Download Discussion of Problems Related to Hormonal

Discussion of Problems Related to Hormonal Factors in
Initiating and Maintaining Tumor Growth*
JACOBFURTH
(Children's
Cancer Research Foundation,
Children's Medical Center, Cancer Research Inst., New England
Deaconess Hospital, and the Dept. of Pathology, Harvard Medical School, Boston, ilass.)
It is a gigantic task to evaluate the mass of re
ported data and opinions well assembled by Drs.
Kirschbaum
and Hertz and to point to avenues
which future research may profitably explore. No
building is solid that rests on crumbling material
or is loosely constructed.
My first task is to ex
amine the assembled information. I trust that the
critical comments directed at vulnerable points
shall not obscure the wealth of ideas cited and ex
pressed by the preceding speakers, which I shall
not underline. Challenge is intended merely to test
the solidity of some observations cited.
Dr. Gardner will, I believe, agree with my quali
fication of his introductory
words that endocrine
neoplasia represents but a small segment of the
cancer problem. If by hormones we mean humoral
influences, specifically regulating the growth of
many if not all cells, hormonal tumorigenesis is a
key subject in cancer research. However, aside
from this, a large percentage of human tumors oc
curs either in endocrine organs or in their target
cells.
Evolution of cancer. Dependent and autonomous
variant^.—The greatest contribution
of research
in endocrines is, in my opinion, the establishment
of models pointing to the sequence of transforma
tion from normal to dependent, and from the latter
to highly autonomous tumor cells, and leading us
to a useful concept on the fundamental nature of
the neoplastic state.
It is a universal belief that the tumor is an ab
normal mass of tissue which persists after cessation
of stimuli which evoked it. Research in endocrine
neoplasia taught us that this definition is errone
ous—that cancers or tumors are a state in which
cells proliferate with limited or with no restraint in
a complex system of cells, either because of a
change in a physiologic mechanism limiting the
number of that cell type or because of an alteration
* Presented at the second meeting of the Scientific Review
Committee of the American Cancer Society, held at the Westehester Country Club, Rye, New York, December 13 and 14,
1956.
in cells resulting in failure of responsiveness to the
physiologic forces. The former type of neoplasm or
tumor is called dependent, the latter autonomous.
Both can metastasize. Dependent tumors can be
arrested by restoring to normal the specific regula
tory mechanism which was disturbed. The sequence
of changes from a normal cell to an autonomous neo
plasm as sketched in Chart 1 is common among the
EVOLUTION OP CANCERS
Sequence of
changes,
to
changeInhormonesCorrection
NORMAL cell
»hyperplasiaDEPENDENT
can
hostIncellResponsiveness
be
completeGrowth
T*
AUTONOMOUS T
responsive,J,
highly
less and less
responsive
\
reversely
responsiveBasic
full autonomy
can be
retardedbut
not arrested
None
CHART1.—Schemeof the sequence of changes induced by
derangement of physiological forces regulating cell growth,
which can result in evolution of cancer cells from normal
cells. From Ref. l, Cancer, 1957, in press.
endocrine organs, but the autonomous tumor can
also arise without an intermediate
dependent
phase.
The core of the cancer problem is not merely
that of detecting forces which bring about a per
manent modification of a normal cell, e.g., a mutagen, but also the forces which create a state which
allows one cell type to proliferate, uncontrolled, in
a system whereby the number of each of hundreds
of different kinds of cells is limited by a specific
mechanism. This neoplastic state can be brought
about by any disturbance which interferes with
the homeostatic
forces specifically limiting the
454
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
FuRTH—Hormonal Factors and Tumor Growth
number of each cell type. The general problem is,
therefore, that of the cancerous or neoplastic state.
One major specific problem is the origin of the
autonomous cell. Another major problem is the
origin of a dependent tumor, and this is an endo
crinologie problem par excellance; in the develop
ment of cell autonomy, endocrines may play a
mere preparatory role.
Chart 2 is an over-simplified sketch showing the
servo-mechanism which maintains the cell level.
Unrestrained proliferation of a cell, here desig
nated as target cell, can be brought about (a) by
excessive stimulation, (6) by lack of the restraining
force, and (c) by altered responsiveness of either
the target or the regulating cell, resulting in an ex
cess of the stimulating factor ("hormonal imbal
ance")- This, too, is an oversimplification of the
situation. Arrows in the sketch indicate that both
regulator and target cell and each force (hor-
SCHEME OF FEED-BACK REGULATION
CHART2.—Sketch of feed-back type of growth regulation
pointing to stimulatory and retarding (push and pull) forces.
mones, etc.) are subject to promoting and retard
ing influences.
The following are simple examples that are well
proved experimentally.
a) Examples of induction of tumor by exces
sive, sustained stimulation: Large quantities of
estrogenic hormones stimulate to progressive pro
liferation one cell type of the pituitary, to be called
the mammotrope. Many of these mammotropic
tumors will not grow on a normal host but pro
liferate with no apparent restraint in hosts treated
with excessive quantities of an estrogen (10). If this
stimulation is not interrupted, dependent tumors
may give rise to autonomous variants. There is a
direct quantitative relationship between the estro
gen administered and the rate of proliferation of
mammotropes (5). The induction of pituitary tu
mors by estrogens has been demonstrated in mice,
455
rats, and hamsters, but only in the former two spe
cies has it thus far been shown that these tumors are
mammotropic. Similar examples are the induction
of Leydig-cell tumors with estrogen and of ovarian
tumor by gonadotropins. The latter is achieved by
grafting ovaries in the spleen of castrates. All tu
mors so induced appear to be at first dependent
but have a strong tendency to give rise to au
tonomous variants.
b) A good example of tumor production by de
ficiency of the specific restraining force is that of
thyrotropic pituitary tumors by lack of thyroid
hormone. Almost every mouse of every strain thus
far tested will develop a thyrotropic pituitary tu
mor. Tumor induction can be stopped by adminis
tration of thyroid hormone. It can be said for a
first approximation that this exemplifies how lack
of an inhibitor can cause tumor development. The
mechanism by which lack of thyroid hormone
causes proliferation of thyrotropes is, however, far
more complex.
c) Lack of responsiveness of a target cell, the
third type of derangement, is probably the most
common and certainly the most important one.
Good examples are tumors induced by ionizing
radiation and mutagenic chemicals; e.g., ovarian
tumors are induced by ionizing radiation in al
most every female mouse. If a threshold dose
of about 30 r whole-body radiation is exceeded,
in time almost every female mouse will devel
op an ovarian tumor. Ovarian irradiation alone
will also induce such tumors. The irradiated ova
ries are injured but not destroyed. Irradiated
animals can become pregnant, but after a few
pregnancies they become sterile, and after about a
year and a half they will develop ovarian tumors.
Conclusive evidence for the role of gonadotropic
hormones in the induction mechanism of these tu
mors has been reviewed by Dr. Kirschbaum. Ir
radiated ovaries secrete gonadal hormones, but,
apparently, the feed-back mechanism of gonadalgonadotropic hormones is so disturbed by irradia
tion that the balance is tilted to a sustained overstimulation of granulosa and lutein cells of the
ovary, leading to tumor development. Irradiation
of ovaries before transplantation into the spleen of
gonadectomized rats resulted in the development
of larger tumors (Kullander [13]), indicating fur
ther that irradiation induces some change in ovari
an cells, disturbing but not abolishing their respon
siveness to gonad-stimulating hormones.
A variant of the first two possibilities is tumor
induction by metabolic antagonists. A good ex
ample is the induction of thyroid and pituitary tu
mors by long-continued administration of antithyroidal compounds. In thyroid tumorigenesis by
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
456
Cancer Research
thiouracil the sequence of changes from normal
cell to dependent and from dependent to autono
mous tumors has been thoroughly studied. This
sequence of events has been fully described else
where (9). Charts 3 and 4 are schematic diagrams
illustrating the behavior of dependent and autono
mous tumors in variously conditioned hosts.
The time required for transformation of depend
ent to autonomous tumor cells varies with differ
ent types of tumors and is characteristic for each,
although there are great individual variations. For
example, in the case of thyrotropes, acquisition of
DEPENDENT
TUMOR
cells were dependent. Tumors recurring after simi
lar treatment, and in the absence of excretion of
androgen metabolites, can be supposed to be au
tonomous. Acquired reverse responsiveness, an
important event from theoretical and practical
standpoints, has not been adequately studied.
Animal experiments are not immediately ap
plicable to man but should be looked upon as
models to explain events in humans and as tools to
test hypotheses on stimulating and restraining
forces of cells (both normal and neoplastic) and as
tools in the search for antagonists of hormonally
responsive tumors.
Is the neoplastic change sudden or gradual?
With thyrotropes, dependent tumors arise in dis
tinct loci ("micro-tumors")- Are these already al
tered but still fully responsive beta cells? Acquisi
tion of autonomy appears to be gradual and pro
gressive in severity. Yet, this may not be so. Cur
rent observations relate to populations of cells the
IN »EU.CONDITIONEDHOST
MODIFICATIONOF TUMOR GROWTH
BY CORRECTIONOF FEED-BACK DISTURBANCE
ACCELERATION OF GROWTH
CHART3.—Schemeof the relative growth rate of depend
ent tumors in different hosts.
TUMOR AUTONOMOUS.
REVERSEUr RESPONSIVE
PROGRESSIVE
-TUMOR
GROWTH'
AUTONOMOUS.
NONRESPONSIVE.
.RETARDATION
OF GROWTH
TUMOR AUTONOMOUS
AUTONOMOUS
NON-RESPONSIVE
UIMOR
TUMORS
BOT RESPONSIVE.
RESPONSIVETUMOR
REGRESSION
TUMOR FUU.Y DEPENDENT
K NORM«.HOST
CHART5.—Scheme of modification of response of tumor
growth by attempted correction of a feed-back disturbance.
CHART4.—Schemeof the relative growth rates of respon
sive and nonresponsive autonomous tumors in different hosts.
autonomy has not been noted in the original host
and first passage, while with mammotropes it is
usual in the first passage. With both testicular and
ovarian tumors, autonomous variants commonly
arise in the original hosts.
Chart 5 is a diagrammatic illustration of how tu
mor growth is modified by therapeutic application
of its presumed physiologic regulator. The rare
cases of prostatic carcinoma, described by Huggins, in which regression was permanent following
operative removal of the source of androgens,
could be explained by supposing that all tumor
composition of which is influenced by host factors
and changes with time. Mammotropic tumors ap
pear in diffuse hyperplasia, and no borderline is
known between hyperplasia and dependent neo
plasia. Conclusive answers will not be forthcoming
until the progeny of different cells can be followed,
as has been done with mammalian cells with the
use of ascites and tissue culture technics.
Current nomenclature is inadequate to desig
nate the various types of autonomous and depend
ent tumors. The term malignancy is currently used
to express autonomy, but autonomous tumors can
be highly responsive. Metastasis is considered in
dicative of autonomy, but dependent tumors can
also metastasize by both the blood and lymph
stream, and they can invade adjacent structures
by continuity. The difference is merely quantita
tive. Dependent tumors are progressive in, and
fatal to, conditioned hosts. Many benign tumors
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
FÜRTH—Hormonal
Factors and Tumor Groivth
are probably conditioned growth disturbances
(Bungeler [3]).
\Vhere is the borderline between hyperplasia
and dependent neoplasia? Withdrawal of the stim
ulus will correct both. The difference lies in the
host. In hyperplasia the disturbance in homeostasis of cell numbers is temporary, and the balance is
ultimately restored. In dependent neoplasia the
disturbance is lasting. Conceivably, a dependent
tumor is an uncompensated hyperplasia. Parallel
comparative investigations (biological, morpho
logical, and biochemical) on hyperplastic, depend
ent, and autonomous tumor cells derived from the
same normal cell are much wanted for understand
ing the basic differences among them.
Pituitary tumors.—I shall now discuss experi
mental pituitary tumorigenesis because of its unu
sual research potentialities : (a) there is the possi
bility of biologic dissection of the pituitary into its
morphologic units; (6) to obtain monomorphous
tropic hormone-secreting cells for isolation of hor
mones and for morphologic and physiologic char
acterization of functional units of the pituitary;
(c) to provide systems for investigations on dis
turbance in feed-back mechanisms; (d) to follow
the transformation of normal cells to fully depend
ent tumor cells and these into autonomous but
highly responsive tumor cells, and the latter into
fully autonomous cells.
With some pituitary tumors, such as those of
thyrotropes, tumor induction and transformation
occur slowly, so that each type of neoplasm can
be fixed in the frozen state, and later all can be
recovered and examined under identical environ
mental conditions. Biochemical efforts thus far
have failed to elucidate the basic neoplastic
change, as we learned from the proceedings of the
last conference of the Scientific Review Committee
of the American Cancer Society (17). The theory
of Warburg is negated by Weinhouse and others,
and Greenstein's review indicates that no specific
enzymatic or other biochemical differences have
been discovered which would clearly distinguish a
cancer cell from a normal cell. The availability of
dependent and autonomous neoplasms should en
courage chemists to renew their efforts under more
favorable conditions than was done earlier.
Although histologists consider the pituitary as a
mosaic of well differentiated, differently function
ing cell types, in the cancer literature pituitary tu
mors are lumped together without clear characteri
zation of the tumor cell. Our reviewers give too
much credence to work which ignores the specific
character of pituitary tumors induced by diverse
procedures without ever assaying any tumor, and
457
too little credence to the existence of monomor
phous pituitary tumors of diverse types.
Three distinct pituitary tumor types are avail
able in our laboratory: thyrotropic, mammo tropic,
and adrenotropic. These can be readily induced,
and several strains of each type have been exten
sively studied. Their distinctness is clearly indi
cated in hypophysectomized hosts. Transplanta
tion assays are essential to characterize them,
since the secondary changes in primary hosts do
not disclose with certainty the identity of the
tropic tumor; e.g., primary thyrotropic tumors can
occur either with enlarged (but hypofunctional) or
with an atrophie thyroid gland. Secondary and
tertiary changes often obscure the basic event;
e.g., thyrotropes invariably have a trace of gonadotropic activity (2), but, given time, the estro
gen overproduction from stimulated ovaries will,
in turn, stimulate the mammotropes and these the
mammary gland. The latter change is blocked by
hypophysectomy of tumor-bearing hosts, but not
the former (unpublished data with Clifton).
Mammotropic tumors were induced in our labo
ratory by two procedures: (a) stilbestrol pellets
and (6) ionizing radiations (11). Prof. Lacassagne,
who is with us today, was perhaps the first to indi
cate pituitary tumor induction by estrogens.
Others, including Dr. Gardner, followed him
closely. The attractive assumption that the two
procedures have a common denominator, namely
estrogen excess, remains to be proved. Some pitui
tary tumors induced by Woolley et al. by gonadectomy at birth may also be of this type, since
gonadectomy in their strain causes gonadal hor
mone-secreting adrenal tumors. Mammary gland
hyperplasia in mice bearing such tumors was men
tioned by Dickie and Woolley. This is also a sec
ondary change with thyrotropes. Our observations
(10) suggested that a major force in the induction
of mammary tumors with estrogens is the mammotrope. The literature on the hormonal genesis of
mammary tumors has been recently reviewed by
Milhlbock in Advances in Cancer Research (15)
without mentioning the mammotrope and its hor
mone. However, now that the picture of mammo
tropes clearly emerges, older observations can be
re-interpreted as favoring this view; e.g., pituitary
grafts outside the cranial cavity cause mammary
tumors, presumably by virtue of surviving func
tional mammotropes (luteotropes, Mühlbock).
Hypophysectomy of estrogen-treated mice will
prevent mammary tumor development (Gard
ner).1 The possible significance of mammotropes in
1Symposium of the American Cancer Society on Endocrines
and Cancer, October, 1956.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
458
Cancer Research
causing human tumors has been recognized by
Hadfield (12), whose efforts are directed to assay
this hormone in a mammal. The usual assay in
pigeons that measures secretion (hence, the name
prolactin) may not be a true measure of this
tropic hormone.
Adrenotropic tumors can be induced by totalbody ionizing radiation. Their induction mecha
nism is yet to be worked out. Current experiments
(with Buffett) indicate that head irradiation alone
will induce them, but not adrenal irradiation or
adrenal-gonadectomy.
The current view that the pituitary is a radioresistant organ is due to failure to observe the
animals over sufficiently long periods of time. The
latency period of this tumor is more than half the
lifespan of the animal. Whether or not this applies
to man remains to be seen. I recall Dr. E. Shorr de
nying the carcinogenicity of estrogens in man, now
amply documented by the references cited by Dr.
Hertz.
The remarkable specific features and side effects
of these three types of tropic tumors have been de
scribed elsewhere (see 9). The mammotropes have
a "built-in" somatotropic effect. The mouse adrenotropes do not have any other manifestations
than those resulting from adrenal hyperfunction,
but assays of Steelman (16) have shown that they
possess a marked melanotropic activity. The thyrotropes have some gonadotropic effects and cause
dilation of the extrahepatic biliary tracts.
These findings on the existence of three distinct
types of pituitary tumors should encourage re
search on induction of monomorphous pituitary
tumors of all other pituitary cell types. The exist
ence of a folliculotrope and of a luteotrope is gen
erally accepted; if this is true, they too should yield
monomorphous tumors.
The growth hormone is of special interest in can
cer research. Is there a specific somatotrope? Per
haps the acromegaly syndrome is due to a tumor
of somatotropes. The possible existence of a soma
totropic tumor in mice is suggested by our frag
mentary observations (9). Three tropic cells have
distinct general growth-promoting effects: the
mammotropes, apparently by direct effect of the
hormones they secrete; the thyrotropes, by way of
thyroid hormone (TH) production; and gonadotropes, by way of androgen production. The spe
cific differences in growth promotion by these hor
mones remain to be fully analyzed.
Dr. Kirschbaum raised the question as to the
induction mechanism of somatotropic tumors. I
have no conception (and have heard of none) con
cerning the homeostatic mechanism of growth
hormone secretion. The growth-promoting tropic
tumors studied by us are linked to mammotropes,
and estrogen is their stimulant. As mentioned ear
lier, two other tropic hormones (thyrotropins and
gonadotropins) have indirect somatotropic effects.
The existence of a somatotrope distinct from that
of the mammotrope is being postulated on the
basis of chemical isolation of such a hormone. It is
also related to acidophils which are conceivably
distinct from the mammotrope. Growth hormone
is an anabolic hormone, related to protein, nucleoprotein, and carbohydrate metabolism, and its
homeostasis may somehow be linked to these proc
esses.
In the following, I shall comment more spe
cifically on papers reviewed by Dr. Kirschbaum.
In the induction of pituitary tumors by Im
(and by other means), the view of Gorbman and
Edelmann is cited, who attribute an essential role
to such nonspecific events as stress. Investigations
reviewed by us elsewhere indicate that these tu
mors are thyrotropic and that any of four proce
dures will induce such tumors: radiothyroidectomy, surgical thyroidectomy, antithyroidal com
pounds, and iodine deficiency. Obviously, the
common denominator of these procedures is lack
of TH.
Complete surgical thyroidectomy in mice is a
very difficult procedure and is seldom completely
successful. A few cells left behind and ectopie cells
will undergo compensatory hyperplasia. Radiothyroidectomy, on the contrary, can reach all cells.
If a few cells are left undestroyed, they do not
proliferate, probably because of radiation fibrosis
and vascular stenosis.
Noting that Gorbman and Edelmann's idea
that radiation is essential to induce tumors by I131
met with wide acceptance, I should like to present
a simplified tabulation of our relevant work, indi
cating the contrary. Table 1 shows that the thresh
old tumorigenic dose is about 25 pc. of I131in fe
male, and about 50 /ic. in male mice. Following this
background information, the borderline dose of
30 (ic. was selected for the study of the possible en
hancing effect of radiation on induction of thyro
tropic tumors by I131.
Table 2 shows that the incidence of tumors was
about the same in all females, but in the x-radiated
group more reached a macroscopic size. Monthly
tabulation of the pituitary changes after radiothyroidectomy indicates that whether an animal
has a macroscopic tumor or a microtumor depends
entirely on the time when the animal dies after I131
treatment. The succession of events seems inevi
table: most, if not all, thyroidectomized animals
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
FTJRTH—Hormonal Factors and Tumor Growth
that live long develop a macroscopic tumor. As
Table 2 indicates, 94 per cent of the female mice
given 30 juc.alone had pituitary tumors (including
microtumors), as compared with 84 per cent of
mice given 30 /¿c.
and irradiated over various parts
of the body. However, more of the animals receiv
ing the added irradiation had macroscopic tumors.
In the same experiment, no tumors were produced
in males by the combined treatment. Thus, added
radiation may have hastened tumor growth but
did not increase the tumor incidence or lower the
threshold in males.
The surgical thyroidectomy experiments (Table
3) indicate conclusively the unessentiality of radia
tion. In the first series the animals which were op
erated upon received 5-9 juc. of I131(one or two
doses), to test the completeness of thyroidectomy.
459
In the second experiment, no I131was given. The
operations were not so successful in the second se
ries as in the first. Many mice had regenerated
thyroid tissue. Nevertheless, 15 per cent had mac
roscopic tumors, and 57 per cent had microscopic
tumors.
Thus, there is no evidence to support the sug
gestion of Gorbman that nonspecific stress is a ma
jor factor in induction of pituitary tumors by I13'.
This investigator did not assay the tropic features
of these tumors. The radiation-induced tumors
studied in two large series were generally adrenotropic or mammotropic, and without thyrotropic
activity. The ideas of Gorbman (1956) completely
ignore the specific features of pituitary tumors in
duced by different procedures. We failed to find
published data supporting the statement that
TABLE1
RELATION
OFQUANTITY
OFI"1 TOINDUCTION
OFPITUITARY
TUMORS
IN MICE
FEUALES
im(MC.)2550100-200Totalno*22343—562±640
Total
MALES
Tumors*
Total
no.
16
Groas
0
13
±
3
Tumors*
Total
Gross
0
(45 per cent)
( 5 per cent)
13
9
13
22
6
3
(57 per cent)
(39 per cent)
(59 per cent)
32
22
4Ü
2
34
4
(75 per cent)
(51 per cent)
(85 per cent)
—¿
= no tumor; ±= thyroidectomy changes.
FT* "Gross" indicates replacement of the pituitary with a macroscopically identifiable pituitary tumor. "Total"
microscopically detected tumors in enlarged pituitaries.
9
(41 per cent)
27
(67 per cent)
includes the
TABLE 2
THE EFFECTOFADDEDX-RADIATIONONTHYROTROPIC
TUMORINDUCTIONBYI111IN MICE*
FEMALESNo.
MALM
No.
ingroup17152121192:¡Per
in
centTotal94867686890tumorsGross18S3284847Per
Per cent tumors
centnegative614341411100
Per cent
No. in
Per cent
TREATMENT
I'«
30 MC.
"
"
X-ray
group
17
Total
94
Gross
18
negative
6
500 r totalf
500 r upperf
500 r low-erf
50 r total
group
6
9
2
negative
100
100
100
100
100
500 r total
* Survey 240—408days after thyroidectomy.
t Total-body,
upper and lower half (approximate)
irradiations,
respectively.
nitrogen mustard is a co-carcinogen in pituitary
tumorigenesis.
There is ample evidence indicating
INDUCTION
OFPITUITARY
TUMORS
BY
SURGICAL
THYROIDECTOMY*
that, in general, ionizing radiations arc powerful
co-carcinogens, and, conceivably, they alone can
150-299431011DATS300-3996141312400-409151410103Õ2
EM.
induce a tumorigenic change in every type of
No. in group
I
pituitary cell; but in the induction of thyrotropic
0 and ±
pituitary tumors by I131,they appear to play an
Microtumor
Gross tumor
insignificant role, if any at all.
The pituitary tumors found in gonadectomized
II
No. in group
0 and ±
mice,
to our knowledge, have not been adequately
Microtumor
assayed. They were not transplanted in series.
Gross tumor
* Simplified retabulation of data published earlier.
Changes in the original host, e.g., mammary gland
TABLE
3
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
460
Cancer Research
stimulation, do not prove the mammotropic char
acter of the tumor (witness the situation with
thyrotropes already cited). On theoretical grounds,
one can presume that these tumors are either
gonadotropic or mammotropic.
If lack of gonadal
hormone is sustained, the former is expected. If
compensating gonadal hormone secretion by the
adrenals goes on unchecked, the latter is expected.
The original observations
(with Upton) on
radiation-induced pituitary tumors were made in an
experiment on the late effects of an atomic explo
sion ("Operation Greenhouse"). The exposed mice
were LAFi hybrids, the irradiation high energy
gammas with some neutrons, and the exposure was
over the entire body. Of ten such radiation-in
duced tumors that were assayed, three were adrenotropic, six were mammo-somatotropic
as de
scribed, and one was atypical with predominantly
somatotropic effect (9).
In a current large-scale study on the pathogenesis of these tumors,2 pituitary tumors occurred
thus far only in the nonirradiated
parental L
strain and none in normal A and LAFi mice.
Whole-body x-radiation induced them in all three
strains. In LAFi mice, 500 r over the head (pitui
tary?) also induced pituitary tumors, but not 400750 r over the abdomen, including the adrenals.
Adrenalectomy
did not enhance the tumor induc
tion rate by whole-body irradiation. These findings
were contrary to expectations. Furthermore,
500 r
x-rays over the head appears to be as tumorigenic
as total-body irradiation by a similar dose.
Numerous tumors of the recent series are being
assayed, and the first four proved to be adrenotropic, as were those of "Operation Greenhouse"
series. All radiation-induced
tumors proved to be
autonomous but highly responsive. Growth of the
adrenotropes
is enhanced
by adrenalectomy;
growth of the mammotropes is enhanced by estro
gens and counteracted by androgens. The second
ary changes to adrenotropic tumors (marked obes
ity, thymic involution,
lymphopenia,
polyuria,
polydipsia, and extraordinary
sensitivity to infec
tions) are evident with the new strains. Main
tenance of these strains necessitates adrenalec
tomy or uninterrupted
administration
of anti
biotics. Adrenalectomy
promptly counteracts all
secondary changes and enhances tumor growth.
The main hormone secreted by the stimulated
adrenals has been identified by Hildegard Wilson
and associates (1) to be corticosterone, which is the
predominant
corticoid of the murine adrenal. In
animals receiving 1,250 r or more, there is, as a late
2J. Furth, R. F. Buffett, and E. L. Gadsden. On the Pathogenesis of Pituitary Tumor Induction by Ionizing Radiation
(in preparation).
effect, a marked atrophy of the pituitary gland
with secondary atrophy of its target organs. These
experiments urge caution in using irradiation for
depression of the pituitary.
Induction of thyrotropic tumors by total-body
ionizing radiation, like those developing following
thyroidectomy,
has thus far not been reported. We
described a primarily somatotropic
strain with
some thyrotropic
properties
(9). Recently, two
thyrotropic
tumor strains were isolated in our
laboratories. One occurred in a DBA mouse that
received whole-body 475 r, the other in a headirradiated LAFi mouse. Both had features of au
tonomous
thyrotropic
tumors indistinguishable
from those originating in radiothyroidectomized
mice, possessing, as the latter do, gonad-stimulating properties. Thyrotropic tumors can occur spon
taneously (Bielschowsky), and possibly these were
spontaneous cases. On the other hand, radiation
can enhance the likelihood of a neoplastic change
in every irradiated cell. The latter is well exempli
fied by ovarian tumorigenesis
by ionizing radia
tion. It has been possible to isolate from irradiated
ovaries tumors of every cell type of the ovary.
Since head (pituitary?)3 irradiation alone can in
duce pituitary tumors, it is possible that, with per
sistence and added specific stimuli, tumor strains
can be developed from every tropic cell type.
With respect to thyroid tumors, the evidence is
strong that low iodine intake or antithyroidal com
pounds are tumorigenic in almost every species,
including man, and that the sequence of events is :
decrease in TH, secondary increase in thyroidstimulating hormone (TSH), followed by stimula
tion of the thyroid. The latter is, at first, diffuse;
later, it is nodular. It is also certain that this
adenomatoid
hyperplasia has some tendency to
give rise to carcinomas. Consequently,
the idea
(Astwood) of using, in such cases, thyroid hor
mone for depression of TSH production is well
founded.
With respect to induction of thyroid neoplasms
by I131,the only reported observations are those of
Chaikoff, published in 1951. Numerous investiga
tors have since attempted to induce thyroid tu
mors by I1'1 but with no success. In a recent larger
series, Lindsay, Potter, and Chaikoff (14) found
that the incidence of spontaneous thyroid tumors
(alveolar carcinomas) in Long-Evans strain rats
that were given small doses of I131 (10 and 25 pc.)
was approximately
the same as that in control
rats. However, in addition to the alveolar carcino
mas, they found benign thyroid adenomas and
follicular and papillary carcinomas in rats that
*The question mark after pituitary hints at the unexplored
role of the hypothalamus in pituitary tumorigenesis.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
FuKTH—Hormonal Factors and Tumor Growth
461
had been given injections of 10-100 juc. I131.The ample of tumorigenesis based primarily on an al
incidence of all types of thyroid tumors was de tered responsiveness of the target organ.
pressed in rats that had received 200 and 400 ¿ic. Virtually every cell of the ovary can give rise to
of I131.
a neoplasm. Likewise, there can arise in a single
ovary, singly or in combination, granulosa-cell tu
With respect to the hazards in humans, patients
mors, luteomas, tubular adenomas, theca-like tu
with three diseases are being given conceivably
tumorigenic quantities of I131: hypertension,
mors, hemangio-endotheliomas,
and sarcomas.
exophthalmos, and thyroid carcinoma. In a survey While the Yale workers (Dr. Kirschbaum is one of
of thousands of cases at a recent conference at the them) concentrated on problems related to the
pathogenesis of ovarian tumors, we proceeded to
Argonne Cancer Hospital, no evidence was pre
sented suggesting that I131causes thyroid cancers study the character of the tumors induced in the
in man. The total-body ionizing irradiation inci
ovary by ionizing irradiation. It was noted that
dental to I131therapy is, however, within the leu- pure lines of functional granulosa-cell tumors were
kemogenic range, and several cases (about five or almost invariably associated with hypervolemia,
six) of leukemias have been reported in I131-treated the degree of which paralleled evidence of estrogen
patients. All were myeloid and occurred within a secretion. The luteomas, on the other hand, were
few years after treatment. In my evaluation, the associated with masculinization and profound
sum total of these reports strongly suggests that atrophy of the adrenal cortex. This raised the
these leukemias were induced by I131,but others question whether the lutein cell secretes one or
doubt this. Should it be necessary to give such several types of hormones including corticoids.
large doses of radioiodine to patients who do not Neutralization tests (with Kahn) suggested more
than a thousand-fold increase of ovarian hormonal
have bone marrow métastases,one should con
sider preserving in deep-freeze some of the pa
secretion by grafted autonomous and somewhat
tient's marrow before treatment and re-introduc
responsive induced ovarian tumors. Recent work
ing it into the same patient after treatment. It has on corticosteroidal tumorigenesis now clearly indi
been shown that the hazards of leukemia induction cates the role of progesterone in the pathway of
by irradiation are markedly diminished by bone adrenal cortical hormones and points to simple in
vitro studies to resolve this problem. It is desirable
marrow infusion.
With respect to experimental leukemogenesis by to study further pure lines of these hormonalI181, observations made with Burnett at Oak secreting ovarian tumors of various types, to iden
Ridge have shown that, when the thyroid is par
tify their secretions, and to test them in vitro for
tially destroyed, the total-body retention of I131is steroid hormonal genesis and responsiveness to
greatly enhanced. Consequently, I131,if given in gonadotropic hormones.
fractionated doses, will deliver a greater totalHow is ovarian tumorigenesis by gonadotropins
explained in cells which are not known to be horbody irradiation than if given in a single dose.
The development of thyroid tumors in children monally responsive? If excessive gonadotropins
who received therapeutic irradiation for large alone are the cause of these ovarian tumors, why
thymuses and lymph nodes several years after ir isn't there a cutback of gonadotropins by the
radiation has been reported (Simpson and Hempel- gonadal hormones secreted by these tumors? It
mann, see 8). There are no experiments on record can be supposed, therefore, that disorganization of
indicating that direct irradiation of the thyroid is the ovary by irradiation and altered responsive
carcinogenic to thyroidal epithelium. However, it ness of the irradiated ovarian cells are major fac
is probable that radiation will enhance the likeli tors in this tumorigenesis. The recent work of
hood of thyroidal tumorigenesis in people on diets Kullander (13) supports the view that pre-irradialow in iodine or containing antithyroidal com
tion of ovaries alters ovarian cells, increasing the
likelihood of their tumorigenic transformation,
pounds.
Experimental ovarian tumorigenesis in mice by while showing also the dependence on gonadotro
x-rays does not apply to rats and may not apply to pins of tumors in intrasplenic ovarian grafts in cas
man. When it was discovered in 1932 that most x- trated rats. He visualized these grafts by radiogra
phy and noted their regression following hypophyrayed mice will develop ovarian tumors, it was as
sumed for a first approximation, and in line with sectomy. This is a highly satisfactory technic
then current views, that irradiation altered ovari
for demonstrating the responsiveness of intra
an cells. Subsequent experiments, mainly by splenic ovarian grafts and is eminently suited to
Gardner et al. and by the Biskinds, pointed to hor
the determination of the exact time when these
monal imbalance with excessive gonadotropins as grafts acquire autonomy. Will ovarian tumors so
a major factor. Now we believe that this is an ex induced in irradiated ovaries acquire autonomy
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
462
Cancer Research
sooner than those arising in the nonirradiated
ovaries? Kullander (13) emphasizes that irradia
tion and transplantation
of the ovaries into the
spleen of castrate animals induces a tumor by a
mechanism which is similar to that which is re
sponsible for the development of spontaneous tu
mors. Spontaneous
tumors are likely to arise in
ovaries after they undergo atrophy, the latter
causing overproduction
of pituitary
gonadotropins. This appears to be not unique in the domain
of endocrine organs; e.g., liver tumors arise most
commonly in atrophie cirrhotic livers which are
the seat of secondary compensatory
hyperplasia.
The ovaries of thousands of women have been
irradiated, and few, if any, developed such tumors.
Since, in mice, abdominal exposure alone is con
ducive to ovarian tumor development and since
the practice of irradiating ovaries of women dates
back several decades, it can be presumed that the
high sensitivity of mice to ovarian tumor develop
ment is species characteristic.
A tremendous
amount of published work on
ovarian tumors is full of speculations and contra
dictions as to interrelationship
and function of
various cell types. Clearing up this confusion calls
for isolation of hormones secreted by different
cells, in vitro steroido-genesis by these cells, and
visualization
of transformation
of one cell type
into another under well controlled conditions.
Theoretically,
there are at least five types of
adrenocortical tumors: (a) estrogen-secreting,
(o)
androgen-secreting,
(c) glucocorticoid-secreting,
(d) mineral corticoid-secreting,
(e) nonsecreting,
and (/) mixtures of various types. Of these, the
existence of only the first two types is indicated by
the reviewer. The separateness of estrogen- and
androgen-secreting
types induced by gonadectomy
is suggested by the work of Woolley et al., but the
hormones of different cell types have not been
identified. The work of Paschkis is cited, showing
that these tumors can also secrete corticoids, but
the evidence is inadequate;
the assay on gluconeogenesis in tumor-bearing
animals was carried
out in animals with intact pituitaries and adrenals.
Transplantable
strains of adrenal tumors iso
lated recently in our laboratory (in the mouse and
the rat) are corticoid-secreting,
as indicated by
morphologic, hématologie, and urinary excretion
studies (7). The in vitro response to ACTH of these
cortical tumors was established by Cohen et al. (6).
Both tumors responded to as low ACTH levels
as 0.1-0.2 mU. Under ACTH stimulation, corti
costerone was the major steroid synthesized by
the normal mouse adrenal incubates (72 per cent
of total A4-3-ketosteroids),
and 11/3-hydroxy-A4androstene-3,17-dione
was present in small quan
tity. Mouse adrenal tumor slices incubated with
ACTH produced approximately
equal amounts
of these two steroids. However, 25-65 per cent
of total A4-3-ketosteroids consisted of compounds
with Chromatographie
behavior
suggestive
of
progesterone,
11/3-hydroxyprogesterone,
11-dehydrocorticosterone,
and A4-3-keto-20,21-dihydroxy
steroids.
Gonadal-secreting
adrenal
tumors
obtained
from Dr. Kirschbaum
neither secreted corticoids
nor responded to ACTH. This is the type of ex
perimentation which may shed light upon the con
fused subject of morphologic cell type of the adre
nal and functions, and gauge responsiveness and
function of a given adrenal tumor, thus yielding
information applicable to patients' care.
Transplantable
Leydig cell tumors studied exten
sively in our laboratory (4) were found to exhibit
some features in common with luteomas and corti
cal adenomas. They caused masculinization,
progestational effects with deciduoma formation in
females, adrenal atrophy and obesity in mice of
both sexes, and death from exsanguinating pleuropericardial hemorrhage,
predominantly
in adult
males. The urine of tumor hosts contained a 20to 40-fold increase in two 17-ketosteroids
(androstene and an unidentified
CigCh steroid). It is
most desirable to pursue research with these tu
mors in directions indicated above for adrenal
tumors.
Major directions of research.—It is difficult to
state which lines of investigation
suggested are
major and which are minor. The following three, at
least, have great potentialities :
1. Working out the optimal kind of treatment
on the basis of secretory capacity and responsive
ness of tumors in vitro or in vivo in a given patient.
2. Search for analogs to check excess of tropic
and other hormones causing or maintaining neo
plasms. In this endeavor, dependent or autono
mous tropic tumors can be used for screening; e.g.,
excessive quantities of TSH play an important
role in the genesis of thyroid tumors. Transplantable thyrotropic
tumors may be useful tools in
search for substances which inhibit thyrotropes.
Both fully dependent and autonomous but respon
sive tumors can be used for this purpose. Mere re
tardation of tumor size, i.e., mass of thyrotropes,
will indicate the inhibitory capacity of the sub
stance tested. Specificity can be checked with a
different tropic tumor. Thyroid weights of the ani
mals will reflect upon the quantity of hormone se
creted by thyrotropes.
Similar assays can be de
signed for the mammotropes,
aiming at control of
mammary tumors.
3. Attempts at prophylaxis of tumors caused by
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
FuRTH—Hormonal Factors and Tumor Growth
endocrines by study of the hormonal status preced
ing the onset of tumors, and correction of the
"signal" derangement.
Thus, there is a wealth of unexplored possibili
ties in the domain of endocrine neoplasia in ani
mals and of promise to yield information of theo
retical and practical value.
8.
9.
10.
REFERENCES'
1. BAHN,R. C.; WILSON,H.; ANDERSON,E.; and FURTH,J.
Physiological Effects of Prolonged Endogenous Stimula
tion of the Adrenal Cortex of the Female Mouse. Proc.
20th Internat. Physiol. Congress, 1956.
2. BATES,R. W.; CLIFTON,K. H.; and ANDERSON,E. Prolactin and Thyrotrophin Content of Functional Transplantable Pituitary Tumors. Proc. Soc. Exper. Biol. &
Med., 93:525-27, 1956.
3. BÃœNGELER,
W. Geschwülsteund regulierte abhängige
Wachstumsstörungen (Hyperplasien) im Rahmen der
Cellular- und Relations-pathologie. Ztschr. Krebsforsch.,
68:72-102, 1951.
4. CLIFTON,K. H.; BLOCH,E.; UPTON,A. C.; and FCRTH,J.
Transplantable Leydig-Cell Tumors in Mice. A.M.A.
Arch. Path., 62:354-«8,1956.
5. CLIFTON,K. H., and FURTH,J. Hormonal Influences on
Growth and Somatotropic Actions of Autonomous Mammotropes. Proc. Soc. Exper. Biol. & Med., 94:809-14,
1957.
6. COHEN,A. I.; BLOCH,E.; and CELOZZI,E. The in Vitro
Response of Functional Experimental Adrenal Tumors to
Corticotropin (ACTH). Proc. Soc. Exper. Biol. & Med.
(in press).
7. COHEN,A. I.; FURTH,J.; and BUFFETT,R. F. Histological
and Physiological Characteristics of Hormone-Secreting
4Supplementary to those of the Reviewers.
11.
12.
13.
14.
15.
16.
17.
463
Transplantable Adrenal Tumors in Mice and Rats. Am. J.
Pathol. (in press).
FUHTH,J. Radiation Neoplasia, pp. 27-41. Proc. 3d Nat.
Cancer Conf. Philadelphia: J. B. Lippincott Company,
1957.
FURTH,J., and CLIFTON,K. H. Experimental Pituitary
Tumors and the Role of Pituitary Hormones in Tumorigenesis of the Breast and Thyroid. Cancer (in press).
FURTH,J.; CLIFTON,K. H.; GADSDEN,E. L.; and BUFFETT,
R. F. Dependent and Autonomous Maimnotropic Pituitary
Tumors in Rats; Their Somatotropic Features. Cancer
Research, 16:608-16, 1956.
FURTH,J.; GADSDEN,E. L.; CLIFTON,K. H.; and ANDER
SON, E. Autonomous Mammotropic Pituitary Tumors in
Mice; Their Somatotropic Features and Responsiveness
to Estrogens. Cancer Research, 16:600-607, 1956.
HADFIELD,G. Recent Research in Physiology of the Breast
Applied to Mammary Cancer. Brit. M. J., 1:1507-10,
1956.
KULLANDER,
S. Studies on the Development and Hormone
Production of Ovarian Tissue Autotransplanted to the
Spleen of Spayed Rats with Special Reference to the
Experimental Production of Ovarian Tumours. Suppl., 27,
Acta Endocrinol., Vol. 22, 1956.
LINDSAY,S.; POTTER,G. D.; and CHAIKOFF,I. L. Thyroid
Neoplasms in the Rat: A Comparison of Naturally Occur
ring and Il31-induced Tumors. Cancer Research, 17:18389, 1957.
MÃœHLBOCK,
O. The Hormonal Genesis of Mammary Can
cer. In: Adv. Cancer Research, 4:371. New York: Aca
demic Press, Inc., 1956.
STEELMAN,S. L.; KELLT, T. L.; NORGELLO,H.; and
WEBER,G. F. Occurrence of Melanocj-te Stimulating Hor
mone (MSH) in a Transplantable Pituitary Tumor. Proc.
Soc. Exper. Biol. & Med., 92:392, 1956.
WEINHOUSE,S. A Critical Appraisal of the Biochemical
Characteristics of Morphologically Separable Cancers.
Cancer Research, 16:654-57,1956.
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
Discussion of Problems Related to Hormonal Factors in
Initiating and Maintaining Tumor Growth
Jacob Furth
Cancer Res 1957;17:454-463.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/17/5/454.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 18, 2017. © 1957 American Association for Cancer Research.