t h a t all
t r a n s p l a n t a b l e t u m o r s h a v e lost " a m u l t i t u d e of
p e r t i n e n t f e a t u r e s " because of the "forcignness of
the t u m o r c x p l a n t " (1). T h e r e are now available
t r a n s p l a n t a b l e r a t h e p a t o m a s showing fewer biochemical a n d morphological deviations 1 f r o m
p a r e n c h y m a l liver cells t h a n a n y p r i m a r y hcpat o m a s previously e x a m i n e d (6-10). T h e p r i m a r y tumors f r o m which t h e y wcrc derived w e r e p r o d u c e d
1The word deviation is used hecause it is a more general
term than the word deletion, which was introduced by Miller
and Miller (4) and which implies loss of specific properties (8).
Deviation is intended to be synonymous with the word change
and is not committed to any particular mechanism of change.
The terms are compatible with the concept of succcssivc somatic mutations, which could conceivably result in eithcr loss,
gain, or mere alteration of specific cell propertics. Operationally, one can assay the tumors for cnzyme activity under
standard conditions or one can assay for the ability to produce
increased enzyme activity in response to some kind of a stimulus. The "Deletion Hypothesis" is extremely useful as a guide
for enzyme studies on minimal deviation tumors, since the loss
of enzyme activity is much morc rcadily detected than a slight
change in physico-chcmical properties or amino acid sequences
in specific enzymes. The word deviation should bc used in theoretical discussions, and the word deletion seems appropriate
to describe actual situations where a given enzyme function
appears to be lost. The words addition or alteration might also
be reserved for actual examples.
1331
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1961 American Association for Cancer
Research.
133f~
Cancer Research
either with a slowly acting carcinogen (6) or with
a short intermittent exposure to a very active carcinogen (10). The Morris hepatoma 5193 (6) has
been carried for ~3 transplant generations in the
highly inbred Buffalo strain of rats and has apparently maintained its biological, morphological, and
biochemical characteristics. However, the primary
tumor and the first transplants were not analyzed,
and there may have been significant changes at
any time after the primary event; of course the
possibility of change in future generations cannot
bc denied. All of the transplants have grown slowly, but they are capable of invasion and metastasis
and are able to kill the host in about 3 months
(6). The tumor is now being carried in four parallel
lines, and specimens have been /)laced in deep
frozen storage to preserve the original strain if
mutants shouhl appear (II. P. Morris, personal
communications). The Morris hepatonaa 5193 may
correspond to what Firminger (9) has referred
to, on morphological grounds, as the "early"
type of induced hepatoma, and it is possible that
such tumors differ from the "later" hepatomas (~,
p. 1430) in having fewer deviations from their cell
of origin. The Morris hepatoma is one of a series of
hepatomas that was surveyed in an attempt to find
one with minimal deviations, since it was postulated (8) that many enzymatic changes seen in transplanted tumors are indeed irrelevant to the problem of carcinogenesis and that in these tumors it
is imt)ossible to separate the relevant from the irrelevant, a view not ineoml)atible with the view
of Day (1) quoted earlier. I t was postulated that,
if a hepatoma with minimal deviations possessed
enzymes lacking in other hepatomas, the changes
seen in the other hepatomas could not be claimed
as essential to the carcinogenic process. By the
same line of reasoning, a change seen in an "early"
tumor cannot be claimed as essential to carcinogenesis until meaningful metabolic patterns have
been demonstrated and until similar changes have
been found in other "early" hepatomas.
In the survey mentioned (7-9) about ten different types of rat hepatoma were assayed for a
variety of enzymes and exhibited a complete
spectrum of enzyme patterns ranging f r o m only
a few deviations from normal liver to deviations
so extensive that it has not been possible to state
that the hepatoma cells were derived from liver
cells. In particular the Novikoff hcpatoma fell in
this category and in addition contained deoxycytidylic deaminase, an enzyme that is considered to be associated with proliferating bile
duct epithelium (7-9). It will be convenient to
refer to the hepatomas that are most similar to
liver as "minimal deviation" tumors and hepa-
Vol. ~ 1, N o v e m b e r 1961
tomas t h a t are very dissimilar from liver as
"multiple deviation" tumors, recognizing that a
tumor t h a t is now minimal may be replaced by a
tumor that represents a new minimum, and what
is now a multiple deviation hepatoma may turn
out to be derived from a different cell of origin.
Objective: carcinogenesis or chemotherapy?--The
above studies suggest that, for understanding the
specific mechanisms of carcinogenesis, we need to
identify with certainty the cell of origin and to
have cancers that differ as little as possible from
their normal progenitors in order to narrow the
number of possible irrelevant changes. The Morris 5193 hepatoma (5) and the Reuber hepatoma
(10) appear to bc examples of such minimal-deviation tumors and should be useful progenitors for
studying the possibility of successive deviations
all the way to the multiple-deviation type. At
present, the "multiple-deviation" hepatonlas such
as tile Novikoff present uncertainty, because their
cells of origin are not established. This criticism
applies to the vast majority of transplantaMe tumors, as well as to a large number of primary tumors in animals and in humans. Such cancers may
present great difficulties if used to try to unravel
specific mechanisms of carcinogenesis. On the
other hand they represent de facto enzyme patterns that must be coped with in the reahn of
chemotherapy; and their enzyme patterns are
legitimate objects of inquiry, especially in relation
to correlations between the sensitivity and resistance to specific drugs and the enzymes that
interact with the drugs (3).
Minimal-deviation tumors as standards.--Transplantable cancers such as the Morris 5193 constitute standards that can be produced in quantity, distributed widely, monitored for constancy,
and compared with other minimal-deviation tumors derived from the same type of cell. They
constitute a standard against which primary
hcpatomas, both human and rodent, can be compared. If a sufficient number of minimal-deviation
hepatomas are characterized enzymatically, biochemists may find the least common denominators
of enzymatic change that are associated with the
carcinogenic process. Such studies are at present
under way in several biochemical laboratories in
collaboration with Dr. It. P. Morris. If minimal
deviation tumors can be induced under reproducible conditions it will be possible to test not only
the primary tumors but also the subsequent transplant generations from the identical tumor in
order to learn whether the transplant line is stable
or unstable.
I t is suggested that the recommendations by
Day (9) should be modulated slightly in that ex-
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1961 American Association for Cancer
Research.
POTTER--Transplantable A n i m a l Cancer: G u e s t E d i t o r i a l
perimentalists should not merely rely upon " t h e
large variety of carcinogenic agents for providing
themselves with animal tumors while they are
waiting for a wide spectrum of spontaneous tumors to become commercially available." T h e y
should determine the lowest dose of known carcinogens, as well as the mode of administration
t h a t will induce minimal deviation tumors in specific tissues when given with the proper diet to
highly inbred animals of specified strain and sex.
The resulting tumors should then be transplanted
and tested for evidences of progression. The emphasis should be on reproducibility and understanding, not variety, at this stage. If the specific
enzymatic defect in only one type of cancer could
be established it would be worth more t h a n the
cataloging of hundreds of examples. I t will serve
no purpose to s t u d y cancers t h a t m a y never be
seen again, to produce data t h a t are not subject to
confirmation, to leave the escape hatch of uniqueness open to the careless investigator. This is the
grave danger with specimens of h u m a n t u m o r material, as indeed it is with primary animal tumors.
Minimal-deviation primary tumors from various cells of origin should be looked for and should
be transplanted in highly inbred animals of the
same strain. I t is postulated t h a t such transplantable tumors can serve as the parent strains
for multiple-deviation tumors and can become
standardized as to growth rate, morphology,
enzymatic pattern, and chemotherapeutic response. They can become the standards and the
tools by which we can guide studies on the control
and cure of h u m a n cancer.
The keystone of science is reproducibility of
experiments. If cancers t h a t were identical at the
1883
molecular level could be identified in h u m a n patients or produced at will in animals there might
be no need for transplantable tumors. Until t h a t
day, at least some experimentalists should devote
their energy to perfecting and using the only
standard t h a t we h a v e - - t h e transplantable animal
tumor.
REFERENCES
1. D.~Y, E. D. Animal Cancer: The Primary Tool: Guest Editorial. Cancer Research, 9.1: 581-8~, 1961.
~. Fin.~tiN~mt, H. I. IIistopathology of Carcinogenesis and
Tumors of the Liver in Rats. J. Nat. Cancer Inst., 15:
14~7-41, 1955.
~. HOLLAND,J. F., and HEIDELBERGER, C. Human Cancer,
the Primary Target: Guest Editorial. Cancer Research,
20: 975-76, 1960.
4. MILLER, E. C., and 3{ILLER, J. A. Tim Presence and Significance of Bound Aminoazo Dyes in the Livers of Rats Fed
p-l)imethylaminoazobenzene. Cancer Research, 7: 468-80,
1947.
5. MORItIS, H. P.; SIDRANSKY, II.; W.~GNEIt, B. P.; and
D~'E~, H. M. Some Characteristics of Transplantable Rat
Hepatoma No. 51o.3 Induced by Ingestion of N@2-fluorenyl)-phthalamie Acid. Cancer Research, 20:1"25~2-54,
1960.
6. MOnRIS, H. P., and WAGNEI~, B. P. Some Growth Studies
of Transplantable Hepatomas. Proc. Am. Assoc. Cancer
Research, 3: ~53, 1961.
7. PITOT, lI. C. The Comparative Enzymology and Cell
Origin of Rat Hepatomas. II. Glutamate Dehydrogenase,
Choline Oxidase, and Glucose-6-phosphatase. Cancer Research, 20:1~6'2--68, 1960.
8. POTTER, V. R. Enzyme Studies on the Deletion IIypothesis
of Carcinogenesis: Bertner Izecture. Texas Rep. Biol. &
Med. (in press).
9. POTTER, V. R.; PITOT, H. C.; ONO, T.; and MonaIs, H. P.
The Comparative Enzymology and Cell Origin of Rat
Hcpatomas. I. l)eoxycytidylic Acid I)eaminase and Thyminc Dcgradation. Cancer Research, 20:1~55-61, 1960.
10. REUBEn, _-'~I.A Transplantable Bile-secreting ttepatocellular Carcinoma in the Rat. J. Nat. Cancer Inst., 26:891901, 1961.
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1961 American Association for Cancer
Research.
Transplantable Animal Cancer, the Primary Standard Guest
Editorial
Van R. Potter
Cancer Res 1961;21:1331-1333.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/21/10/1331.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. © 1961 American Association for Cancer
Research.