THE INHERITABILITY OF SPONTANEOUS ... - Cancer Research

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The Inheritability of Spontaneous Tumors of the 

Liver in Mice: Studies in the Incidence and 

Inheritability of Spontaneous Tumors in Mice: 

Seventh Report 

Maud Slye 

J Cancer Res 1916;1:503-522. 

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THE INHERITABILITY OF SPONTANEOUS TUMORS 

OF THE LIVER IN MICE1 

STUDIES IN THE INCIDENCE AND INHERITABILITY OF SPON- 

TANEOUS TUMORS IN MICE 

SEVENTH REPORT 

MAUD SLYE 

From the Cancer Laboratory of the Otho S. A. Spragw Memorial Institute and iAe 

University oj Chicago 

Received for publication, September 18, 1916 

The work of the past six years in this laboratory has definitely 

established two points in regard to the behavior of spontaneous 

cancer. 

I. CANCER IN GENERAL 18 INHERITABLE’ 

This statement is based upon the following observations: 

(1) There are strains of mice in this laboratory which under 

no provocation have ever been made to produce spontaneous 

cancer. 

(2) There are other strains of mice which, under the right 

provocation, inevitably do produce cancer. 

(3) It is possible by selective breeding to manipulate these 

two types of mouse strains with the same certainty with which 

it is possible to manipulate pure-breeding pigmented mice and 

pure-breeding albinos, and to derive therefrom pure-breeding 

cancer strains and pure-breeding non-cancer strains. 

I say “cancer in general,” because until one has completely 

1 Presented before the American Association for Cancer Research, Washington, 

D. C., May, 1916. 

* For the sake of brevity I shall use the expression “inheritability of cancer,” 

although cancer is not transmitted as such; rather it is transmitted aa a 

tumor-producing potentiality. See introduction to Third Report, Jour. Med. 

Research, 1915, xxxii, 159. 

503



504 MAUD SLYE 

analyzed the reproductive potentialities of every individual concerned 

in the genealogy of a family, it is impossible to direct 

what shall be produced in any given case; and the resulting 

strain is likely to show sarcomas or carcinomas, adenomas or 

endotheliomas-of the ovaries, or of the mammary gland, or 

of the lung, or of the liver, or of any other organ. A family, 

therefore, manufactured by the hybridization of cancer-bearing 

with non-cancer-bearing individuals, will be peppered with 

tumors of different organs and of different types. Even 

after the cancer-bearing potentialities of two parents have 

been analyzed as completely as possible, we still discover in the 

offspring some divergence from the ancestral type. From such 

experiments carried on through years and in enormous numbers, 

yielding year after year perfectly consistent and logical results, 

no matter what strains are used, there is but one conclusion 

possible, namely, that this tumor-producing potentiality is a 

thing indubitably transmitted by the right selective breeding. 

11. TUMORS OF SPECIFIC ORGANS AND OF SPECIFIC TYPES ARE 

INHERITABLE 

That is, by selective breeding it is possible to derive strains 

of mice which yield a high percentage of lung tumor or of mammary 

gland tumor, or of liver tumor, or even of stomach and 

uterine tumors which are very rare in mice. And these strains 

of mice, again, can be manipulated, carrying into strains with 

which they are hybridized the types of tumors borne in their 

own ancestral line but from which the family with which they 

are crossed is perfectly free. A general survey of this field 

appears in the fifth report of these studies published in this 

issue. 

The present report concerns itself with the inheritability of B 

single class of these tumors of specific organs, namely, tumors 

of the liver. 

The data presented by a single strain or by many strains 

carrying a bigh percentage of mammary gland or of lung tumors 

when inbred, and introducing a high percentage of tumors of



SPONTANEOUS TUMORS OF THE LIVER IN MICE 505 

these same organs into every strain with which they are hybridized, 

might be contested on the ground of the frequency of these 

types of spontaneous tumors in mice, since about 90 per cent 

of all reported mouse tumors occur in these organs. Or the demonstration 

of a relatively high frequency of stomach or of uterine 

tumors in certain strains might fail to convince, because of 

the paucity of these tumors in mice. 

But tumors of the liver are of sufficient rarity in the literature 

to make an interesting study and are sufficiently frequent 

in this stock to make a most striking one. In all mouse literature 

outside of these studies there is but one tumor of the liver 

reported, namely, an adenoma reported by the Imperial Cancer 

Research Fund of London (Third Report). 

This stock to date has furnished sixty-two primary tumors 

of the liver. These tumors are chiefly adenomas, with a sprinkling 

of sarcomas, and of carcinomas, and they are described 

fully in the Fourth Report of this series.3 It has furnished seventeen 

secondary tumors of the liver; these are mostly spindlecell 

and osteosarcomas, with a few carcinomas. All these primary 

liver tumors have fallen in strains of identical ancestry, 

namely, ancestry derived from Strain 90, and among all the 

other cancer-bearing strains, yielding twenty-five hundred primary 

neoplasms appearing in this stock, not one liver tumor 

has occurred. This fact furnishes a most striking piece of 

negative evidence for the inheritability of liver tumors. 

Chart 1 

Strains 280 and 281. These strains were produced by mating 

female No. 258, who died of a carcinoma of the lung but who 

came of a family carrying a heavy percentage of liver tumors 

(see Chart 8, Strain 202), with two brothers from Strain 90, 

namely, male No. 363 and male No. 286. 

1. Mated with male No. 363, who also had carcinoma of the 

lung, she produced a line of which 100 per cent carry tumor, 

80 per cent of these tumors being tumor of the lungs. 

Jour. Med. Research, 1915, xxxii, 171.



STRAIN -280. STRAIN-28 I. 

CHART 1 

Cucc LUNR D\ac LUNO 

PrnENT 

G3 

c4




2. Mated with male No. 286 with an adenoma of the liver, she 

produced a line showing three cases of liver tumor in two generations, 

or 9 per cent of liver tumor. There was in this strain 

also an adenocarcinoma of the lungs, an adenoma of the lungs, 

and three lung nodules showing pre-adenomatous hyperplasia. 

Chart 2 

Strains 246 and 246. These strains were produced by mating 

male No. 286 (parent male also in Chart l), with an adenoma 

of the liver, with two sisters of Strain 48. Mated with female 

No. 412, who died of acute nephritis, he produced a strain showing 

over 44 per cent of tumor, with four straight generations of 

carcinoma of the mammary gland, three generations of adenoma 

of the lung, and one case of “fibro-endothelioma” of the ovary. 

Mated with the latter’s sister, female No. 26, with earcoma of 

the ovary, liver, kidney and mesentery,4 he produced a line showing 

tumor in 46 per cent of the individuals, and giving two 

generations of primary liver tumors. 

Note then, that in both instances where male No. 286 was 

mated with a female having a liver tumor, the resulting offspring 

showed a high percentage of liver tumor. When the same male 

was mated with a female without liver tumor no liver tumor 

appeared in the resulting strain although that strain carried a 

high percentage of tumor. 

Chart 3 

Strain $02. This chart is drawn to show both maternal and 

paternal ancestry, giving only the fraternities which are concerned 

in the production of liver tumors. The individuals of 

this strain and its“ancestry and of its sister strain, Strain 48 

(inbred) show nine cases of liver tumor among thirtyeight individuals, 

or liver tumor in nearly 24 per cent of the individuals; a 

tremendous percentage, considering the rarity of these tumors 

4 It is practically impossible in this case to say which of these sarcomas is 

primary but it is probable that the ovarian tumor is primary; hence the liver, 

kidney and mesenteric tumors have been classed as secondary.



508 MAUD SLYE 

c 

3 

8 

- ep 

lu 71 

CI m U 5



510 MAUD SLYE 

in mice. The construction of this strain involved the use of 

maternal and paternal ancestry from identical stock, carrying 

liver tumor. The potency of female No. 3 to transmit liver tumor 

is shown in strain after strain derived from her. 

Note here also that female No. 26 when inbred with her brother, 

male No. 814, with myocarditis, produced offspring with liver 

tumor, just as she did when hybridized with male No. 286 in 

Strain 245 (Chart 2). Note then: Female No. 258 (Chart 1) 

with lung carcinoma and coming from a strain rich in liver tumor 

mated with a male with lung carcinoma produced 80 per cent of 

lung tumor; the same female mated with male No. 286 with 

adenoma of the liver produced 9 per cent of liver tumor. 

Again, male No. 286 with adenoma of the liver mated with 

female No. 258, produced liver tumor; mated with female No. 26 

of Strain 48 (Chart 3), he produced liver tumor, while mated with 

female 412 without liver tumor and coming from a branch of the 

family rich in mammary gland tumor, he produced four generations 

of mammary gland tumor. 

Again, female 26 with sarcoma of the liver, outbred as above 

with male No. 286, with adenoma of the liver, produced liver 

tumor. Inbred with male No. 814, she produced liver tumor. 

The assumption of a chance determinant here is absurd where 

every individual parent is doubly or trebly checked as to his 

potentialities in the matter of liver tumor transmission. 

STRAIN 56 

EDEMA URINAW ACUTE ACUTC NCCROSII Aascrrs AOCNOMA 

0 LUN~S RETENTION INFECTION lNFFCTlON LIVER LIVER LIVLR 

GI 

02 

02 

CHART 4



SPONTANEOUS !l7JMORS OF THE LIVER IN MICE 51 1 

Chart 4 

Strain 69. This is another strain derived from female No. 3, 

crossed with a male from Strain 143 who died before autopsies 

were being made. Here again she produced offspring with adenoma 

of the liver. Strain 143 never showed liver tumor. 

Chart 6 

Strain 616. The parent of this strain, female No. 630, with 

metastatic carcinoma of the liver, is shown with her ancestry in 

Chart 3, second filial generation. She was crossed with male 

No. 721 of an allied line to make Strain 215. The resulting 

strain shows three cases of primary liver tumor in three successive 

generations. 

Chart 6 

Chart 6 shows a portion of Strain 215 with its parentage for 

six generations. The result is seven straight generations of 

tumor, three of these involving primary tumor of the liver. 

We come now to the consideration of a strain which alone has 

produced twelve cases of primary liver tumor, namely, Strain 

338. It is a strain manufactured during the last four years from 

stock deliberately selected to test the inheritability of tumor 

types, with emphasis upon liver tumors. 

1. It must be remembered that in work with mice, liver tumor 

can not be diagnosed until autopsy. In deliberately breeding to 

test the inheritability of liver tumor therefore, one is blind as to 

whether or not the individual selected will show it. 

2. It must be remembered again that in order to get sufhient 

numbers of offspring from the tested individuals for such a rare 

tumor as liver tumor, the selected mice must breed young. One 

must therefore frequently use mice which have not yet shown 

any tumor at all. 

3. The worker, then, must be guided by the ancestral history, 

and by the available data in the fraternities of the individuals 

selected for this test. 

In spite of all these handicaps note the results:



CNEPH LOCAL CNEW WOLMDS UNcrrrrur, UNCEF~TUW Aomomr 

STRAIN- 215. 

G5 

HIP LIVER 

LIVER 

Q I2207 Q 9595 6 7976 6 8138 6 8139 9 8871




ANCESTRY: STRAIN-215. 

SARC M GL 

MALIG ADENOMA 

9 3 LIVER 6360 

UNCERTAIN 

-n- 

I- 

I 

CARC. M GL 

PUL.INF 

Q5 METAS LUNQS 

CARC M GL 

METAS LUNGS 

C NEPH 

I 

LUNGS 

9 lLIVER 8871 618139 

CHART 6 

Chart 7 

Strain 112. The parent female of this liver tumor strain, Strain 

338, was female No. 5417. She presented no evidence of liver 

tumor but was selected to start Strain 338 after the appearance of 

her mammary gland carcin0m.a. She had six litters of young after 

the appearance of her tumor and is one of the individuals previously 

reported (Third Report, p. 193), in whom tumor growth



STRAIN-112 

CHART 7 

I 

WOUNDS CNEPH SS CARC 

NECK 

5156 Q 5758 Q 7690 

Q3 

G PARENT 

LABOR L ~ O R VNCERTAI UNCERTAIN CNEPH CNEPH 

Q 1332 Q 1250 62512 Q 3581 Qi5333 Q 5859 

I 

PYELO - WOUNDS WOUNDS SaRc LIVER CAac M GL 

NEPH CNEPH CARC Rivis G2 

639426400664018 Q Q 5305 Q 5417 METAS LUNGS 

G3

uvER 

61~~R0505 

TAPEWOR,.. 

"'·a 

ANCESTRY - STRAIN 3~e. 

SA OC M GL ICWO.N 'C 

MAI..JGAocfWf'tA .i. N E~ 


Association for Cancer Research.




was greatly retarded by constant pregnancy. She lived nearly 

a year after the appearance of her mammary gland carcinoma and 

showed at autopsy an additional carcinoma of the pelvis and 

lungs riddled with metastases. Indeed, at the time of her death 

the mouse was about one-half carcinoma. 

The place of this female within her inbred strain is shown in 

Chart 7, second filial generation. It will be noted that her 

grandmother, female No. 3920, had adenoma of the liver, and 

that her sister born in the same litter, female No. 5305, had sarcoma 

of the liver. Inbred with her brother, male No. 3942, 

with pyelo-nephritis, she produced mammary gland and neck 

carcinoma with metastases in the lungs. 

Chart 8 

Strain 124. The paternal parent of Strain 338 was male No. 

7736. He was selected as the strongest remaining representative 

of strain 124, which had liver tumor ancestry behind it. 

His great-aunt, female No. 1070, had adenoma of the liver. 

His immediate family at the time he was selected showed 25 

per cent of cancer, but no liver tumor. 

He himself lived to be three years and three months old. He 

died of arterial sclerosis, and showed at autopsy a papilloma of 

the lung. 

His place in his inbred strain is shown in Chart 8, Branch 11, 

filial generation 3. 

Chart 9 

Chart 9 is drawn to show the complete ancestry which lay 

behind these two parents, namely, female No. 5417and male No. 

7736. 

Ancestry offemale No. 6417. Five generations back her grandparents 

were female No. 3, with a malignant adenoma of the 

liver, inbred with her brother, male No. 30. with chronic nephritis 

(these original forbears were members of Strain 90). 

The male in her maternal line, and the female in her paternal 

line, were the immediate offspring of this pair, the female No. 

I



BRANCH -It 

BRANCH -I 

STRAIN- 124. 

-I- 

I




. 

883 having adenoma of the liver. Hybridization in this generation 

was with Granby, Mass., red stock, namely, female No. l, 

female No. 24 and male No. 27, which never in my hands produced 

liver tumor, primary or secondary, either in inbreeding or 

in hybridization with non-liver tumor strains. Female No. 1, 

however, carried carcinoma, and male No. 27 had abscess of the 

liver. 

The parent female two generations back, female No. 3920, had 

adenoma of the liver and the male, No. 3024, had an infected 

lung nodule and chronic nephritis. 

There were, then, behind the female, three generations of liver 

tumor and an ancestry carrying a' considerable percentage of 

cancer, with a tendency of the liver to yield to disease. The 

origin of both branches of the ancestry was female No. 3 with 

an adenoma of the liver which appeared later in both sides of 

the family. These facts determined the selection of female No. 

5417, who at the time of her selection had a very small carcinoma 

of the mammary gland and was in excellent breeding 

shape. 

Ancestry of male No. 7736. The original forebears of this line 

also five generations back were female No. 3 with her adenoma 

of the liver, and her brother, male No. 30, both long lived. 

Again, on both sides of this line also, a double dose of the 

immediate offspring of female No. 3 was introduced, namely, 

female No. 73 with carcinoma of the lung and male No. 752 with 

liver necrosis. 

Here as in the maternal line there was a considerable percentage 

of tumor, a reappearance of adenoma of the liver in the 

strain, and a tendency of the liver to yield to disease. There 

were then two generations of liver tumor behind male No. 7736, 

and three generations of liver tumor behind female No. 5417. 

Two adenomas of the liver appeared in the first filial generation 

from this cross, namely, female No. 9544 and male No. 8751. 

The rest of the chart shows Branch .K,.fr~m,~hjg,q~ss, bred 

out in five lines, the female parent o f . t ~ ~ ~ ~ ~ ~ 8619, ~ ~ ' i ' f i ~ ~ ~ 

showing two carcinomas 05 ,$?+.qapppv gImd,.a& t+ ..tq@.e 

parent of the branch, malei~~;,~7~~~*~~*~den~.~~.t~liJer. 

.............. 

:,* 

:..::*:. . -.: 

*.a. . 

.......



518 MAUD SLYE 

In the second filial generation there were three tumors of the 

liver, namely, one sarcoma and two adenomas. 

In the third filial generation also there were three liver tumors, 

all adenomas. 

Note that these liver tumors all fell within two lines from this 

mating, namely, lines A and D. Note also line C, of which 

100 per cent shows carcinoma, all of the mammary gland and of 

the lung; where the parent female had carcinoma of the mammary 

gland and the parent male had carcinoma of the lung. 

Chart 10 

Branch IX of Strain 338. This branch is derived, of course, 

from identical ancestry with Branch V, as shown in Chart 9. 

Here also there are two generations of primary liver tumor. 

Chart I1 

Branches XI1 and XI11 of this same strain show also an outcropping 

of primary liver tumor in the fourth filial generation, a 

lymphosarcoma in female No. 12212, and an adenoma in female 

No. 11245. 

Chart 12 

Parts of Strains 465 and 460. This chart is introduced to 

show how in hybridization also Strain 338 and its sister strain, 

Strain 465, produced liver tumor. 

Two sisters, female No 5305 and female No. 5417, were mated 

with two half-brothers, male No. 5215 and male No. 7736. Note 

the outcropping of liver sarcomas, along with the stomach tumors, 

in the third and fourth filial generations in each case. 

Let me review the striking points demonstrated by these 

charts : 

1. A great many strains have been carried for years in this 

laboratom.&lfi@g .yaying percentages of cancer, some of them 

as highi.%&,$Qp &x@&ti .$$..never showing liver tumor, primary 

.oy.$econdaqy., 9These.strqips hvdaeen carried side by side with 

.the;%$& $,$qbr, .&tra,ii~bj$ $$&$andled with identical tech- 

.............. 

..: :*. a.: ..:: 

: 

........... 

..............



CHART 10 

1- 

PNEUMONIA 

9 12172 

BR~NCH x 

G.PARENT 

STRAIN 338 

z CARC. M.GL PAPILLOMA LUNG 

ARTERIAL SCLEROSIS. 

B 

W 

G. 1 

~ADENOMA 

G. z b 9518 

TAPEWORM 

THYMUS. KIDNEY 

LIV~. CYSTS. 

SQCLLLCARC FACE ~NK,~NF. SARCOMA 

[SITE OF WOUNDl 

METAS.DIAPHRAGM ? 12386 0 12138 ? 11828 8 68.34 

G.3 

ADENOMA LUNG



G.PARENT- 

G. i 

G.2 

63



PARTS Of STRAINS 405 AN0 480 WITH ANCCSTRX %OWING OCCURRENC 

Srorucrr TUMO 

CHART 12 

~NTUTlNAL~NFtCTlO 

nc.Lu~~. ADENC++ALWCR



522 MAUD SLYE 

nique, and hybridized with identical non-liver tumor strains, thus 

eliminating every possible cause for this divergence except 

heredity. 

2. One cancer bearing strain, Strain 90, has been used either in 

inbreeding or in hybridization (a) in the origin of every strain in 

this laboratory which has ever produced a primary tumor of the 

liver; (b) in the origin of every strain which has ever furnished a 

secondary tumor of the liver, with the exception of two osteosarcomas 

which metastasized in practically every organ in the 

body. 

3. One individual female, No. 3, with a malignant adenoma of 

the liver and a sarcoma of the mammary gland, stands out preeminently 

in this production of liver tumor. Either she or her 

immediate offspring has been used in one or both origins of 

every strain which has ever produced a liver tumor, primary or 

secondary, in this laboratory, with the exception of the two 

metastatic osteosarcomas noted above. 

The emergence of liver tumor in these hybrid strains derived 

from female No. 3, or her immediate offspring, frequently takes 

place years after the death of their liver tumor progenitors, 

thereby eliminating every possibility of a contact transmission 

of this disease even in the nature of a germ plasm infection. 

4. Certain individuals, both when inbred anti when outbred 

and when tested with many mates, consistently show liver 

tumor in every resulting strain. 

Consider (1) that outside of this stock there is just one liver 

tumor recorded among all the thousands of mouse tumors, (2), 

that these results are deliberately produced by the manipulatioii 

of selective breeding alone, (3) that they have consistently occurred 

for years in every test made, (4) that there are over 

twenty-five hundred primary neoplasms, and over fourteen thousand 

individuals involved in this perfect and persistent consistency. 

What explanation remains but that of heredity?

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