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[CANCER RESEARCH 38, 950-954, April 1978)

Alterations in of Amino in of Rats Bearing the Morris 7800 Hepatoma1

Guglielmo de Rosa2 and Henry C. Pitot

Departments of Oncology [G. de R., H. C. P.] and Pathology [H. C. P.], McArdle Laboratory for Cancer Research, The Medical School, University of Wisconsin, Madison, Wisconsin 53706

ABSTRACT composition of the have also been reported (32). The activities of the -catabolizing enzymes, In addition to these general changes, considerable evi dehydratase (EC 4.2.1.16), aminotrans- dence of alterations occurring in almost every ferase (EC 2.6.1.13), aminotransferase (EC of the host has been reported. Lundholm ef al. (15) 2.6.1.5), and aminotransferase (EC 2.6.1.12), were and Schersténetal. (24) reported an increase of lysosomal measured in the livers of rats bearing the Morris 7800 enzymes in and in the liver and of tumor-bearing patients, with a decreased incorporation of hepatoma for varying periods. A relatively rapid decrease in the activities of hepatic and orni amino into and an increased fractional rate of thine aminotransferase beginning within 1 week after protein degradation in muscle. The literature on enzyme changes occurring in the host liver of tumor-bearing ani inoculation of the tumor into the host was observed. The levels of tyrosine and alanine aminotransferases re mals has recently been reviewed (9, 14). There is some mained comparable to that in livers of non-tumor-bearing indication that the observed alterations of the enzymatic animals for approximately 4 weeks after the initial tumor pattern in host livers are related to the degree of differ transplantation. entiation of the growing neoplasm. In animals bearing the The induction of serine dehydratase and tyrosine ami rapidly growing AH130 hepatoma, tyrosine aminotrans notransferase by was studied in these tumor- ferase in the host liver is increased, as compared with the bearing animals. The response of serine dehydratase to level of the enzyme in the liver of the normal animal (26). this decreased progressively with time after On the other hand, no changes were observed in the activity inoculation of the neoplasm. By 30 days after tumor of this enzyme in animals bearing a slowly growing hepa inoculation, no response of this enzyme to glucagon ad toma. Similar behavior has been reported by Hunt ef al. (12) for the mitochondrial form of a-glycerophosphate de- ministration was elicited. Tyrosine aminotransferase in these rats, on the other hand, was still inducible at least . A normal level of activity of this enzyme was 5-fold at 35 days after tumor transplantation. By 14 days observed in rats bearing the Morris 7800 hepatoma, while of tumor growth, ornithine aminotransferase activity was the activity of the dehydrogenase was above normal in the decreased in kidney and muscle as well as liver, although livers of rats bearing the rapidly growing Novikoff hepa no changes in alanine aminotransferase activity in these toma. tissues of the host could be detected. These results lend Both the general effects on whole and on organ further support to the concept that highly differentiated by the neoplasm may be the result of the hepatocellular induce selective effects in host competition of the tumor with the host tissues for specific tissues, reflected by alterations in the levels of these four , or the neoplastic cells may release specific fac enzymes of amino acid catabolism. tors affecting directly or indirectly the metabolic mecha nisms in host cells, especially those involved in the regula tion of and protein synthesis. INTRODUCTION oxygenase (EC 1.13.1.12) can be induced by its in Generalized effects resulting from the presence of neo host livers, but its response to appears to be plasms in the host organism have been demonstrated in impaired in this respect, compared with normal livers (4). both humans and experimental animals. Alterations of The diurnal variation of tyrosine aminotransferase, together plasma components such as (28) and with the response of this enzyme to treat ment, is altered in the liver of some tumor-bearing animals (1), as well as altered tolerance (3), have been reported in cancer patients. In experimental animals or (11). On the other hand, the of this ganic and biochemical alterations occur in tissues not enzyme and of serine dehydratase to different dietary treat directly involved in the neoplastic transformation. Enlarge ments has been previously shown to be qualitatively similar ment of the liver and (2, 19, 31), together with an in host liver and livers of control animals (23). increase in both nucleic acid synthesis and content of these These 2 mechanisms indicated above are not mutually tissues, has been observed (17). Changes in the exclusive; both are probably operating in the host orga nism, as suggested by the study of Tryfiates ef al. (30), 1 This work was supported in part by Grant CA-07175 from the National which demonstrated the cooperative interaction of hor Cancer Institute. monal balance and B6availability in determining the 2 Damon Runyon-Walter Winchell Fellow in Cancer Research, 1974 to metabolic alterations in the host liver. The studies reported 1976. Present address: Department of , College of Agricultural and Environmental Sciences, University of California at Davis, Calif. 95616. in this paper are directed at attempting to distinguish Received September 6, 1977; accepted January 11, 1978. between the primary reactions of the host to the presence

950 CANCER RESEARCH VOL. 38

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. Amino Acid Catabolism in Host Liver of viable, replicating neoplastia tissue and those changes was developed: aliquots of the 150,000 x g supernatant occurring secondary to degenerative processes that ensue (100 to 200 /^il) were incubated for 4 min at 30°in the in the neoplastic tissue or in the organs of a tumor-bearing presence of 2 ml of 0.1 M L-serine in 0.15 M Tris-HCI buffer animal as death is approached. This study was undertaken containing 10~3M dithiothreitol and 10~4M pyridoxal at pH to determine the stage of growth of an implanted hepato- 8.1. The reaction was stopped by the addition of 0.2 ml of cellular at which the first metabolic changes in chilled 30% trichloroacetic acid. The precipitate was re enzymes of amino acid catabolism in the liver were detect moved by centrifugation, and an aliquot of the clear super able and the of such changes in those tissues, as natant was used for the spectrophotometric determination reflected by alterations in the activity of amino acid-cata- of pyruvate in the presence of NADH and excess lactate bolizing enzymes and their responsiveness to environmen dehydrogenase in a 0.2 M tCHPO., solution. The molar tal stimuli. extinction coefficient for NADH was taken to be 6.22 x 106. The results are expressed as /¿molof product formed per MATERIALS AND METHODS min per g of tissue, wet weight.

Animals. Adult male Buffalo rats, weighing 150 to 200 g, RESULTS were fed ad libitum a commercial and housed in a room lighted between 8 p.m. and 8 a.m. and dark from 8 a.m. to The activities of serine dehydratase, tyrosine aminotrans 8 p.m. After at least 1 week of acclimatization, the Morris ferase, ornithine aminotransferase, and alanine amino 7800 hepatoma was inoculated s.c. in both posterior limbs in the livers of rats bearing Morris hepatoma (see below). The night before sacrifice (light for the 7800 at various day intervals after tumor transplantation animals), food was withdrawn, but drinking remained may be seen in Charts 1 and 2. To obtain the control or available to the animals. For elimination of possible influ initial value of enzyme activity in host livers at Time 0, we ences of diurnal oscillations on enzyme activities, all ani sacrificed a group of animals immediately after inoculation mals were sacrificed between 10:30 and 11:30 a.m. with the tumor. The points obtained at subsequent 5-day For transplantation the tumors, after excision, were intervals were from animals randomly selected from the trimmed of any visible connective, adipose, and necrotic pool inoculated at Time 0. material, and the remaining solid tissue was minced in As has been reported previously (21, 29), the presence of chilled "suspension medium" (Swim's-77 medium; Grand Morris hepatoma 7800 had a striking influence on the Island Biological Company, Grand Island, N. Y.). An aliquot activity of serine dehydratase (Chart 1). As early as 5 days of 0.2 ml of the resulting suspension was inoculated s.c. after inoculation of the tumor, serine dehydratase activity with a 15-gauge needle. At intervals after inoculation had decreased slightly. Thereafter, a relatively rapid decay groups of 3 rats each were sacrificed by decapitation and in the activity of the enzyme occurred, such that, by 15 days exsanguination. Samples of tissue were promptly removed. after transplantation, serine dehydratase activity was signif Control rats were treated with 0.25 ml of the suspension icantly below that of the Time 0 control, exhibiting only medium. about 50% of the original activity of the enzyme. The liver Preparation of Tissues. Samples were frozen in liquid itself was grossly normal. Fifteen days later the activity of immediately after excision and were kept frozen at this enzyme was only barely detectable in the host liver, and -70° until ready to be used. Generally the same day the it was undetectable thereafter. tissues were processed in the following way: the frozen In agreement with other studies in which different neo tissue was crushed; approximately 1 g was weighed and plasms were used (9), the activity of ornithine aminotrans immersed in an aliquot of homogenizing buffer (0.1 M Tris- ferase also decayed rather rapidly in the host liver as tumor HCI, IO"3 M dithiothreitol, 10 3 M EDTA, and 10" M pyri- growth progressed. As can be seen from Chart 2, the decay doxal PO4,pH 8.0) sufficient to give a ratio of tissue to buffer of 1/3 (w/v). After being thawed the tissue suspension was homogenized in a glass homogenizer with a tight-fitting pestle. Samples of the whole homogenate were frozen at -70°and saved for the determination of ornithine amino- transferase activity. The remaining homogenate was centri- fuged at 150,000 x g for 60 min. The floating layer of fat was discarded, and the supernatant fluid was immediately assayed for alanine aminotransferase and serine dehydra- tase activities. Aliquots of the supernate were frozen at -70° and assayed for tyrosine aminotransferase activity generally on the next day. Enzyme Assays. Tyrosine aminotransferase activity was measured by an automated combination unit (22). The IO I5 20 25 30 35 activity of ornithine aminotransferase was determined by TIME IN DAYS the procedure described by Peraino and Pitot (20). Alanine Chart 1. Serine dehydratase (SDH) and tyrosine aminotransferase (TAT) aminotransferase activity was measured by the interrupted activities in the host liver of rats bearing Morris hepatoma 7800. Abscissa. time in days from the inoculation of the hepatoma at Time 0, as described in assay system described by de Rosa and Swick (7). For the "Materials and Methods." The values are expressed as enzyme units/g of determination of serine dehydratase activity, a similar assay tissue, wet weight, ±S.E.of 3 animals at each point. Bar, S.E.

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15 20 25 30 35 TIME IN DAYS 15 20 25 Chart 3. The response of serine dehydratase and tyrosine aminotrans TIME IN DAYS ferase to the administration of glucagon (1 mg/100 g) in rats bearing Morris Chart 2. Ornithine aminotransferase (Of) and alanine aminotransferase hepatoma 7800. The results are expressed as the -fold increase in the activity (AAT) activities in host liver of rats bearing Morris hepatoma 7800. See of each of the enzymes with respect to the enzyme activities observed in legend of Chart 1 for details. The values are expressed as the mean activities untreated tumor-bearing animals at each of the time intervals studied. from 3 different animals ±S.E.Bar, S.E. Abscissa, days after inoculation from Time 0. The values are the mean of 3 animals •S.E..as expressed in Charts 1 and 2. O, serine dehydratase activity; D, tyrosine aminotransferase activity. in the activity of this enzyme exhibited a plateau between 10 and 25 days after tumor inoculation. Subsequently, there inducibility of this enzyme was about 30 to 50% lower than was a rapid linear decay in the activity of the enzyme in the was that in control normal liver. host liver. On the other hand, the behavior of the 2 soluble To investigate the possibility that, during the growth of aminotransferases was significantly different from that ob Morris hepatoma 7800, metabolic alteration of the enzymes served for the mitochondrial ornithine aminotransferase or might occur in tissues other than liver, we determined the for serine dehydratase. Both alanine aminotransferase and levels of ornithine aminotransferase and alanine amino tyrosine aminotransferase were significantly increased over transferase in muscle and kidney 15 days after tumor the Time 0 control 15 days after transplantation of the implantation (Table 1). This interval between tumor inocula Morris 7800 hepatomas into the host. However, the activity tion and sacrifice of the host was selected as the shortest of the enzyme tended to decrease slowly for the next 10 period giving the most consistent metabolic changes in the days and then precipitously subsequent to 30 days after host liver without any visible degenerative alterations in tumor inoculation. Thirty-five days after transplantation the either liver or hepatoma. As can be seen from the table, the rats usually exhibited a terminal cachexia (6) with signifi activity of ornithine aminotransferase is consistently and cant loss of weight, fatty metamorphosis of the liver, and significantly lower in these tissues of tumor-bearing ani tumor necrosis. Even at this advanced state, however, the mals than in normal controls. No significant changes were activities of the soluble aminotransferases were between 30 observed in the levels of alanine aminotransferase when and 40% of the initial control values. normal and host tissues were compared. Not shown in the The response of tyrosine aminotransferase and serine table is a further decrease of ornithine aminotransferase dehydratase of the host liver to the s.c. injection of gluca- in muscle and kidney noted at 35 days after tumor inocula gon (1 mg/100 g of body weight) 8 hr prior to sacrifice was tion, while alanine aminotransferase activities in these 2 investigated to determine whether the response of these tissues remained unchanged, as did the activity of these enzymes to hormonal regulatory stimuli was altered in the enzymes in and heart at 15 and 35 days postinocula- host liver during the 5-week period subsequent to inocula tion. After the 25th postinoculation day, tumor-bearing tion of the tumor. Both of these enzymes in normal liver animals lost total body weight, while the tumors, which have been reported to be induced by the administration of weighed 1 to 2 g at the 25th day, doubled or tripled their glucagon at these dosages (10, 13). As can be seen from weight prior to the 35th postinoculation day. the data in Chart 3, the responses to the administration of glucagon of these 2 enzymes are distinctly different in the DISCUSSION tumor-bearing host. There is a progressive decrease in the inducibility of serine dehydratase in the host liver by gluca The influence of an implanted tumor on the level of a gon after the inoculation of the tumor. Twenty-five days number of hepatic enzymes has been described previously subsequent to tumor transplantation and thereafter, no (9). In these studies only 1 or, at the most, 3 time intervals induction of serine dehydratase by glucagon was evident in after transplantation of the tumor were studied. Such ex the host liver. On the other hand, at 10 days after inocula periments have the disadvantage of not showing the pro tion of the tumor the response of tyrosine aminotransferase gression of events in the process under study. Some inves to glucagon was significantly enhanced over control values, tigations in which the evolution of changes occurring in although by 20 days postinoculation and thereafter the host tissues has been monitored during the course of

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Table 1 Alanine aminotransferasecontrol and ornithine rats 15 aminotransferase days after inoculation activities of the in Morris liver, kidney, 7800 hepatoma and muscle of tumor-bearing and

Activity (¿tmol/min/g tissue, wet weight)

Liver Kidney Muscle

EnzymeAAT" ±2.036 ±7.55 ±0.09 ±0.38 ±0.58 ±0.22 OfControl54.86 2.83 ±0.21Host67.081.83 ±0.29Control3.973.36 ±0.24Host3.442.10 ±0.34Control7.690.14 ±0.01Host8.360.087 ±0.02 " AAT, alanine aminotransferase; OT, ornithine aminotransferase. 6 Mean ±S.E. of enzyme activity from 3 rats. The liver weights and body weights of control and tumor-bearing animals were comparable at this time. tumor development have indicated that misleading conclu necrotic tumor or bacterial toxins. sions can result by limiting the study of host-tumor relation From the experiments reported in this paper, it is possible ships to observations at only 1 point in time (33). to divide the time of host-tumor interaction after transplan During the advanced phase of tumor growth, many host tation into 3 stages, which are quite comparable to those tissues, liver in particular, often undergo degenerative originally described by Mider ef al. (16) in rats bearing the changes (6). The use of animals bearing fully developed transplanted Walker 256 tumor: an early phase, which tumors will, as a consequence, always carry the uncertainty develops during the first 10 days of the process, when of whether the observed effects are the direct result of the selective alterations occur in tissues; an intermediate pe presence of neoplastic cells in the organism or an indica riod, between 10 and 20 days after tumor transplantation, tion of nonspecific degenerative changes resulting only which could be interpreted as an attempt of the host indirectly from the presence of the neoplasm. Such nonspe organism to compensate for the metabolic imbalance cific degenerative changes may be the result of necrotic evoked by the growing tumor; and a final stage of exhaus degeneration of neoplastic tissue or of secondary bacterial tion of the compensatory mechanism of the host. The infection, or they may be by-products of either of these metabolic alterations observed in the host liver in the first processes. days after tumor implantation could be the result either of The results reported here indicate that several host tis specific nutritional requirements of the tumor cells [an sues, especially liver, are affected at very early stages of elevated uptake of amino acids is characteristic of many development of the tumor, as demonstrated by the fact that neoplastic tissues, and a selective affinity for specific amino the basal levels of some enzymes (serine dehydratase and acids has been demonstrated (5)] or of an aberrant metab ornithine aminotransferase) appear to be already repressed olism of the growing neoplastic tissue, which could result between 5 and 10 days after the inoculation of a suspension in changes in plasma metabolites other than amino acids. of neoplastic cells into the host animal. The decreased level Many tumor cells have a predominantly anaerobic metabo of these 2 enzymes does not appear to be merely 1 aspect lism with high rates of lactate production (8). Catabolites of a generalized depression of host liver function; rather, it might also be produced by the neoplastic cells, which are probably indicates the occurrence of selective metabolic not present in the plasma of normal animals. In this cate changes in the host. Such selectivity is indicated by the gory could be included the "toxohormones," the presence observation that, at the same time, increases in the levels of of which in the plasma of tumor-bearing animals has been other enzymes (tyrosine aminotransferase and alanine ami postulated by a number of investigators (for review see Ref. notransferase) are observed. The different sensitivity of 27). these 2 groups of enzymes to glucagon treatment further The observations that alanine aminotransferase activity supports the hypothesis of selective modification of liver was not altered in kidney and muscle and that both alanine metabolism occurring at this stage. and ornithine aminotransferase remained at control levels While our results do not give evidence of mechanisms in brain and heart at 35 days of tumor development sug responsible for the early changes in amino acid-cataboliz- gest that the specificity of the regulatory mechanism ing enzymes in host liver, several possibilities suggest operating in different tissues is preserved even in the more themselves. Since many neoplasms stimulate increased advanced stages of neoplastic growth. These results, taken adrenal hormone production in the host (6), it is possible together with the effects on amino acid-catabolizing en that the increases noted at 15 days in tyrosine and alanine zymes exhibited in liver (even early after transplantation of aminotransferases may be due to the increased production the Morris 7800 hepatoma), demonstrate that effects of this of by the host in response to the neoplasm neoplasm on host metabolism are a dynamic feature of the (10, 25). In a similar manner but through opposite effects, overall host-tumor relationship in this and quite likely other an increase in plasma glucocorticoid concentration could host-tumor interactions. account for the marked suppression of ornithine amino transferase (18). Furthermore, the fact that changes in the levels of some of these enzymes may be seen as early as 10 to 15 days after tumor transplantation when no neoplastic ACKNOWLEDGMENTS tissue is grossly visible at the site of inoculation suggests The authors wish to express their appreciation to Annabelle Cutler for that the observed effects are not secondarily mediated by assistance with the enzyme analyses.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1978 American Association for Cancer Research. Alterations in Enzymes of Amino Acid Catabolism in Livers of Rats Bearing the Morris 7800 Hepatoma

Guglielmo de Rosa and Henry C. Pitot

Cancer Res 1978;38:950-954.

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