Effect of Mammary Tumor Virus Infection on in Vivo ... · 2747, 3001 Bern, Switzerland. 3The...

[CANCER RESEARCH 31, 1955-1961, December 1971]

Effect of Mammary Tumor Virus Infection on in Vivo Oxidationof Glucose-l-14C and Glucose-6-14C in C3H Mice1

Hans R. Burki2 and George T. Okita

Northwestern University Medical School, Department of Pharmacology, Chicago, Illinois 60611

SUMMARY

The in vivo oxidation of glucose-1-14C and glucose-6-14C

was measured in C3H and C3Hf female virgin mice of differentages. C3H virgins after the age of 4 to 6 months exhibited afaster rate of glucose-6-14C, but not glucose-1-14C, oxidationthan C3Hf factor-free controls. No difference was observedbetween the two strains of mice with respect to the bloodglucose level, but C3H virgins attained lower body weightsthan C3Hf controls. These results suggested that the mammarytumor virus, transmitted in the milk of C3H mice, may inducein the host alterations in regulatory systems controlling growthand glucose metabolism. The presence of a transplantedmammary tumor, which had arisen spontaneously in a C3Hexbreeder female, had no effect on body weight andglucose-6-'4C oxidation of C3H virgins but caused anelevation in glucose-6-14C oxidation and a reduction in bodyweight in C3Hf virgin hosts. Thus, the level of glucose-6-14 C

oxidation and the body weight of C3Hf recipients ofmammary tumor transplants were comparable to that of C3Hvirgins with or without mammary tumor transplants.

INTRODUCTION

Early studies on the genesis of mammary tumors in C3Hmice led to the concept that 3 factors are essential for thedevelopment of mammary tumors: milk-transmitted MTV,3

inherited mammary tumor susceptibility, and hormonalstimulation of the breast tissue (6). More recent studies,however, indicated that the MTV may not be necessary fortumorigenesis (8, 11, 12) and that adequate hormonalstimulation of the mammary glands, in genetically susceptiblemice, may be sufficient for mammary carcinogenesis.

Recently, papers of Batra and Okita (5), Ezz et al. (10), andOkita et al. (18, 19) described alterations in in vivo oxidationof specifically labeled glucose-14 C to I4C02 in MTV-infected

C3H mice compared to factor-free C3Hf controls.Precancerous and tumor-bearing C3H females exhibited afaster rate of glucose-6-14C oxidation and also a lower ratio ofglucose-l-14C to glucose-6-14C degradation than did C3Hf

'This investigation was supported by USPHS Research Grant CA07930 from the National Cancer Institute and NIH Training GrantGM-00162 from the National Institute of General Medical Sciences.

2Present address: Research Institute, Dr. A. Wander Ltd., P. O. Box2747, 3001 Bern, Switzerland.

3The abbreviation used is: MTV, mammary tumor virus.Received January 26, 1971; accepted August 3, 1971.

controls. There also appeared to exist a correlation betweenthe magnitude of the metabolic changes and the extent ofcancerous involvement of the mammary tissue in these mice.For example, C3H exbreeders with multiple tumors showedthe greatest deviations in in vivo glucose metabolism. Theseobservations seemed to suggest that the increased mammarytumor yield observed in MTV-infected animals may be relatedto distortions of physiological metabolic control systems inthe host by MTV (10). Thus, further experiments were carriedout to explore the consequences of MTV infection on glucosemetabolism in vivo. The purpose of the present study was2-fold: (a) to investigate the temporal development ofalterations in glucose metabolism in vivo in C3H virgins. Thus,the rate of oxidation of glucose-l-I4C and glucose-6-14C was

compared in C3H and C3Hf virgins of different ages; (6) todetermine whether the presence of small foci of tumor tissuemight elicit a host response, hormonal or immunological,which may lead to alterations in glucose metabolism in vivo.For this purpose, the degradation of glucose-14C was

measured in mice with transplanted mammary tumors.

MATERIALS AND METHODS

Mice. C3H and C3Hf female mice were obtained from TheJackson Memorial Laboratory, Bar Harbor, Maine, and fromCumberland View Farm, Clinton, Tenn. In one experiment,C3H and C3HfB females, generously donated to us by Dr.Walter Heston, NIH, were used. The animals were kept in ouranimal quarters for at least 1 month before use and had accessto water and standard mouse diet of Purina laboratory chowpellets ad libitum.

Chemicals. D-Glucose-1 -14C(specific activity, 7 mCi/mmole)

was obtained from Nuclear Research Chemicals, Inc.. Orlando,Fla. D-Glucose-6-14C (specific activity, 27.5 mCi/mmole) was

obtained from Nuclear Chicago, Chicago, 111.For injection purposes, glucose-1-14C and glucose-6-14C

were diluted with 0.9% NaCl solution under sterile conditions(Millipore filtration) to a concentration of about 4/jCi/ml.These sterile solutions were stored in the deep freeze at -10Â°.At regular intervals, the glucose-l-14C and glucose-6-'4C

solutions were checked for purity by paper chromatography(10).

Blood Glucose. Blood glucose levels were determined with aTechnicon Auto Analyzer by a procedure utilizing thepotassium ferricyanide-potassium ferrocyanide oxidationreduction reaction as described by Hoffman (13). The changein color was measured at 420 mÃŸ.

DECEMBER 1955

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Hans R. Burki

Estimation of Tumor Size. The tumor volumes were RESULTSestimated by the formula V= (0.4) ab2, where a equals longest

axis of tumor in millimeters, b equals shortest axis inmillimeters, and V equals volume in cu mm (1). Tumorvolumes calculated with this formula were in close agreementwith those found by immersing the tumors in 0.9% NaClsolution.

Measurement of Expired C02 and 14CO2. The apparatus

used has been described previously (16) and consisted of thefollowing components: an all-glass mouse chamber and afreezing trap (C02-acetone mixture) connected in series with a250-ml ionization chamber (Gary stainless steel sphericalionization chamber) and a CO2 analyzer (Lira Model 300infrared analyzer). Outputs from both the ionization chamberand the C02 analyzer were recorded on a Speedomaxrecording instrument (Speedomax G Model S Multiple PointRecorder) as well as fed into an analog-to-digital converter.The digital output was recorded on a paper tape punch (Fridentape punch). The equipment was standardized with gasescontaining 0.5 and 1.0% CO2 in air as well as with a gascontaining a known amount of 14C02 in air. The experiments

were performed in air-conditioned laboratories where theroom temperature varied between 22 and 24Â°.

Mice deprived of food for 8 to 14 hr were given i.p.injections of 0.02 i/Ci/g glucose-14 C and placed into the

mouse chamber. A continuous flow of air of 250 ml/min wasestablished through the entire system, and a recording of theexpired CO2 and 14C02 was taken every 20 sec. In mostinstances, it was sufficient to measure the recovery of 14C02

for 40 min. In some experiments, the measurements wereextended to 60 min. The length of the recording is indicated inthe respective tables.

All calculations were performed on an IBM 1800 digitalcomputer utilizing the data punched on to the paper tape. Foreach 20-sec segment, the recovery of 14C02 was determined(expressed in percentage of the injected dose of glucose-14C),

and the excretion of C02 was measured (mmoles CO2corrected to 0Â°and 760 mm Hg). Adding all 180 (= 60 min) or

120 (=40 min) 20-sec segments yielded the cumulativerecovery of 14CO2 and the total excretion of C02 for 60 and

40 min, respectively. Also, for each 20-sec segment, thespecific activity (percentage of injected glucose-14C excretedas 14C02 per mmole of CO2) was calculated. The slope of thecumulative specific activity curve of 14C02 was calculated,

with the use of all data points between 20 and 40 min afterinjection of glucose-14C, by the method of least squares. Thisslope (expressed as percentage of 14C excreted as 14CO2 per

mmole of C02 per hr) represents the average specific activityof the expired ' 4CO2 and is used in this paper to compare the

metabolic activities of different treatment groups.As in previous studies (10, 19), glucose-1-14C and

glucose-6-14C were selected as substrates for the

measurements of in vivo oxidation of glucose. Thesecompounds are often used to evaluate the relativeparticipation of the Embden-Meyerhof pathway and thepentose cycle in the degradation of glucose (15).

Statistics. Statistical significance was determined by the ChartStudent t test. givenan

Recovery Patterns of CO2 and 14C02. Chart 1 shows asample of C02 and 14C02 recovery patterns from a mousegiven an injection of glucose-6-14C, 0.02 Â¿/Ci/gi.p. (injection

at O min). For simplification of the presentation of data in thischart, the amounts of CO2 and 14C02 excreted were pooled

into 5-min segments. Chart 1 demonstrates that the C02excretion was high for the first several min after the animalwas treated and placed into the mouse chamber. This initialpeak output of C02 correlated with the exploratory activityof the animal. Later the rate of the CO2 excretion dropped offconsiderably as the animal went to sleep. Occasional physicalactivity resulted in increased output of CO2. The recovery of14CO2 increased rapidly within 25 to 30 min after theinjection of glucose-6-14C to reach a peak after 30 to 40 min.At times of elevated C02 excretion, the recovery of 14C02

was also increased. However, as expected, the specific activitycurve was not appreciably affected by the physical activity ofthe animal. The specific activity curve rose to a maximumbetween 25 and 40 min after the injection of glucose-6-14C

and decreased steadily thereafter. The cumulative specificactivity curve, 15 to 20 min after the injection ofglucose-6-14C, entered a near-linear phase. The slope of this

05-

20 60 80 100TIME, MINUTES

KO 160

1. CO2 and I4CO2 excreted by a C3H mouse, age 40 weeks,i.p. injection, at Omin, of glucose-6-14C, 0.02 /iCi/g.

1956 CANCER RESEARCH VOL. 31



GLUCOSE-I-UC

GLUCOSE -6- '*C

15-

40 O 10

TIME. MINUTES

Chart 2. Specific activity curves and cumulative specific activitycurves of expired "CO2 of C3H (o) and C3Hf (â€¢)virgins, 60 weeksold, given i.p. injections of glucose-1-1 *C or glucose-6-' 4C. Each point

is the average of 5 to 6 mice.

Glucose Metabolism in C3H Mice

linear portion proved to be highly reproducible in animals ofthe same treatment group and independent of their physicalactivity. Therefore, this slope (14C02 in percentage ofinjected glucose-14C per mmole of CO2 per hr) was considered

not only an accurate but also a convenient measurement of therate of glucose-14 C degradation and is used in this paper to

compare the metabolic activity of different treatment groups.In Vivo Oxidation of Glucose-14C in C3H and C3Hf Virgins

of Different Ages. The first objective of this study was toinvestigate the temporal development of the metabolicdifferences between C3H and C3Hf mice observed by Okitaand coworkers. For this purpose, the rate of oxidation ofglucose-1-14C and glucose-6-14C to 14C02 in vivo was

measured in C3H and C3Hf virgins of different ages. Allanimals used for this study were free of mammary tumors. Theresults of these experiments are presented in Chart 2 and inTables 1 and 2.

Chart 2 shows the specific activity curves and thecumulative specific activity curves of expired 14C02 of60-week-old C3H and C3Hf virgins, given i.p. injections ofglucose-l-'4C or glucose-6-14C, 0.02 Â¿iCi/g. It may be

observed that there was no difference in the rate of excretionof 14CO2 in terms of specific activity when glucose-l-14C was

used as substrate. In contrast, the rate of conversion ofglucose-6-14C to 14C02 was increased in C3H virgins

compared to C3Hf controls, the slope of the cumulativespecific activity curve for C3H virgins being significantlygreater (p < 0.01) than that of C3Hf controls.

Table 1 presents a summary of the results of measurementsof glucose-6-14C oxidation in C3H and C3Hf virgins of

different ages. At the age of 18 weeks, no differences wereapparent between the 2 strains of mice with respect to body

Table 1In vivo oxidation of glucose-6-'4C in C3H and C3Hf mice of different ages

Mice were given i.p. injections of glucose-6-"C, 0.02 jiCi/g, and the expired '4CO2 was measured asdescribed in "Materials and Methods." All values are mean Â±S.E.

State ofmiceAge

18wkC3HfvirginsC3H

virginsAge

40wk"C3HfvirginsC3H

virginsAge

46wk*C3HfvirginsC3H

virginsAge

60wkC3Hf

virginsC3HvirginsNo.55656556Weight

(g)19.0

Â±0.320.2Â±0.6n.s."28.7

Â±1.123.6Â±0.7p

<0.0125.8

Â±0.523.4Â±0.5p

<0.0130.3

Â±0.825.9Â±0.7p

< 0.02Total

"Crecovered

0â€”60min(%)36.68

Â±2.4630.82Â±1.50n.s.24.66

Â±0.9426.80Â±3.06n.s.21.83

Â±1.0825.64Â±2.85n.s.25.51

Â±2.1429.77Â±2.65n.s.Total

C020â€”60min

(mmoles)2.70

Â±0.282.31Â±0.14n.s.2.82

Â±0.132.37Â±0.21n.s.2.70

Â±0.082.56Â±0.08n.s.3.27

Â±0.223.05Â±0.21n.s.Slope

of cumulativespecific activity curve

(% "CO2/mmoleCO./hr)19.60

Â±0.3320.52Â±1.41n.s.14.25

Â±0.7017.22Â±0.84p

<0.0513.72

Â±0.5416.64Â±0.83p

<0.0211.60

Â±0.2515.02Â±0.89p

< 0.01

'n.s., not significant.1Duration of experiments. 40 min.

DECEMBER 1971 1957



Hans R. Burki

Table 2In vivo oxidation of glucose-1-"C in C3H and C3Hf mice of different ages

Mice were given i.p. injections of glucose-l-"C, 0.02 Â¿iCi/g,and the expired "CO2 was measured asdescribed in "Materials and Methods." All values are mean Â±S.E.

State ofmiceAge

18wkC3HfvirginsC3H

virginsAge

60wkC3HfvirginsC3H

virginsNo.6555Weight(g)20.0

Â±1.1419.4Â±0.94n.s."30.2

Â±1.1126.6Â±1.07p

< 0.05Total

"Crecovered0â€”60

min(%)45.03

3=4.1336.02Â±3.25n.s.34.20

Â±2.1233.25Â±2.47n.s.TotalCO20

â€”60min(mmoles)3.29

Â±0.232.78Â±0.28n.s.3.37

Â±0.133.02Â±0.07n.s.Slope

ofcumulativespecificactivitycurve(%

"CO2/mmoleC02/hr)19.15

Â±0.4719.92Â±1.39n.s.15.67

Â±0.7815.96Â±0.99n.s.

" n.s. not significant.

Table 3In vivo oxidation of glucose-6-"C in C3H and C3HfB mice" of different ages

Mice were given i.p. injections of glucose-6-"C, 0.02 nC\/g, and the expired "CO2 was measured asdescribed in "Materials and Methods." All values are mean Â±S.E.

State ofmiceAge

15wkC3HfBvirginsC3H

virginsAge

19wkC3HfBvirginsC3H

virginsNo.6464Weight(g)24.5

Â±0.720.0Â±1.7p

<0.0529.00

Â±0.919.25Â±0.6p

< 0.01Total

"Crecovered0â€”40

min(%)18.48

Â±0.7226.36Â±3.44p

<0.0520.52

Â±2.0531.47Â±3.18p

< 0.02TotalCOZ0â€”40

min(mmoles)1..82

Â±0.042.15Â±0.08p

<0.012.51

Â±0.092.10Â±0.05p

< 0.01Slope

ofcumulativespecificactivitycurve(%

"CO2/mmoleC02/hr)17.73

Â±1.3419.66Â±1.56n.s.613.44

Â±0.2320.11Â±0.83p

< 0.01

"C3H and C3HfB females obtained from Dr. W. Heston, NIH.a n.s., not significant.

weight and glucose-6-'4C oxidation as measured by the slope

of the cumulative specific activity curve. Part of the variationsin total recovery of 14CO2 and in the total amount of C02

excreted is due to differences in random physical activity. At40, 46, and 60 weeks, however, C3H mice oxidizedglucose-6-14C significantly faster and had lower body weights

than did C3Hf controls.In Table 2 are summarized the results of measurements of

glucose-1-1 4C degradation in 18- and 60-week-old C3H and

C3Hf virgins. There was again a significant difference in bodyweight between the 2 strains at 60 weeks but not at 18 weeks.Contrary to the findings with glucose-6-14C, no significant

differences were found at either age between C3H and C3Hfmice with respect to the rate of glucose-1-14C oxidation.Thus, the ratio glucose-l-"*C/glucose-6-14 C degradation was

0.98 for C3Hf and 0.97 for C3H mice, respectively at 18weeks. At 60 weeks, these ratios were 1.35 forC3Hfand 1.06for C3H virgins, respectively.

The measurements of glucose-6-14C degradation and body

weight were repeated with C3H and C3HfB virgin femalesfrom Dr. Heston's laboratory. As indicated in Table 3,

significant differences between the 2 strains of mice withrespect to body weight were already apparent at 15 weeks of

Table 4Blood glucose levels in blood collected from the tails of C3H and C3Hf

mice, ages 64 to 66 weeks

GroupsC3Hf

virginsC3H virginsNo.11 9Blood

glucose(mg/100ml)104.3

Â±4.9Â«97 . 1 Â±2.5

" Mean -HS.E.

age, while a significant difference in glucose-6-'4C oxidation

between C3H and C3HfB virgins was observed at 19 weeks ofage.

Since it is known that the rate of the in vivo oxidation ofglucose-14 C is in part dependent on the body glucose pool, theblood glucose level was measured in 64- to 66-week-old C3Hand C3Hf virgins. Table 4 shows that there was no significantdifferences between these 2 strains with respect to the bloodglucose level.

In Vivo Oxidation of Glucose-14 C in C3H and C3Hf Virgins

with Transplanted Mammary Tumors. Because C3H mice ofage 5 to 6 months and older (14) develop precanceroushyperplastic nodules in the mammary tissue which are




Ã¼ C3Hf VIRGINS

D C3H VIRGINS


32

s28g 24ÃœJ

O 16om 12

Oi 8

BODY WEIGHT

T T

4 I

TUMOR VOLUME

UJ

D 1200-

>1000-

QCO 800-

zP 600^

_ 400-

E 200-

3

Chart 3. Body weights and mammary tumorvolumes of C3H and C3Hf virgins. T, recipients oftumor transplants.

350 35 8

DAYS AFTER TUMOR TRANSPLANTATION

Table 5In vivo oxidation of glucose-6-"C in C3H and C3Hf virgins, age 40 weeks, with transplanted

mammary tumorsMice were given i.p. injections of glucose-6-"C, 0.02 Â¿iCi/g,and the expired "CO2 was measured as

described in "Materials and Methods." Values are mean Â±S.E.

TumorvolumeWeight1.2.3.4.GroupsC3Hf

virginsC3Hf

virgins withtumortransplant"C3H

virginsC3H

virgins withtumortransplant"No.6656(cu

mm)28.131

Â±6322P23P849

Â±21423p< 0.05' pSlope

specific(g)76*i1.0.16<

0.01".6<.2<Â±0t00.010.,0l7A61418.P17.P18.Pof

cumulativeactivity curve

ColminoleC02/hr).2524<22<40<it0.Â±0.â€¢i0.0.701.3202"0.8405"1.0301"

Â°35 days after tumor transplantation."Compared to Group 1.'Compared to Group 2.

characterized by a high tumorigenic potential (17),experiments were therefore designed to test the possibilitythat the alterations in glucose-6-I4C oxidation and in bodyweight observed in C3H females compared to factor-freecontrols could be related to the presence of small foci oftumor tissue in the mammary gland, eliciting a host responseof hormonal or immunological nature (7). For this purpose, 1mammary tumor, surgically removed from a C3H exbreederwhere it had arisen spontaneously, was homogenized in 0.9%NaCl solution ( l g tumor tissue per 10 ml 0.9% NaCl solution),and 0.1 ml of this homogenate was injected s.c. into each of 6C3Hf and 6 C3H virgins. Six C3Hf and 5 C3H virgin mice ofthe same age (35 weeks) were used as untreated controls. Bodyweights and glucose-6-14C oxidation were measured 35 days

after transplantation of tumor tissue (Chart 3, Table 5).Chart 3 indicates that the transplantation of the mammary

tumor caused a significant reduction (p<0.01) in bodyweight in C3Hf but not C3H virgins. It may also be observedthat until around 8 days after inoculation, the tumor nodulesarising from the sites of transplantation were about equal in

size in both strains of mice. These tumor nodules increasedprogressively in size in C3H virgins only, however, while theirgrowth in C3Hf virgins appeared to be retarded.

Table 5 presents a summary of the results of measurementsof in vivo oxidation of glucose-6-14C in C3H and C3Hf virgins

with transplanted mammary tumors, 35 days after theinoculation. In C3H virgins, neither the body weight nor therate of glucose-6-14C degradation was altered in the presence

of the tumor transplant. In C3Hf virgins, on the other hand,the transplantation of the mammary tumor resulted in asignificant reduction in body weight and a significant increasein glucose-6-14C oxidation compared to C3Hf controls. Withrespect to body weight and glucose-6-14C oxidation, the C3Hf

virgins with transplanted tumor tissue exhibited now thecharacteristics of C3H mice.

DISCUSSION

The yields of expired 14C02 from glucose-1-C andglucose-6-14C may be used, after making several simplifying

DECEMBER 1971 1959



Hans R. Burki

assumptions, to estimate the relative participation of thepentose cycle and the glycolysis-Krebs cycle pathway in themetabolism of glucose (15). In this study, it was found that,after the mice were about 4 months old, the rate of oxidationof glucose-6-14C, but not of glucose-1-14C, was increased in

MTV-infected C3H mice when compared to factor-freecontrols of the same age. This suggests that there was nodifference between the 2 strains of mice with respect tometabolism via the pentose cycle, whereas there was anincreased degradation via the glycolysis-Krebs cycle pathwayin C3H mice compared to controls. Similar findings have beenpublished previously (5, 10, 18, 19). Since it was also notedthat MTV-infected C3H mice attained lower body weightsthan did C3Hf controls, it seems likely that the alterations inglucose-6-14C oxidation in C3H mice when compared to

controls were caused by a general alteration in regulatorysystems controlling growth and glucose metabolism. With theavailable data, no statement can be made about the nature ofthe regulatory systems presumed to be affected, althoughthere is evidence that in vivo glucose-14C metabolism in C3H

mice can be influenced by altering the hormonal status of theanimals (10, 19).

The age at which differences in glucose metabolism andgrowth between C3H and C3Hf mice became apparent variedaccording to the source of the mice. Enhanced oxidation ofglucose-6-14C and reduction in growth occurred earlier in C3H

mice when these mice were compared with the C3HfB strainthan when compared with C3Hf mice. It seems reasonable toassume that the differences in metabolic characteristicsbetween the 2 C3Hf strains may have been caused byprolonged inbreeding in different institutions with consequentselection for slightly different genetic traits.

Attempts were made to elucidate possible factors that mayhave caused the differences in growth and glucose metabolismbetween C3H and C3Hf mice. Since only virgin mice wereused, metabolic alterations resulting from pregnancy andlactation can be excluded. The age (4 to 6 months) at whichmetabolic differences between C3H and C3Hf females becamedetectable coincides with the age at which hyperplasticalveolar nodules develop in the mammary tissue of C3Hfemales (14). Thus, it appeared likely that alterations inglucose-14C metabolism and growth in C3H females when

compared to factor-free controls may have been due to a hostresponse to the presence of the tumor tissue. However, in thisstudy it was shown that the presence of a transplantedmammary tumor had no effect on body weight andglucose-6-14C oxidation of C3H mice. It was therefore

concluded that the presence of a tumor mass per se had noeffect ontheseparameters. C3Hf recipients of mammary tumortransplants, on the other hand, showed an elevated rate ofglucose-6-14C oxidation and a reduction in body weight. This

appeared to suggest that the transplantation of mammarytumor tissue resulted in infection of the C3Hf recipients withMTV and probably other pathogens, thus causing a reductionin body weight and an alteration in glucose-6-14 C oxidation.

In the present experiments, it was also found that mammarytumor transplants grew well in C3H recipients but not in C3Hfmice, a finding that has also been reported by others (2â€”4,7).This seemed to suggest that one important role of MTV may

be to create in the host conditions favorable for tumor growth,provided that the MTV is introduced into the animal at anearly age (14). Thus it has been shown, with recipients oftransplants of mammary tissue from different strains of mice,that the susceptibility of tumor development is determined atthe level of the mammary gland tissue (8, 9). The presence ofMTV in the recipients of mammary tissue transplants resultedin a reduction of the average tumor detection age from 400 to600 days to 200 to 300 days (8). Thus, one may speculate thatthe reduction of the average tumor detection age inMTV-infected mice may have been related to metabolicalterations produced in the host by the presence of MTV.

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C in C3H Mice14C and Glucose-6-14of Glucose-1- Oxidationin VivoEffect of Mammary Tumor Virus Infection on

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