Problems in Experimental Tumorigenesis of the
Pituitary Gland, Gonads, Adrenal Cortices,
and Mammary Glands" A Review*
KELLY H.
CLIFTON
(Children's Cancer Research Foundation, Children's Medical Center, and Department of Pathology,
Harvard Medical School, Boston, Mass.)
The growth of interest in endocrine aspects of
oncogenesis and cancer control is reflected in reports originating from a number of recent special
conferences and has led to a massive literature. A
large portion of these publications is concerned
with studies of experimental tumor induction in
the endocrine glands and their target organs (23,
62, 67, 72, 98, 124, 129, 150, 195). Recently, interest has increased in the use of secretory tumors as
endogenous sources of high hormone titers or as
nomenclature will be used here (67, 71). Neoplasms t h a t will grow only in specifically modified
(conditioned) hosts will be spoken of as dependent.
These will not grow when grafted in normal histocompatible animals but, when grafted in conditioned hosts, invade locally, can metastasize, and
are eventually fatal. In contrast, tumors t h a t will
grow in untreated animals are termed autonomous.
These often develop from dependent neoplasms of
endocrine glands, may be highly secretory, and
TABLE 1
ABBREVIATIONS FOR PITUITARY CELLS, HORMONES, AND TUMORS
ABBREVIATIONS
Tumor
Hormone
Adrenotrope
adrenocorticotropin
At
AtT
AtH
Mammotrope
mammotropin
Mt
MtT
MtH
Thyrotrope
thyrotropin
Tt
TtT
TtH
Somatotrope
somatotropin
St
StT*
StH
Gonadotrope
gonadotropin
Gt
GtT*
GtHt
* Tumors of these cells have not yet been obtained.
t Factors with primarily follicle-stimulating activity are designated GtH/f; those
with primarily luteinizing or interstitial-cell stimulating activity, GtH/1.
CELL TYPE
HORMONE
sources for hormone purification. I t is not the purpose of the present paper to review this literature
exhaustively; it is, rather, to summarize information gained from studies of experimental tumorigenesis in the pituitary and some of its target organs and, where possible, to point out apparent
conflicts and areas for further investigation. The
interpretations presented were gleaned, in the
main, from the literature and from discussions
with colleagues.
Nomenclature.--Rapid development in this field
has led to confusion in the use of terms, particularly those borrowed from the clinician by the
experimentalist, and vice versa. The following
* This investigation was supported in part by grant #C~59
from the National Institutes of Health, Public Health Service.
Received for publication August 18, 1958.
Cell
often are responsive in t h a t they are stimulated by
specific physiologic factors.
Abbreviations.--The system outlined in Table 1
will be used to designate the various cells, hormones, and tumors of the pituitary gland (77, 82).
PITUITARY TUMORS
Adenomas of the anterior pituitary were first
experimentally induced in mice and rats by the
chronic administration of estrogen (35, 176, 244)
and in mice by ionizing irradiation (76, 227). Neonatal gonadectomy (41) and administration of 1181
(111) were later found to be effective in mice. I t
is now clear that each of these procedures typically
results in tumorous proliferation of different and
specific functional cell types. The problems are
now not concerned with pituitary tumorigenesis
per se, but with tumorigenesis of one or more of
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CLIFTON--Experimental Tumorigenesis of Several Glands: Review
these types of "tropic" cells. Inasmuch as results
with three functional types of tumors (adrenotropic, mammotropic, and thyrotropic) established in transplantation have been reviewed recently (77, 78), they are discussed briefly here. For
the older literature on estrogen-induced tumors,
see Gardner et al. (104).
Mammotropic tumors.--Tumorous growth of the
M t results from prolonged specific stimulation by
estrogen (31, 80). Mitotic activity in these cells,
which are acidophilic by standard histologic technics, is high during normal estrus, and this proliferative response is increased and maintained
during continuous administration of estrogen (31).
Susceptibility to induction of M t T varies with
strain (48, 105). Estrogen given in vivo or in vitro
increases oxygen consumption of pituitary tissue
(229), and tumor growth is preceded by specific
increases in f~-glucuronidase (177) and "pituitary
proteinase I I " activities (178). The exact role of
these enzymes in the cell economy is unknown,
but it is conceivable that they may be involved in
estrogen inactivation or ground substance formation and synthetic processes, respectively, and
thus in tumorigenesis.
Acidophilic granulation of primary and transplanted MtT is often sparse (31, 80), and they
have thus been described as chromophobic (85).
Primary tumors contain at least normal levels of
pigeon crop gland-stimulating activity and are
poor in or devoid of other hormones (179); transplanted M t T are a fair source of crop gland-stimulating factor (11).
MtT have also been isolated from LAF1 mice
17-28 months after exposure to ionizing irradiation from an atomic test detonation or 400-700 r
x-rays (82). Liability to tumor formation in the
F~ generation is inherited from the L parent (78,
74). Irradiation of the head (pituitary area) is effective, but irradiation of the body (target organs)
is not. Incidence is decreased by ovariectomy, indicating that both radiation-induced changes in
the cell and physiologic driving forces from the
ovaries are involved (72).
M t T from all sources in both rats and mice have
similar characteristics, with one exception: estrogen-induced M t T in rats are initially dependent,
growing when grafted only in estrogenized hosts;
spontaneous M t T of both rats and mice and radiation-induced M t T of mice are autonomous, with
varying degrees of respo~nsiveness from the outset
(80, 82). Dependent M t T give rise, in the first subpassages, to autonomous responsive variants that
grow and secrete in proportion to the levels of estrogen. Threshold for stimulating effect is about
10/~g. diethylstilbestrol (DES) administered in a
single pellet (30). Growth is greatly accelerated by
1.0 rag. DES (80) but inhibited by 10 nag. I In contrast, primary M t T are obtained more quickly at
the higher dosage, indicating a fundamental difference in sensitivity between the autonomous
cells and dependent cells from which they arise. 1
All M t T cause hyperplasia of all elements of the
mammary glands with milk secretion, body
growth, and disproportionate increase in weight of
viscera (80, 82). In rats, enlargement of the liver
and adrenal cortex is coupled with fatty degenerative changes but not hypercorticoidism, and enlargement of the kidney with a puzzling nephrosis.
These effects are not dependent on gonadal or
other hypophyseal hormones, since they also
occur in gonadectomized rats of either sex and in
hypophysectomized rats (80).
Although the hormonal effects of different
strains of M t T are qualitatively similar, they may
differ quantitatively. For example, one strain of
estrogen-induced M t T in the rat was fully dependent; established grafts regressed after cessation of
estrogen treatment, ttosts of this strain, however,
showed but slight mammary stimulation or growth
effects. Another strain of M t T of similar source
and genetic constitution is now highly autonomous, yet hosts of this strain uniformly show evidence of high secretory activity. 1
The relation of M t and M t t I to mammary
tumorigenesis is discussed in a later section.
Thyrotropic tumors.--Tumorous hyperplasia of
the T t occurs after radiothyroidectomy in all
strains of mice thus far examined (69, 111). Induction is apparently due to prolonged thyroid hormone (TH) deficiency in that T t T also occur after
surgical thyroidectomy (88, 39), and the tumors
that arise in rats (6) or mice (187) treated with
goitrogens are probably of similar nature. T t T are
prevented by TIt administration (89, 112). They
occur rarely in LAF1 mice irradiated with x-rays,
and in about the same percentage in unirradiated
controls (74).
Although T t T arise from the aldehyde fuchsinpositive beta basophils (121), chromophilic granules are very few in number or absent in the cytoplasm of both primary and grafted Tt. Like MtT,
T t T are initially dependent, growing on transplantation only in TH-deficient hosts (75). Autonomous variants may arise after a few or several
serial passages, and these may respond to T I t
deficiency or, rarely, are reversely responsive, i.e.,
grow better in intact hosts (81).
Circulating T t t t levels in mice with dependent
T t T may reach 1000-2000 times that in normal
blood serum (10). TtT of three dependent strains
1K. H. Clifton and J. Furth, unpublished data.
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contained 0.01-0.17 U.S.P. units T t H / m g of lyophilized tissue, as compared with 0.1-0.~ units/
mg normal mouse pituitary powder (10).
Autonomous T t T cause massive thyroid hyperplasia with formation of dependent thyroid adenomas (77). The increased T H levels cause body
growth and splanchnomegaly (8~). In thyroidectomized female mice with highly functional TtT
there is ovarian hypertrophy with follicular development, uterine hyperplasia, and mammary
growth, the latter probably mediated through the
M t (68, 77). Some hosts in early passages display
a puzzling hyperplasia and cyst formation of the
common bile duct (88).
In recent experiments, Reynolds 2 measured the
oxygen consumption and lactate formation of
slices of several strains of autonomous T t T possessing decreasing degrees of responsiveness. Highly responsive tumors showed near normal values,
i.e., high oxygen consumption with little accumulation of lactate. With progressive loss of responsiveness, oxygen consumption decreased, and lactate formation increased. Pretreatment of highly
autonomous tumors with large doses of thyroid
hormone in vivo brought a shift in these parameters to near the normal range. These results suggest at least partial correction of a biochemical
deficiency in tumor cells by hormone therapy.
Adrenotropic tumors.--AtT were the first type
of pituitary neoplasms to appear in irradiated mice
(84). All were autonomous in the first transplant
generation, and only slightly responsive to adrenalectomy. The histogenesis of these tumors is
unknown; they are "chromophobic" by the usual
staining methods.
All the physiologic effects of AtT thus far described are attributable to the consequent hypercorticoidism and can be blocked by adrenalectomy. These include lymphopenia, "thymolysis,"
eosinopenia, polyuria and hypernatremia, obesity,
and sensitivity to infection (7) and to acceptance
of heterografts (1~). Fat synthesis proceeds at
the expense of other processes in intact hosts even
when fasting (175). High levels of corticosterone
have been identified in the blood, and l lfi-hydroxy-A4-androstene-3,17-dione and llfi-hydroxyandrostane-3,17-dione in the urine of AtT-bearing
mice (~3~). AtH levels in sucrose homogenates of
tumor tissue, determined by an in vitro assay,
varied from 4 to 55 milliunits/mg; normal mouse
pituitary tissue contained ~4-~7 milliunits/mg
(33). These figures for ArT tissue are higher than
those obtained in an in vivo assay by Steelman et
al. with older tumor strains (~3). The latter
authors also found high levels of melanocyte2v. H. Reynolds and J. Furth, personal communication.
Vol. 19, J a n u a r y , 1959
stimulating activity in AtT (223). About 85 per
cent of the AtIt activity of tumor homogenates
was recovered in the particulate fraction sedimenting between s
and 1~,000 X g (33).
Somato-thyrotropic tumor.--A tumor strain, initially described as somato-thyrotropic, was isolated from an atomic blast-irradiated LAF1 mouse
(70, 78). In intact hosts, this tumor strain, which
is chromophobic, induces marked body growth
with splanchnomegaly, thyroid hypertrophy, and,
in females, growth of the breast. The latter two
effects are not as marked as in mice bearing T t T
or MtT, respectively. There is no hyperglycemia.
It has not yet been determined whether tumors of
this strain secrete a growth-promoting hormone
distinct from M t H or TtH.
Induction by gonadectomy.--Neonatal gonadectomy results in formation of tumors in the anterior
pituitary as well as the adrenal cortex and the
mammary glands of mice of the Ce strain and its
hybrids, and in other strains often results in pituitary abnormalities (40, 41). Although tumorigenesis in these three organs is interrelated, pituitary
tumors may appear before or after adrenal tumors,
depending on the strain (40).
The gonadectomy-induced pituitary tumors
have been described as "basophilic" and are postulated to be secretory neoplasms of the Gt (41).
It has also been suggested, however, that such
tumors might be M t T secondary to adrenal hypersecretion of estrogen (80). The mammary glands
of gonadectomized mice with primary pituitary
tumors are overdeveloped (see below). Secretory
effects of gx~afts of these tumors have not yet, however, been reported.
Pituitary tumors of other types.--Spontaneous
pituitary tumors are common in old rats of many
strains, occurring in 50 per cent of males and 13
per cent of females of the Yale strain by 400-600
days of age (~07). Reported attempts at transplantation have been few and the results poor,
probably because of genetically heterogeneous
recipients. Two tumors from Yale strain animals
grew in intra-ocular grafts in rats of the same
strain, and one of these also grew on passage to
rats of another strain (~07). Age of host was not
an important factor, and secretory function was
not established.
Bielschowsky reported a spontaneous mammotropic tumor in an aged gonadectomized female
rat (14) and eight probably thyrotropic tumors
in aged rats maintained on an iodine-deficient diet
(13). Four of the latter animals also had thyroid
adenomas. None of these pituitary tumors was
transplanted.
Recently, four transplantable lines of spontane-
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CLIFToN--Experimental Tumorigenesis of Several Glands: Review
ous tumors from aged female rats of an inbred Wistar (W) strain and one from the Fischer (F) strain
have been successfully established, x All appear to
be MtT, having both mammotropic and growthpromoting effects. All spontaneous pituitary tumors of the L strain of mice thus far grafted have
also been M t T (73, 74).
In female rats of the Buffalo strain fed a diet
containing 3,4-dimethylaniline, o-hydroxyacetanilide, or p-fluoracetanilide, incidence of pituitary
tumors was increased from 10-15 per cent to 5060 per cent by 19.5 months of age (188). The functional nature of these tumors was not established.
Anterior pituitary neoplasms are the most common tumor of the parakeet (Melapsittaeus undulatus), occurring in equal incidence in both sexes
(~08). Syndrome of these primary tumors includes
bilateral exophthalamos, blindness, somnolence,
polyuria, polydipsia, and obesity. These is no
adrenal or gonadal hyperplasia.
Three of ten tumors grew on being grafted in
other birds (~09). All were locally invasive but not
metastasizing and caused obesity with fatty degeneration of the liver and hyperglycemia. Tibial
line assays indicated the equivalent of 1 mg
growth hormone/~50 nag of tumor, but assays for
lactogenic hormone and AtH were negative. Plasma
of birds with primary or transplanted tumors contained a new "paraprotein" with distinct mobility
characteristics on ultracentrifugation or electrophoresis (~81). It would be of interest to know
whether this is hormone or tumor protein.
Estrogen treatment of the golden hamster results
in tumorous hyperplasia of the pars intermedia,
with invasion of both the pars distalis and infundibulum (see 1~8). The process terminates in degeneration of the tumor cells. No hormonal function has been attributed to these tumors, but it
has been suggested that inhibitory effects of estrogen on melanoma induction may be mediated
through the pars intermedia (1~8).
Problems.--The possible role of the central
nervous system in induction and growth of anterior pituitary tumors has not been clarified. I-Iypothalamic control of some pituitary functions is
well established. Some hypothalamic lesions selectively suppress release of Aft-I, TttI, or GtH,
whereas others induce constant estrus (see 43,
119). Extracts or cultures of hypothalamus cause
AtIt but not TtI-I release by pituitary tissue in
vitro (57, 1~0). If the circulatory connection of the
pituitary gland with the hypothalamus is severed
by transection of the infundibular stalk or transplantation of the pituitary to a distant site, the
gonads, thyroid, and adrenal cortices atrophy to
hypophysectomy levels, and reproductive cycles
cease (119). Pituitary grafts, however, retain the
ability to release some AtI-I in response to stressors
involving tissue damage, but not those mediated
by the central nervous system (59). TtI-I is released from pituitary grafts in sufficient quantity
to maintain normal thyroid-iodide to serum-iodide
ratios, but is not of sufficient quantity or, perhaps,
quality to support goiterous growth in response
to propylthiouracil (119). Basophils decrease in
pituitary grafts beneath the kidney capsule, but
acidophils persist and are reported to continue
release of luteotropin (53, 194).
Direct circulatory connection with the hypothalamus is unnecessary for the stimulatory action
of estrogen on Mr. Preliminary experiments indicate that proliferation of these cells occurs in
grafts of normal pituitary tissue in estrogen-treated animals,' as it does in grafted M t T in the thigh.
Similarly, TtT and AfT grafted in the thigh are
inhibited by T H and adrenal hormones, respectively. If these actions are mediated by neurohumors, the latter must reach the peripheral circulation in levels adequate to bring about marked
physiologic effects, which seems unlikely.
Events leading to induction of AfT are obscure.
Attempts at induction by uncompensated adrenalectomy have thus far failed, as have attempts
to induce GtT by gonadectomy or combined gonadectomy and adrenalectomy of young adult
LAF1 mice) This failure could be due to lack of
a really "steroid-free" diet or to endogenous extraadrenal and gonadal sources of steroid hormones,
as suggested by low steroid hormone metabolite
levels in the urine of such animals. It may also
result from hypothalamic factors or a fundamentally higher resistance to tumor formation in these
cell types. Of interest in this connection is the difference in response of Tt of rats and mice to radiothyroidectomy. In mice, TtT are almost inevitable
following thyroid-destroying doses of I TM. In rats,
T t T have not been induced by this means. Rational experimental design for induction of neoplasms
of the St (if they, in fact, exist as separate entities)
awaits further knowledge of their physiologic
control.
On the basis of "enhancement" of tumor induction by additional radiation after radio-thyroidectomy (11~, 114), Gorbman postulated that
"stress" plays an essential role in pituitary tumorigenesis (113). This postulate does not consider the
specificity of T t T formation in response to TIT
deficiency induced by means other than I TM,or the
fact that radiation alone induces predominantly
M t T and AfT (71).
Growth promotion by M t T and the gonadoaj. Furth, personal communication.
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tropic and common duct effects of TtT may be
inherent actions of M t H and T t H or their precursors. Overlap in physiologic effects of pituitary
hormones has been clearly demonstrated with AtH
and the melanocyte-stimulating factor (5), and
purified prolactin 4 and growth hormone preparations have shown markedly similar effects on the
mammary glands and body growth of hypophyseetomized rats in this laboratory. 1 All the actions of
pituitary hormones may not be readily detected
when purified heterospecific preparations are used
because of difficulty in maintaining high hormone
titers by injection and because of species differences in hormone structure (as has been indicated
with growth hormone [152, 153]). An alternative
possibility is that some pituitary cell types normally have a dual hormonal function but can give
rise to neoplastic cells in which one function is
specifically accentuated. If this is indeed the case,
release of the "second" hormone also occurs when
the neoplastic cell is highly stimulated to release
its principle secretory product. Chemical studies
of the hormones of these cells are needed.
Knowledge of induction mechanisms of tumors
that follow gonadectomy of mice soon after birth,
estrogen treatment in hamsters, or those that occur spontaneously in parakeets awaits further information. It is clear that criteria for the recognition of pituitary cells based on the degree of chromophilic granulation are inadequate. Wolfe (233)
and others have pointed out that highly functional
pituitary cells need not have histologically obvious
cytoplasmic granulation. Further development of
specific histochemical methods, coupled with physiologic studies, such as those of Barnett et al. (9),
is desirable.
OVARIAN TUMORS
Spontaneous ovarian tumors are rare, but such
tumors do occur in high incidence in female mice
receiving total-body ionizing radiation. Tumors
similar in many respects may be experimentally
induced in several species by transplantation of
ovarian tissue to sites drained by the hepatic portal system. Both may retain secretory function.
Induction by irradiation.--Ovarian tumors induced in mice by ionizing radiation (76, 227) include tubular adenomas, granulosa-cell tumors,
luteomas, sarcomas, and angiomas and endotheliomas (8). The granulosa cells that form tumors are
postulated to originate from tubular downgrowths
4 The term "prolactin" is used here to designate the purified
preparations from pituitary tissue that stimulate the crop
gland of pigeons and induce milk secretion in developed
mammary glands. For the native product(s) of the Mt, "mammotropin" (MtH) is used.
Vol. 19, J a n u a r y , 1959
of the germinal epithelium, and luteomas in turn
from the granulosa cells (8) or directly from germinal epithelium (161). Some investigators, however, consider stromal cells to be the source of
most ovarian neoplasms (see 198).
GttI is elevated in irradiated mice (~28) and
seems essential for tumorigenesis. Chronic administration of estrogen, which inhibits GtH release
and prevents tumors (97), and chronic treatment
with rabbit serum anti-Gttt inhibit pretumorous
changes (52). Androgen, which less effectively inhibits G t t t release, did not prevent tumors at
doses used (97). Injection of heterospecific GttI
does not, however, alter the incidence or time of
appearance of tumors (102).
Direct irradiation of the ovaries with shielding
of the body is effective (164), and tumorigenesis
may occur in response to "normal" GtH levels
when irradiated ovaries are grafted in male mice
(151). If one ovary is irradiated while the other is
shielded (164), or if irradiated ovaries are transplanted to normal females, tumors do not occur
(147). Explanation of this sex difference probably
lies in the difference in secretory pattern between
male and female pituitaries. Intrasplenic grafts of
ovaries in gonadectomized males are follicular,
with no corpora lutea; in unilaterally ovariectomized females, corpora lutea are common (162).
Higher titers of estrogen are required in males
than in females to prevent hypersecretion of GtH
following gonadectomy (1~5).
Induction by grafting.--Grafting ovaries to sites
drained by the hepatic portal system (spleen, pancreas) induces tumors in rats (19) and in several
other species. Transplantation is followed by
marked stimulation and progressive depletion of
follicles, formation of corpora lutea, and luteinization of the interstitium. In female rats, lutein
bodies predominate during the first several
months, giving rise to luteomas in some (19).
Small granulosa-cell tumors are present by 6
months, however, and lutein cells are progressively
replaced (18, 54). In mice, changes are more variable, leading to development of several types of
tumors, including granulosa-ceU tumors, luteomas,
tubular adenomas, thecomas, and papillary cystadenomas (188).
The probable mechanism of tumor induction is
the demonstrated chronic hypersecretion of GtH
(1, 184) secondary to hepatic inactivation of estrogen (19, 16~). Tumorigenesis occurs in grafts in
gonadectomized mice of either sex in all strains
tested, but not in unilaterally gonadectomized or
intact male or female hosts (16~). Inhibition of the
hypersecretion of GtH by adhesions, which allow
ovarian hormones to by-pass the liver (19), or
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CLIFToN--Experimental Tumorigenesis of Several Glands: Review
chronic administration of estrogen or androgen
prevents tumor formation (162), and anti-GtI-I
inhibits early tumorigenic changes (51). Treatment with exogenous GtH/1 (17, 162) or concurrent grafts of pituitary tissue (215) moderately
shortens the tumor induction period in mice and
tends to increase the incidence of luteomas. Administration of progesterone to grafted mice does
not prevent tumors (162) but reduces luteoma formation in guinea pigs (140). Irradiation of ovarian
tissue in vitro before grafting does not affect incidence or time of appearance (168). Reduced food
intake or treatment with desiccated thyroid reduces tumor incidence (188). ttypophysectomy
prevents tumorigenesis in spleen-grafted ovaries
in rats, although established granulosa-cell tumors
persist (155).
No tumors were found in unilaterally gonadectomized rats with intrasplenic ovarian grafts that
were in parabiosis with gonadectomized partners
(155). Under such circumstances, GtH titers acting on the grafts were presumed to be nearly as
high as those in completely gonadectomized,
spleen-grafted animals, and a direct inhibitory
action of ovarian hormones from the organ in situ
on the grafted tissue was suggested.
Damage during transplantation may play a role
in ovarian tumor induction (10~). Ovaries implanted subcutaneously in one member of a parabiotic pair of neonatally castrated male rats gave
rise to granulosa-cell tumors, with evidence of androgen production (148). The same incidence of
tumors was observed in ovaries grafted from bursae of DBA mice to bursae of DBA X CSH hybrids, as from bursae to spleens of similar animals
(186). Tumors have also been found in ovaries
transplanted to the testes of untreated male mice
(102). Common to these three experimental situations are any damage to ovarian tissue that occurs
during grafting and probable disruption of the
ovary-Gt feed-back mechanism. Quantitative
assay of levels and kinds of GtI-I in all these situations would be informative.
The predominant type of tumor obtained in
ovarian grafts drained by the hepatic portal system varies with the species and sex of the host.
Luteomas are most frequent in guinea pigs (140),
though granulosa-cell tumors occur if sufficient
time is allowed to elapse (172). Granulosa tumors
are most common in rats (19, 155) and rabbits
(201). Mixed tumors are common in mice, although granulosa cells tend to predominate in
male hosts and lutein cells in females (16~).
Transplantati~
tumors, induced by
either means, are transplantable. Radiation-induced tumors are autonomous but often respon-
sive to gonadectomy (66). Spleen graft-induced
tumors of mice transplanted during the first 9
months were dependent, growing only in grafts
drained by the portal circulation, but gave rise to
autonomous variants (87). Autonomous transformation occurred in the majority of tumors in primary host mice when spleen grafts remained in
place a year or more before further transplantation (118). M:onomorphous tumor lines may be
isolated from mixed tumors in mice by selective
transplantation and, once established, retain their
specific identity (8, 86). Effects of sex of host and
of exogenous hormones differ with tumor type and
strain. Granulosa-cell tumors of mice (8, 102, 190)
and rats (141) grow faster in intact males than
females, and luteomas of mice faster in females
(8, 190). Tubular adenomas grow fastest in gonadectomized males and endotheliomas in gonadectomized hosts of either sex (8). Growth of
some granulosa-cell tumors in both mice and rats
is reported to be stimulated by exogenous androgens, natural or synthetic estrogens in high dosage, and progestins (28, 141,190). Deoxycorticosterone stimulated growth of granulosa tumors in
mice (190), but both cortisone and deoxycorticosterone were ineffective in rats (141). Estrone
stimulated a luteoma of mice when given a t low
doses and inhibited it at higher doses (190).
Grafts of an estrogen-secreting spontaneous carcinoma were also inhibited by estrogen (102).
Exogenous GtI-I has, in general, been ineffective in
influencing growth of ovarian tumor grafts (102,
117), but hypophysectomy may reduce it (190).
Secretory activity.--The estrogen secreted by
intrasplenic grafts is almost completely inactivated in the liver until tumors are large (99). There
is evidence, however, that progestins reach the
general circulation during the induction period
(154). Pieces of vagina (154) and uterus (109)
grafted in the spleens of animals with ovarian
transplants show evidence of high ovarian hormone titers, the latter even when placed at the
end of the spleen distant from the grafted ovary.
Secondary changes in mice bearing grafts of
autonomous functional granulosa-cell tumors
usually include uterine hypertrophy, vaginal cornification, atrophy of testes and sex accessory
glands of males, and feminization of kidneys and
submaxillary glands, suggesting estrogen release
(66, 190), and estrone and estradiol have been isolated from one such tumor (190). Progesterone
(102) and androgen (148) may also be released.
An unusual effect of some highly functional granulosa tumor strains is a profound hypervolemia,
apparently due to a secretion distinct from the
feminizing hormones (85, 190).
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Functional luteomas induce vaginal mucification and uterine hypertrophy (indications of progestin release) (86), but often have androgenic
effects, cause profound adrenocortical atrophy
(86), and may secrete estrogen (190). An additional action, perhaps related to androgenic effects, is
polycythemia (115). Secretory function has not
been detected in tumors of other ovarian cell
types.
Problems.--The ability to secrete estrogen has
been attributed to the stratum granulosum, the
theca interna, the interstitial cells, and the corpus
luteum; ability to secrete progesterone primarily
to the corpus luteum; and androgen principally to
the interstitial cells of the normal ovary (~6). Interstitial cells are thought to be related to thecal
elements and the corpus luteum formed in ovulated follicles to cells of the stratum granulosum, the
latter arising from germinal epithelium. Lutein
bodies arising from thecal cells develop in anovulatory follicles (~6). It is of interest to note that, as
progesterone is a probable intermediate in biosynthesis of both androgens and estrogens (4~), origin
of progesterone-secreting from estrogen- or androgen-secreting cells could occur by differential loss
or inhibition of specific enzymes and would not
represent acquisition of new enzyme systems. As
noted above, luteomas in mice are postulated to
arise from granulosa cells, but granulosa-cell tumors have not been observed to transform into
luteomas, and in rats and guinea pigs occur in
intrasplenic grafts after luteomas are found. The
pathway taken by a given granulosa cell is apparently established early in the neoplastic process,
the cells ultimately giving rise to granulosa-cell
tumors differing from the cells that give rise to
luteomas.
Gardner (99) recorded five patterns of growth
of intrasplenic grafts in mice differing in rate and
in the number and duration of plateaus in growth,
but could establish no correlation with the type of
tumor ultimately obtained. Analysis of such results is difficult in that any change in the peripheral levels of sex hormones (due to hypersecretion
by the graft or the adrenal cortex, or to adhesions)
would affect the pattern of pituitary hormones
released and these, in turn, the nature and rate of
growth of the various ovarian cells. Variability
may be further increased by the direct effect (as
yet poorly understood) of hormones from one
ovarian cell type on another.
Nature of the damage incurred during transplantation that predisposes to tumorigenesis deserves further attention, as does the failure to induce ovarian tumors by irradiation in species other
than the mouse.
Vo]. 19, J a n u a r y , 1959
Knowledge of the nature and of loss or gain in
the synthetic capacity of tumor cells is of value in
understanding changes during neoplasia. Conclusions concerning the secretory products of ovarian
tumors are based primarily on biologic criteria.
Hormonal basis of the hypervolemia in granulosa
tumor hosts and polycythemia in luteoma hosts is
unknown.
Adrenocortical atrophy in luteoma hosts could
be due either to progestins in high levels, or to
production of corticosterone-like compounds of the
type produced primarily by the adrenal cortices.
The steroids directly responsible for masculinization by luteomas are unknown, and the possibility
of secretion of relaxin by any of these tumor types
has not been considered.
TESTICULAR TUMORS
Spontaneous tumors of the Leydig cells are rare
in mice but are readily induced by prolonged administration of estrogen (~5). In rats, such tumors
are also obtained by grafting infantile testes into
the spleens of gonadectomized adults (s ~ 6 ) .
Sertoli-cell tumors have not been induced experimentally, but spontaneous tumors have been
studied in dogs (133). Earlier literature on induction, types, and incidence of testicular tumors
occurring in several species is well reviewed elsewhere (56, 104).
Induction by estrogen.--Burrows noted hyperplasia of the Leydig cells in an estrogen-treated
mouse (~7), and tumor induction was later described in mice of the A strain (~5, 1~6). Susceptibility is strain-limited, and resides in the testicular tissue (101). With estrogen in high dosage, the
testes are drawn into the body cavity, and there
is cessation of spermatogenesis. Hypertrophy, degranulation, and degeneration of Leydig cells ensue, and macrophages appear in the interstitium.
Leydig cells reappear later and form nodular
growths that are locally invasive and may metastasize. The cells that develop directly into tumors
induced by this means thus represent a generation
distinct from those forming the population at
start of treatment (1~6). Induction period is
lengthened by concurrent testosterone treatment
(1~6).
Constant treatment with estrogen is not essential, and effects of estrogen treatment persist for
several months after its withdrawal. Treatment of
BALB/c males with pellets containing DES was
suspended before tumors were apparent, after 1-7
months of administration. :Five to 9 months later,
treatment was reinstituted, and 50 per cent of
mice developed tumors within 4 months (4). Controls, without pretreatment, developed 7 per cent
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CLiFToN--Experimental Tumorigenesis of Several Glands: Review
tumors in 4 months. When pellets were removed
after testes were tumorous (measuring 10-12
ram.), about 50 per cent regressed to normal size.
The rest continued to grow (4). Bilateral tumors
reacted independently, and some tumors recurred
spontaneously. When treatment was reinstituted,
most regressed tumors recurred within a month.
I t has been suggested that tumorigenesis is
mediated by estrogen-induced release of interstitial-cell stimulating hormone (GtH/1) (96, 126).
Chronic administration of anti-GtH to estrogenized animals prevents pretumorous changes (50).
Leydig-cell hypertrophy follows injection of exogenous G t H / l in mice (202) and monkeys (217).
With prolonged treatment, however, the changes
in mice regress, and no tumors are obtained (202).
Recent experimental evidence indicates that the
cryptorchid environment plays an important role
in Leydig-cell tumor induction. Mice made surgically cryptorchid and receiving mild (nonsterilizing) doses of estrogen in food or from grafted
ovaries developed 77-8~ per cent gross tumors
(137). In animals which had not been operated on
and which received the same dose of estrogen,
gross tumors occurred in 33 per cent; in untreated
cryptorchid animals, incidence of tumors was 44
per cent, but these were microscopic. Under these
circumstances, tumors arise directly from Leydig
cells initially present.
Pretreatment of the donor with G t H / l or GtH/1
and estrogen did not enhance tumorigenesis in
testes subsequently grafted in estrogen-treated,
castrated males (137).
Induction by grafting.--Grafting of infantile
testes to the spleens of castrated adult rats of
either sex resulted in high incidence of tumors (20,
226). Of 29 such tumors, sixteen were pure Leydig
cells, and the rest were teratomas or mixed (226).
Similar grafts in intact males showed slight hyperplasia or no change. Autografting of adult testes
to spleens of bilaterally gonadectomized hosts was
also effective and yielded pure Leydig-cell tumors
(145).
Tumorous growth is postulated to result from
hyperstimulation by increased G t H levels consequent to hepatic inactivation of gonadal hormones, as in similar ovarian grafts (226). As previously noted, however, the eryptorehid state itself
is tumorigenic. Furthermore, there may be interaction between testicular cell types. Prolonged injection of an extract of infantile testes into intact
male rats bearing intrasplenic grafts of infantile
testieular tissue is reported to cause Leydig-eell
hyperplasia in the grafts (2~4). Hyperplasia did
not occur in grafts in untreated intact males. The
authors postulate a tissue-specific growth-stimu-
lator in the extracts of infantile testicular tissue
(~4).
Transplantation.--Leydig-eell tumors induced
by continuous estrogenization are consistently dependent in the first transplant generation, growing
only in estrogen-treated animals or occasionally in
untreated females (4, 95, 101, 1~6). ~Iowever,
eight of ten primary tumors t h a t developed in
BALB/c mice 1-1~ months after estrogen treatment was discontinued were autonomous in the
initial grafts (4). Dependent tumor cells remained
dormant when grafted in untreated hosts for as
long as s days, growing as rapidly as fresh transplants when estrogen treatment was initiated (95).
Grafted tumors persisted up to 188 days after estrogen treatment ceased and did not regress in
estrogen-treated hosts surviving up to 28 days
after hypophysectomy (95).
Reverse responsiveness was noted in an estrogen-induced Leydig tumor in the 25th-38th transplant generations. The tumor grew equally well in
intact males or gonadeetomized hosts of either sex,
but was retarded in intact females or by injection
of estrogen (146).
The effects of several types of hosts on the
growth of seven estrogen-induced Leydig-cell tumors during the 2d-15th generation of grafts were
recently reported by Huseby (137). All but one
grew as well or better in estrogenized hosts, as in
others. One was completely estrogen-dependent.
One gained increasing responsiveness to the environment of the intact female over the course of
passages, finally growing best in such animals.
Two grew as well in untreated gonadectomized
hosts of either sex as in estrogenized hosts, and
better than in untreated intact animals.
An apparently direct action of estrogen was
noted when bits of responsive tumor were grafted
intrasplenically next to estrogen pellets (157). No
growth was noted when pellets were of pure cholesterol. Exogenous G t H / 1 in general inhibited tumor growth in castrated males, and enhanced it
slightly in estrogen-treated intact males but not
in estrogen-treated female hosts. The growth-promoting effect of G t H / I in intact estrogenized
males is postulated to be mediated by testicular
hormones (137). (The tumors studied by Huseby
[157] were, in the main, autonomous but responsive according to the definitions used here.)
Injection of GtH/1 into mice bearing grafts of
a "primitive" Leydig-cell tumor of spontaneous
origin caused cell maturation and increased secretion, but did not accelerate growth (127).
Better growth was initially obtained in male
than in female mice with grafts of a spontaneous
Leydig-cell tumor and of a similar tumor originat-
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Cancer Research
ing in an irradiated mouse (29). Responsiveness of
the spontaneous tumor was lost by the second subpassage generation. Another spontaneous Leydigcell tumor was unaffected by the sex of the host
(29). Whether Leydig-cell tumors induced in rats
in intrasplenic grafts are dependent or autonomous on further grafting is unknown. One of ten
such tumors grew when transplanted to the spleens
of other adult castrates, but apparently was not
grafted subcutaneously or in intact controls (226).
Secretion.--Mice bearing primary estrogen-induced testicular tumors usually show evidence of
high androgen levels (101, 126). Secretory ability
persists in grafts of many estrogen-induced and
spontaneous tumors. Grafts of a spontaneous Leydig-cell tumor in the R F strain of mice induced
masculinization of castrated males, profound adrenoccrtical atrophy, and deciduoma formation in
females without uterine trauma (29). There was a
high incidence of death in both sexes from exsanguinating pleuropericardial hemorrhage, a disease
that occurs spontaneously in low incidence in old
males of this strain. Analysis of steroid metabolites
in urine of tumor hosts revealed a 28 X increase in
excretion of androsterone, as compared with normal, and a 50 X increase in excretion of an uncharacterized 17-ketosteroid (29).
Exogenous GtH/1 increased secretion of androgen by grafts of a spontaneous Leydig-cell tumor
(127) and several estrogen-induced tumors (137).
Estrogen production by the male gonad is well
established--the stallion testis is the richest natural source (45)--but the cell type that normally
secretes testicular estrogen is uncertain. Evidence
of both estrogen and progesterone secretion occurs
in mice bearing some estrogen-induced Leydig cell
tumors (101, 137), and high levels of estrogen were
found in the urine of a male dog bearing a metastasizing tumor of these cells (160). The intratubular Sertoli cell is, however, most generally considered the primary source of testicular estrogens,
and spontaneous tumors of these cells in dogs
secrete high levels of estrogen (183).
Data from studies of enzyme systems involved
in biosynthesis of steroids by estrogen-induced
Leydig-cell tumors in mice indicated a correlation
between side-chain splitting and hydroxylase activities at C-17 and degree of in vivo masculinization (42). No such correlation existed between the
3#-ol dehydrogenase (an enzyme probably necessary for synthesis of both gonadal and adrenocortical hormones) and biological effects of such tumors (42, 139). Two Leydig-cell tumors with weak
masculinizing effects converted progesterone to
phenolic compounds, probably estrogens (42, 137).
Of great interest was the discovery of the capacity
Vol. 19, J a n u a r y , 1959
of some Leydig tumor tissue to hydroxylate at
C-21, an essential step in the synthesis of corticosterone, usually thought to occur only in adrenocortical tissue (42).
Problems.--The exact role of the pituitary in
the induction of Leydig-cell tumors by estrogen or
by intrasplenic grafting has not been established.
Experiments with heterospecific GtH may be inconclusive because of species differences in hormone structure. Heightened levels of GtIt/1 have
not been demonstrated in estrogen-treated mice
or gonadectomized rats bearing intrasplenic testicular grafts before or after appearance of Leydigcell tumors, and the mechanism of the effect of
the intra-abdominal position has not been clarified. The responsiveness to the normal female environment and to gonadectomy gained by estrogen-induced Leydig-cell tumors after several generations of grafting may be due to pituitary factors, but this does not imply that similar factors
are involved in tumor induction. The possibility of
interplay between the Sertoli and Leydig cells and
perhaps other cells of the testis has not been adequately investigated. Studies of enzymatic capacity and hormonal control of Sertoli cells similar to
those of Huseby et al. (42, 137) would be of interest. Such information is requisite to understanding
both normal and pathologic physiology.
ADRENOCORTICAL T U M O R S
Tumors of the adrenal cortex in laboratory animals may be divided arbitrarily into two categories: those that occur in response to gonadectomy and have marked gonad-mimetic actions and
those that are induced by chemicals or arise spontaneously. Since the discovery of the association
of mammary tumors with gonadectomy-induced
adrenal neoplasms (237, 238), there has been considerable experimentation with these, particularly
by Woolley and his associates. Inasmuch as these
studies have been reviewed recently by Woolley
(235), they will be summarized only briefly. For
types and incidence of tumors in various species,
see also Gardner et al. (104).
Induction by gonadectomy.--Removal of the
gonads of young animals of several species results,
after a prolonged induction period, in adrenocortical tumors) These have been most extensively
studied in mice in which response to gonadectomy
varies with strain. Some, such as the Ce strain,
develop metastasizing carcinomas (239). Other
strains develop adenomas, and still others develop
few tumors or none. The tumors arise from subcapsular cells and thus are distinct from the sex
steroid-secreting juxta-medullary " X zone" of
5 For references not cited here see (~35).
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CLIFToN--Experimental Tumorigenesis of Several Glands: Review
young mice. Genetic susceptibility resides in the
adrenal tissue (138). In Ft hybrids of strains with
varying susceptibility to cortical neoplasia, susceptibility to carcinoma development is dominant
to susceptibility to adenomas, and the latter to
resistance to tumor formation (236). Tumors are
prevented by hypophysectomy (55) and treatment
with estrogen or androgen. Adrenocorticoids are
ineffective or weak in preventive action (235).
In consideration of the gonad-mimetic actions
of the tumors, it has been suggested that they result from hyperstimulation of cells in the cortex by
heightened levels of GtH consequent to gonadectomy, and t h a t they may possibly arise from rests
of embryonic gonadal cells (54). An alternative
postulate suggests that increased inactivation or
utilization of corticoids consequent to decreased
gonadal hormone levels results in a Cushing's disease-like syndrome, presumably with increa~d
AtH release, and, in turn, cortical neoplasia (234,
239).
The syndrome caused by gonadectomy of susceptible mice involves tumorigenesis of the pituitary and mammary glands, as well as of the adrenal cortex, and these changes (discussed elsewhere)
appear intimately related.
Other induced and spontaneous tumors.--Cortical
adenomas, similar to those appearing after gonadectomy, occur spontaneously with high incidence
in old female mice of the N H strain. The ovaries
of these mice undergo senescence early, becoming
refractory to gonadotropins by 1 year of age and
thus causing a state of "physiologic castration"
(65). Adrenal tumors were more common in estrogen-treated rats of the August strain (86 per cent
in males, 17 per cent in females) than in untreated
rats in which incidence was less than 1 per cent
(49). Incidence of cortical adenoma was increased
to 62 per cent, and carcinomas to 9 per cent (from
less than 1 per cent) in rats of the Osborne-Mendel
strain, fed a low-protein diet and butter-yellow
(192). Cortical tumors were also induced at a low
rate in LAF1 mice by gamma rays and at a
higher rate by neutrons (88).
Transplantation.--Cortical carcinomas induced
by gonadectomy are autonomous (241) and, when
grafted in gonadectomized hosts, they exert a restraining influence on development of primary
adrenal tumors. A functional cortical tumor from
a rat fed p-dimethylaminoazobenzene was also
successfully transplanted into untreated hosts
(192).
A carcinoma t h a t arose in an irradiated LAF~
mouse was autonomous though responsive when
grafted, although it readily metastasized to the
lungs (84). Latency was prolonged slightly by
11
gonadectomy or adrenalectomy of female hosts,
but not of males. Hypophysectomy doubled t h e
latency in female mice. Original grafts of an adrenal tumor originating from a radio-thyroidectomized rat of a highly inbred Wistar (W) strain
were dependent on thyroid deficiency or gonadectomy. No tumors were found in intact hosts up to
615 days after transplantation of the primary
tumors (34). On further passage, however, t h e
tumor became autonomous but still was responsive, growing best in thyroid-deficient hosts, less
fast in gonadectomized or gonadectomized-adrenalectomized hosts, and poorly in intact hosts.
Secretory activity.--Biological effects of primary
and transplanted adrenal tumors induced b y
gonadectomy in mice indicate secretion of high
levels of estrogens or androgens, or both, depending on the sex and strain in which the tumors arise
(64, 92, 240, 241). Secretion of detectable levels of
estrogen often precedes development of tumors by
several months (173). Urine levels of assayable estrogen in adrenal tumor-bearing gonadectomized
N H females was 6 times, and fecal levels, 2-3
times that of normal females (44). In contrast to
results with Leydig-cell tumors (see above), the
3-/~-ol dehydrogenase activity of a grafted cortical
carcinoma roughly paralleled the androgenic effects of the tumor (139).
Corticosteroids may also be secreted by gonadectomy-induced adrenal tumors. A Ce-strain carcinoma had 5-30 per cent per unit weight of the
glycogen-deposition potency of normal adrenal
tissue. This would result in calculated levels of
glucocorticoid 50-100 times normal in the blood of
tumor hosts (199). Host mice were not hyperglycemic, however (199), and the syndrome does
not closely resemble that caused either by ArT
or corticoid-secreting adrenal tumors in LAF~
mice (84).
Grafts of an adrenal carcinoma induced in the
rat by p-dimethylaminoazobenzene were apparently functional, causing adrenocortical atrophy of
hosts (192); functional capacity of estrogen-induced tumors in rats was not reported. Neither the
transplanted adrenal carcinoma strains originating
in the irradiated LAFt mouse noted above nor
that from the radio-thyroidectomized W strain rat
had gonad-mimetic activity. Both caused profound adrenocortical atrophy, lymphopenia, thymic involution, and eosinopenia, all indicative of
glucocorticoid secretion. In host mice there was, in
addition, hypernatremia and polyuria. Tissue
slices of these strains of adrenal tumors secreted
corticoids in proportion to the amount of AtH
added in vitro (32, 3S). T h o u g h the maximal secretory activity of both tumor strains was consid-
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Cancer Research
erably less than that of slices of normal adrenals
(13.6 ~g equivalents cortisol/100 mg tumor/2 hr
vs 57.2 pg equivalents cortisol/100 mg in normal
mouse adrenals; 17.4 ~g equivalents cortisol/100
mg tumor vs. 71.0 vg equivalents cortisol/100 mg
in normal rat adrenals), sensitivity to AtH was
greater than with normal tissue. Mouse tumor
slices were thus used in in vitro assay of AtH activity of pituitary tumors and of purified preparations (33).
Major steroids initially synthesized by slices of
the LAF1 mouse tumor were corticosterone (the
major product of normal mouse adrenals) and
ll-~-hydroxy-A4-androstene-3,17-dione (a minor
product of normal adrenals), e With further
transplantation, major products changed to l l-Bhydroxy-A4-androstene-3,17-dione and an uncharaeterized 6-oxygenated steroid. Conversion studies
showed the presence of 6- and ll-hydroxylation
and hydrogenation enzymes in tumor tissue and a
decrease in ability to hydroxylate in the C-21
position. 6
Problems.--The pituitary hormone involved in
adrenal tumor formation after gonadectomy is in
question. Evidence is lacking for stimulation of
Attt secretion by gonadectomy. If heightened
levels of GtH are responsible, however, either some
type of neoplastic change occurs in the tumorforming cells before nodules are apparent, or the
Gt of susceptible animals become refractory to
gonadal hormones by the time they are released in
quantity by cortical cells. Small doses of sex
steroids inhibit secretion of GtH in gonadectomized rats (125), and there is evidence that adrenals of gonadectomized mice that are susceptible
to cortical tumors may produce estrogen before
appearance of the adrenal adenomas (173).
The marked responsiveness of the transplanted
adrenal tumor of the W rat to thyroidectomy is an
enigma--hypothyroidism has generally been
thought to inhibit the pituitary-adrenal axis (43) ;
increased thyroid hormone levels have been reported to inhibit development and growth of some
tumors, however (221).
Marked obesity occurs in LAF1 mice grafted
with ArT and not in mice of the same strain with
functional cortical carcinomas. Corticosterone, a
major product in both, is known to induce obesity
(123); perhaps other steroids released by the cortical tumor depress fat synthesis.
Results with adrenocortical tumors, as those
with ovarian and testicular tumors, emphasize the
overlap in functional activity between the gonadal
and cortical cells, probably reflecting the similarity
in embryologic origin. Release of estrogens as a
6E. Bloch and A. I. Cohen, personal communication.
Vol. 19, J a n u a r y , 1959
principal product of cells of cortical origin or corticosterone compounds by cells of the gonads implies (a) that the ability to produce the "finished
products" of steroidogenesis (estrogens and corticosterone derivatives) resides in all or most
steroid-secreting cells, the enzymatic differences
between steroid-secreting cortical and gonadal
cells being quantitative; (b) that cortico-mimetic
gonadal cells and estrogen-secreting cortical cells
represent embryologic "rests" of the other organ
(this seems ruled out in some Leydig-cell tumors
[42]) ; or (c) that "new" enzyme systems may arise
in neoplastic cells (Bloch and Cohen, however,
observed evidence of loss of enzymatic capacity
with progressive transplantation of an adrenal
tumor strain), e The solution of these problems
requires further analysis of the responsiveness,
enzymatic capacities, and steroid products of each
of the cell types in question.
MAMMARY TUMORS
The pioneer work of Loeb and his associates,
who demonstrated involvement of the ovaries in
mammary tumor induction, stimulated interest in
the hormonal genesis of mammary cancer. In 194s
Bittner outlined three groups of factors in "spontaneous" mammary tumorigenesis in mice: (a)
genetically controlled susceptibility, (b) the maternal milk factor (the mammary tumor agent,
MTA); and (c) genetically controlled hormone
patterns (21). The MTA has not yet, however,
been demonstrated in other species and apparently
is not essential to tumorigenesis in mice under
many circumstances (3, 21). Ablation of endocrine
organs and/or treatment with exogenous hormones is now accepted therapy for breast cancer
of women. A detailed discussion of each of these
aspects is beyond the scope of this paper. It will
be limited to a summary of endocrine influences in
the genesis and control of experimental mammary
tumors, with emphasis on the role of the anterior
pituitary gland. For more detailed reviews on this
and other aspects, see refs. 36, 124, 129, 150, 195,
200. The histologic types of mammary tumors of
mice, most of which are adenomas or adenocarcinomas, are reviewed by Dunn (46) and by
Foulds (63).
Ovarian influence.--In classic experiments, Lathrop and Loeb showed that mammary tumor
incidence in female mice was increased by breeding (158). Conversely, ovariectomy prevented normal growth of the mammary glands and reduced
the incidence of spontaneous mammary cancer
(159). Both of these observations have been amply
confirmed. The most significant precancerous
lesion in mice is the "hyperplastic nodule" of al-
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CLIFToN--Experimental Tumorigenesis of Several Glands: Review
veoli (46), although in some strains development
of "plaques" of radially arranged tubular structures appears to be the most common first step in
neoplasia (63). Incidence of these hyperplastic
nodules was increased by breeding or by the MTA
(91,191), and the frequency of tumors was proportional to their number (191). Ovariectomy of virgin or multiparous female mice markedly reduced
the incidence of tumors (165, 205,213) and caused
general mammary atrophy but not regression of
nodules already present (12). The incidence of
mammary tumors in RIIIb females increased with
parity but not with age after five litters (204).
Mammary carcinomas occurred in females under
13 months of age only if they had borne three or
more litters (204). In adrenocortical adenoma-susceptible strains of mice, ovariectomy of virgin females had no effect on hyperplastic nodules,
though tumorigenesis may have been slightly enhanced (see below) (12, 203).
Ovarian involvement is further illustrated by
the higher incidence of mammary tumors in irradiated mice that also bore ovarian granulosa-cell
tumors than in those that did not (76), and decrease in incidence of mammary tumors in irradiated rats after gonadectomy.7
Estrogen given locally (170, 243) or systematically induces some mammary growth, but both
estrogen and progesterone are necessary for "normal" development (37, 103, 130, 149, 219). Sensitivity to stimulation by estrogen is greater in
mammary glands of strains of mice that have a
high incidence of spontaneous tumors than in
those with low incidence (~5), and in high dosages
estrogen inhibits mammary growth (93). Prolonged administration of estrogen induces mammary tumors in mice (156) and rats (107, 193,
197) of either sex. Incidence depends on strain in
both species (21, 48, 49, 91, 171), is related to dose
(49, 107), and affected by diet (47, 148). In mice,
mammary tumors usually gain early independence
of the ovaries, continuing to grow after ovariectomy (174), although pregnancy-dependent tumors
have been described (60, 61). In rats, dependent
tumors have been described that regress on withdrawal of estrogen or on co-treatment with progesterone (196, 197). Tumors have not been induced
by prolonged progesterone administration.
Pituitary influence.--Hypophysectomy abolishes or markedly decreases the mammary growth
response to estrogen (110, 157, s
although
growth may occur if small pituitary fragments remain (110, 14~). When both estrogen and progestins are given, growth is slight (90, 149) but may
be further increased by insulin (2). Most preShellabarger et al. (~1~) and personal communication.
13
tumorous hyperplastic nodules in mammary
glands of mice, but few established tumors, regress
after removal of the pituitary (12, 94, 157, 174,
189). Little is known of the effect of prolonged
treatment of hypophysectomized animals with
estrogen, undoubtedly because of their fragility.
Mammary tumors were not found, however, in
estrogen-treated rats surviving 6 months or more
after hypophysectomy, although they occurred in
intact, treated animals (107). Conversely, transplantation of pituitary tissue in female mice or
concurrent pituitary and ovarian tissues in males
stimulated mammary growth and tumorigenesis in
susceptible strains (106, 166, 167, 214, 216). The
effect of pituitary transplantation is not attributable to increased titers of Grit; the gonadotropic
function of such transplants is markedly impaired
(see above).
Known actions of presently available pituitary
hormone preparations from heterospecific sources
do not readily account for these results. Prolactin
and growth hormone have slight activity when
given alone, though estrogen given with prolactin
may cause some mammary growth (37, 106, 135).
Nearly normal mammary development is achieved
in hypophysectomized-gonadectomized rats only
when growth hormone, prolactin, estrogen, and
progesterone are given in combined optimum dosages (168, 169). Chronic administration of prolactin did not affect incidence of tumors in intact
mice pretreated with estrogen (206).
In contrast to the relative ineffectiveness of
purified pituitary preparations, functional autonomous M t T induce full mammary growth with milk
secretion in the absence of other hormone treatment (79, 80, 82). Mammary glands of MtT-bearing rats show both ductal and alveolar hyperplasia with cyst formations and almost invariably
have hyperchromatic adenomatoid areas. A few
carcinomas in situ have been found in host rats
under 8 months of age (79). The response is not
markedly modified in quality by the sex of the host
or by hypophysectomy or gonadectomy (79). Response to M t T in mice is less marked and more
sex-dependent, perhaps as a reflection of a lower
secretory capacity of the mouse M t T used and the
small size of mammary rudiment of the male
mouse (58).
Primary M t T are a common finding in both
mice and rats bearing estrogen-induced primary
mammary tumors (48, 49, 171,193, 197, 206), and
spontaneous enlargement of the pituitary occurs
in association with mammary tumors in some
strains of mice (16) and rabbits (116). The evidence indicates that the M t is a single functional
cell species, is under direct control of estrogen
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levels, and is, in fact, the mediator of the principal
actions of estrogen in the growth of the normal
mammary gland and probably in tumorigenesis.
Stimulating effeets of estrogen direetly applied to
the mammary glands have not been demonstrated
in hypophyseetomized animals and may represent
potentiation of M t t I present. The relationship between the hormonal produet(s) of the M t and
heterospeeifie growth hormone, prolactin, and the
mammogens of Turner (see 58) has yet to be determined. The data suggest, however, that effeets of
hypophysectomy and of pituitary transplants on
tumor induetion and growth of the mammary
glands can be attributed largely to removal or addition of Mt, although other pituitary factors may
play synergistie or antagonistie roles.
Adrenal factors.--Cortisone, hydrocortisone,
and AtH induee branching of mammary duets and
alveolus formation and increase the pituitary
stores of prolactin (144), and the mammary glands
of intact ArT-bearing mice are hypersensitive to
stimulation by estrogen (79). Adrenalectomy decreases both proliferative activity and milk secretion in MtT-bearing rats (79), but has little effect
in MtT-bearing LAF1 mice. 1 Lyons et al. (168)
found eorticoids neeessary in addition to prolactin,
growth hormone, and ovarian hormones for mammary growth in gonadectomized-adrenaleetomized-hypophyseetomized rats.
In CStI mice, adrenaleetomy had no apparent
effect on hyperplastie nodules of the mammary
glands (1~). Adrenalectomy or combined adrenaleetomy and gonadeetomy, however, caused
growth stasis or temporary regression of about 10
per cent of spontaneous mammary tumors in
mice, and complete regression in two animals
(about 3 per cent) (174).
In susceptible mice, gonadectomy leads to
mammary tumors and adrenocortical and pituitary neoplasms (~35, 237). The cortical tumors
often secrete estrogens (see above). As estrogens
stimulate M t t t release, it seems probable that the
mammary growth and tumorigenesis in such mice
is a result of abnormal adrenal function mediated
through the pituitary. Although the "inherited
hormonal influence" of Bittner and adrenal tumor
susceptibility seem closely associated, they are apparently distinct (~-~4). :Further investigation of
these phenomena is required.
Transplantation and chemotherapy.--Mammary
tumors of mice have been generally found to be
freely transplantable to untreated histocompatible hosts. Dependent mammary growths have
been described in hybrid mice, however, that grew
during pregnancy and regressed post-partum (61).
The latter ultimately gave rise to autonomo us tu-
Vol. 19, J a n u a r y , 1959
mors that retained responsiveness to pregnancy
and finally to nonresponsive tumors (60, 61).
Autologous grafts of portions of these tumors progressed independently (60). Isologous grafts of several such tumors grew only in females or estrogenized males, and many responded to pregnancy
or estrogen treatment with milk secretion (60).
There are few other reports of hormone-responsive mammary tumors in mice. Corfisol or AtH
were found to inhibit the growth of grafts of a
mammary tumor of the C3H strain ( ~ 0 ) , but
eaused profound loss of body weight. Growth hormone or prolactin given concurrently with either
prevented loss of weight but did not reverse the
inhibition of tumor growth. The latter hormone
preparations, alone or in combination, had no effect on tumor growth (s163 In other studies, however, grafts of mammary tumors were stimulated
by the injection of growth hormone (185, ~18).
Growth of a grafted mammary fibroadenoma, a
common tumor of old rats (180), was stimulated
by low doses of estrogen in males but not in females of a hooded strain (181). tIigh estrogen dosage inhibited growth and inereased incidence of
transformation to sarcoma, and testosterone had
a slight suppressive effect. Crude extracts of beef
and sheep pituitaries also stimulated tumor
growth, but a purified growth hormone preparation was ineffeetive.
In the studies of tIuggins and his assoeiates,
grafts of several fibroadenomas in the SpragueDawley strain of rats were stimulated by estrogen
and progesterone, either alone or in combination,
but not by heterospecific growth hormone or prolactin given alone or in combination. They were
inhibited by gonadectomy, adrenalectomy, and
hypophysectomy (13~, 185). A series of androstane
compounds were tested for anti-mammary tumor
action in intact and gonadectomized rats. Most
potent of these was ~-a-methyldihydrotestosterone, but dihydrostestosterone, testosterone, and
androsterone were all effective. Surprisingly, these
compounds stimulated the growth of the normal
mammary t issue (131). Dihydrotestosterone completely overcame the stimulating action of concurrently administered estradiol and progesterone.
The androstane derivative appeared to have a
dual effect, one directly on the tumor tissue and
the other mediated by the pituitary (131).
Some fibroadenomas showed little responsiveness to treatment with androstane derivatives, but
were inhibited by 3-methylchotanthrene in combination with androstan-17-/~-ot-3-one (134). The
inhibitory actions of 3-methylcholanthrene were
also apparently mediated both directly and by ~
way of the pituitary, since the secretion of Gttt
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Research.
CLIFTON--Experimental Tumorigenesis of Several Glands: Review
was suppressed in intact treated animals and an
anti-tumor effect obtained in hypophysectomized
hosts.
Estrogen in physiologic levels also enhanced the
growth of grafts of a pure fibroma in rats (186).
Grafts of a fibrosarcoma grew faster than the fibroadenoma from which it arose and was much less
responsive to hormones (183). Recently, several
fibroadenomas originating in inbred rats of the W
and F strains have been transplanted to variously
treated histocompatible hosts. Results thus far
indicate that some of these are responsive to M t H
from M t T grafted in the same animals. 1
Results with several chemotherapeutic agents
[trimethylenethiophosphoramide
(thioTEPA),
6-dimethylamino-9- (S'-deoxy - S'-amino- ~- D-ribofuranosyl)-purine (ARDMA), cortisol acetate, and
derivatives of dimethyldiaminobenzene] on grafts
of mammary tumors in mice were encouraging,
but, when mice bearing primary tumors were similarly treated, results were less satisfactory (310,
e43).
Problems.--It is apparent that endocrine factors
in induction and growth of mammary tumors are
not yet well known or exploited. The evidence suggests that M t H is the primary stimulant of mammary growth, but it remains to be shown whether
a single or several hormones are involved in tumorigenesis, and whether or not exogenous agents
are also required. Knowledge is sufficient, however, to indicate t h a t agents with endocrine activity are of promise for further investigation of
antitumor effects.
The hormone responsiveness of rat tumors induced by carcinogens (!08, 333) and radiation
(313), or these combined with endocrine treatment, should be investigated for their potential
value as tools in screening studies. I t has been suggested that the ideal animal for such screening is
a female bearing both a responsive M t T and a
mammary tumor (79). Activity of compounds
could be assessed on the mammary tumor, the normal mammary gland, and the Mt. An inhibitor of
M t activity, perhaps an anti-estrogen (see 330),
might well make hypophysectomy unnecessary as
a mode of treatment.
REMARKS AND CONCLUSION
Tumorigenesis following endocrine derangement apparently occurs in response to excess or
deficiency of those physiologic agents that control
proliferation of the normal cells from which the
tumors arise (67, 73). Usually, these are the same
physiologic agents that control secretory function
as well as proliferation of the cells involved. The
tumorigenic actions of hormones thus seem, for the
15
most part, to be intimately associated with their
normal physiologic effects. The possibility t h a t
some hormones or their derivatives possess a carcinogenic action distinct from their normal action
has been suggested (15, 100). Though it cannot be
ignored, this postulate seems unnecessary to explain results cited here. In cases cited above, where
nonhormonal carcinogenic agents were employed,
the specific physiologic stimulators often played an
important accessory role (73).
Tumors arising from endocrine imbalance are
characterized by a prolonged induction period and
a dependent phase. I t has been suggested t h a t this
induction period is the time required for development of a "growth-promoting environment" (96).
On the other hand, in cases where the affected cells
initially comprise only part of an organ, the induction period could represent the time during which
geometric increase in the numbers of stimulated
cells is not grossly apparent--i.e., dependent tumor growth begins at the initiation of treatment
but is not detected grossly. This appears to be the
case with induction of M t T in estrogenized
rats (S1).
The nature of the dependent tumor cell awaits
further analysis. In many cases it can be conceived of as a normal cell reacting to an abnormal
environment (67). However, fully dependent tumors of the same cell type, source, and genetic
constitution may vary in secretory activity and
rate of growth (e.g., M t T and TtT). Furthermore,
pretreatment with a stimulating agent can increase tumorous response when the stimulating
agent is reintroduced after elapse of a considerable
period of time (e.g., estrogen-induced Leydig-cell
tumors) indicating persistence of increased sensitivity to the stimulant. Adaptive enzyme formation is a widespread biologic phenomenon. :Perhaps
such increased responsiveness to specific hormonal
stimulation is due to adaptive enzyme formation
in response to chronic excess of the stimulant.
Such adaptation would be reversible and would
not lead to tumorigenesis in the absence of the
stimulating agent, i n any event, investigation of
the relationship between quantity of stimulant
and proliferative response of autonomous and dependent cells and the normal cells from which they
arise would be informative.
In general, the same physiologic factor(s) required for the formation of dependent tumors are
required for their growth. Responsiveness to these
factors may be retained by autonomous variants
and yield clues to the mechanism of their induction. However, responsiveness to other factors
may be gained by autonomous tumors (e.g., Leydig-cell tumors), and reverse responsiveness may
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1959 American Association for Cancer
Research.
16
Cancer Research
occur (e.g., T t T ) . Observations m u s t thus be interpreted with caution.
Secretory function is generally, b u t n o t necessarily, decreased with autonomous transformation
and decreasing responsiveness. However, some
fully d e p e n d e n t tumors derived from functional
cells h a v e little hormonal potency, a n d some highly autonomous tumors of the same cell species retain high functional capacity. This is in agreement
with F o u l d ' s s t a t e m e n t of independent progression
of characteristics (62).
Hormones released by endocrine tumors need
not be identical with the principal products of the
cells from which t h e y are derived (102), and
changes m a y occur in the nature of the secretions
after tumors are established. 6 This is particularly t r u e of tumors of steroid hormone-secreting
organs, probably as a reflection of the similarity in
embryonic origin of the cells and the common steps
in the synthesis of their products. Similar changes
have n o t been observed with monomorphous
p i t u i t a r y tumors, despite a t t e m p t s to change the
major secretory product by various conditioning
of the hosts (74).
T h e studies reviewed here emphasize the importance of the internal environment in oncogenic
transformation. M a n y dependent tumors rapidly
give rise to m a r k e d l y altered variants in hormonally conditioned b u t genetically compatible environs. Such variants have a proliferative a d v a n t a g e
under m a n y circumstances and can be readily
selected from mixed cell populations b y modification of t h e hormonal constitution of the host.
T r a n s p l a n t e d tumors m a y be more readily inhibited b y chemotherapeutic agents t h a n their corresponding p r i m a r y tumors. As has been stated (210,
242), t h e best subjects for s t u d y of the controlling
factors in t u m o r growth are animals with spontaneous p r i m a r y cancers, b u t this, with few exceptions, is limited b y practicality. T h e second best
experimental material would seem to be tumors of
recent origin carried in genetically compatible
hosts. T u m o r s of endocrine glands induced b y der a n g e m e n t in hormone balance have an a d v a n t a g e
in t h a t stages of transformation to highly autonomous cells can usually be obtained in sufficient
q u a n t i t y a n d p u r i t y for detailed biological a n d
biochemical analysis. Such material would seem
ideal for studies of endocrine interrelationships
and h o r m o n e synthesis as well. :For m a n y purposes, these assets more t h a n compensate for the
liabilities of long induction and latency periods.
Studies of endocrine tumorigenesis have profited greatly from knowledge gained in basic endocrinology. I n turn, research in endocrine neoplasia
has led to the isolation of functional units of the
Vol. 19, J a n u a r y , 1959
complex endocrine system, and has thus contributed tools for basic endocrine research. I t seems
probable t h a t , as knowledge of i n t e r p l a y within
the endocrine system increases, technics m a y be
developed to uncover the more subtle physiologic
mediators t h a t control cell numbers in nonendocrine organs.
ACKNOWLEDGMENTS
The author is indebted to Drs. Rita F. Buffett and Arthur
I. Cohen for helpful suggestions, and particularly to Drs.
Jacob Furth and Vernon H. Reynolds for critical reading
of the manuscript.
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Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1959 American Association for Cancer
Research.
Problems in Experimental Tumorigenesis of the Pituitary
Gland, Gonads, Adrenal Cortices, and Mammary Glands: A
Review
Kelly H. Clifton
Cancer Res 1959;19:2-22.
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