Reversibility and Irreversibility of Liver Tumors in Mice ... · Nobuyuki Ito, Motoo Hananouchi,...

[CANCER RESEARCH 36, 2227-2234, July 1976]

Reversibility and Irreversibility of Liver Tumors in Mice Induced by the e Isomer of 1,2,3,4,5,6- Hexachlorocyclohexane

Nobuyuki Ito, Motoo Hananouchi, Seiichi Sugihara, Tomoyuki Shirai, Hiroyuki Tsuda, Shoji Fukushima, and Hiroshi Nagasaki First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

SUMMARY

The characterist ics of liver tumors in mice induced by the o~ isomer of 1,2,3,4,5,6-hexachlorocyclohexane (~x-BHC), were studied with emphasis on their reversibil i ty or irreversibility. Male 8-week-old DDY mice were fed basal diet supplemented w i th 500 ppm of e-BHC for 16, 20, 24, and 36 weeks and then were fed basal diet wi thout (x-BHC for 4, 8, 12, 16, 24, or 36 weeks. At various intervals, 13 to 20 mice were killed fo r l ight and electron microscopic observations.

The incidences of liver tumors in mice induced by o~-BHC increased progressively on cont inuous administrat ion of o~- BHC, but when its administrat ion was discont inued some tumors disappeared. Histologically, after (x-BHC administration for 24 weeks, most tumors were nodular hyperplasias, and there were only a few well-dif ferentiated hepatocellular carcinomas. However, 60 or 72 weeks after the beginning of the experiment, most of the liver tumors were hepatocel lular carcinomas and there were only a few nodular hyperplasias. At a later stage, 60 or 72 weeks, the liver parenchymal t issue in nontumorous areas was essentially normal, but smal l foci were occasional ly seen in nontumorous areas that were composed of remaining hyperplastic nodular cells, phagocytic cells, Kupffer cells, and leukocytes. These f indings suggest that the reversible tumors were usuarly nodular hyperptasias whereas the irreversible tumors were hepatocel lular carcinomas. After o~-BHC administration was stopped, many mesenchymal cells infil- trated the nodular hyperplastic lesions, and degenerated liver cells were found. These observations indicate that mesenchymal cell elements may be important in reversing the growth of l iver tumors induced by e-BHC.

INTRODUCTION

Increasing numbers of synthetic chemicals including pes- ticides and natural ly occurr ing carcinogens have been iden- tified in our environment. Many of the organochlor ide pesti- cides are h ighly stable and persist in the environment and some of them, such as aldrin, dieldrin (3, 5), and DDT (23- 25), have been demonstrated to have carcinogenic activity

, Supported in part by grants for scientific research from the Ministry of Educatioh, Culture and Science of Japan (001055, 001561,001062; 1975) and by a grant from the Experimental Pathological Research Association (1975).

Received October 14, 1975; accepted March 30, 1976.

when-given p.o. to experimental animals, especia l ly mice. Recently, the carcinogenic activity of the o rganoch lo r ide pesticide e-BHC 2 has also been observed in mice (11, 12, 16, 20) and rats (10).

The question of the nature of the liver tumors induced by chemical carcinogens in mice has frequently been raised (9, 19). One opinion is that liver tumors in mice do not have a neoplastic character because they show no s igns of inva- sion or metastasis to distant organs and because their histological patterns do not resemble those of ma l ignant tumors. That is, some of them do not resemble the lesions described as hepatocel lular carcinomas in rats or man (18). With regard to this problem, Kyriazis et al. (14) reported that detection of a high rate of lung metastasis was possib le only through detailed histological examinat ion, not s imply by macroscopic examinat ion of whole lungs. The observat ions reported here provide some suggestions for h isto logical criteria of cancer of tumors in mouse liver induced by chemicals.

MATERIALS AND METHODS

Three hundred forty-one male 8-week-old DDY mice (Awazu Animal Farm, Osaka, Japan), in i t ia l ly weigh ing about 18.6 g, were divided into 5 groups of 21 to 140 animals. They were fed basal diet (commercia l stock diet; Oriental Yeast Co., Tokyo, Japan) supplemented with 500 ppm of (x-BHC (Tokyo Kasei Chemical Co., Tokyo, Japan) for different periods as shown in Table 1. Twenty-one mice were fed basal diet containing e-BHC for 16 weeks and then sacrificed (Group 1). A total of 300 mice were fed basal diet containing (x-BHC for 20 (Group 2), 24 (Group 3), and 36 (Group 4) weeks. Then a total of 248 animals were kil led or maintained on basal diet wi thout (x-BHC for d i f ferent periods of 4, 8, and 12 (Group 2); 4, 8, 12, 16, 24, and 36 (Group 3); or 12, 24, and 36 (Group 4) weeks. Twenty con- trol mice (Group 5) were fed basal diet wi thout ~x-BHC for 72 weeks. Twelve to 20 mice were killed at these intervals. Mice that died during the experiment were excluded. The sample of o~-BHC used appeared to be over 99.0% pure by gas chromatography. Mixed diets were prepared once a week and kept in a cold room. Mice were housed ind iv idua l ly in a luminum cages in an air-condit ioned room under natural

2 The abbreviation used is: ~-BHC, ~ isomer of 1,2,3,4,5,6-hexachlorocyclohexane.

JULY 1976 2227

Research. on April 7, 2021. © 1976 American Association for Cancercancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

N. Ito et al.

Table 1 Changes of fiver weight and incidence of liver tumors in DDY mice induced by administration of 500 ppm of ot-BHC for different periods

Observation period (wk) Body wt (g) Liver wt

With o~- Without No. of Group BHC

in these areas had irregular cytoplasm, but mitotic figures were rare (Fig. 4).

When the d iet containing (x-BHC was discontinued, dark red nodules usually appeared. These were not clearly de- marcated f rom the surrounding liver tissues. These areas were composed of various kinds of cells, such as large phagocytic cells, Kupffer cells, lymphocytes, and polymor- phonuclear leukocytes, and the nodular hyperplastic cells frequently showed nuclear irregularities (Figs. 5 and 6). In these areas, small foci of myeloid metaplasia were occasionally seen. A few typical hyperplastic nodules and some areas of well-differentiated hepatocellular carcinoma were also found.

At a later stage, 60 or 72 weeks in the experiment, almost all the tumors appeared to be well-differentiated hepatocellular carcinomas. Areas of tumor showed large trabecular patterns with distended sinusoidal spaces and mitotic figures (Fig. 8). Nuclear irregularities and hemorrhagic changes were seen (Fig. 7). In nontumorous lesions in this stage, hepatic cells and periportal regions were essentially normal, al though small foci of phagocytic cells and histio- cytes were found as the remains of the dark red nodules. Areas of typical nodular hyperplasia were very rare.

No metastatic foci were found by careful examination of serially sectioned specimen of lungs, kidneys, and regional lymph nodes.

Ultrastructural Findings in Tumorous or Nontumorous Areas. In areas of nodular hyperplasia, the cytoplasm of the cells was elongated, the mitochondria were irregularly shaped, and the amount of smooth endoplasmic reticulum was greatly increased. The nuclei were usually smooth, and inclusions were frequently seen. Cytoplasmic areas occasionally contained concentrated lamellar bodies of various size.

In areas of well-differentiated hepatocellular carcinoma, the nuclei were irregular in shape, inclusions were frequently seen, and the nucleoplasm contained loose chromatin material and had low electron density. The nucleoli were enlarged and the nucleolonemata were deformed. Gly- cogen granules were not seen, but the number of free ribosomes on cytoplasmic areas was increased. Cells of nonnodular areas had an increased amount of smooth endoplasmic ret iculum, but nuclear irregularities were rare.

Areas of dark red nodules had a very peculiar appear- ance. These nodules were occasionally composed of different kinds of cells, such as phagocytic cells, monocytes, Kupffer cells, and remaining nodular hyperplastic cells. Many lysosomes were noticed in the cytoplasm (Fig. 9).

The cells in remaining areas of nodular hyperplasia had irregularly shaped mitochondria and a decreased amount of smooth endoplasmic reticulum. Glycogen granules were observed in the cytoplasm of some cells in dark red nodules. The nuclei were irregular in shape, and chromatin associated with the nucleolus was increased. Many degenerated cells were seen in hyperplastic nodules (Fig. 10). Some cells in dark red nodular areas had increased numbers of glycogen granules in their cytoplasm. Smooth endoplasmic ret iculum and elongated mitochondria were seen in remaining areas of hyperplasia in mice fed first an o~-BHC diet and then a diet without (x-BHC for 12 weeks.

~BHC Carcinogenesis

At a later stage of the experiment, after the diet containing (x-BHC was stopped, areas of hepatocellular carcinoma contained irregularly shaped cells with irregular or oval nuclei. Their nucleoplasm contained loose chromatin material, their nucleoli were enlarged, and their nucleolonemata were deformed.

Characteristic of a-BHC-induced Liver Tumors in Mice. The incidences of liver tumors in mice induced by o~-BHC are shown graphically in Chart 1. The incidence increased progressively on continuous administration of (x-BHC up to 36 weeks, but when its administration was discontinued some tumors disappeared. Thus tumors induced by o~-BHC may show either reversible or irreversible growth. After e- BHC administration for 24 weeks (Group 3), most tumors were nodular hyperplasias, and there were only a few well- differentiated hepatocellular carcinomas. However, 60 or 72 weeks from the beginning of the experiment (Groups 3 and 4), most of the liver tumors were hepatocellular carcinomas and there were only a few nodular hyperplasias. At this stage, the nontumorous liver parenchymal tissue was essentially normal, but small foci were occasionally seen in nontumorous areas that were composed of remaining hyperplastic nodular cells, phagocytic cells, Kupffer cells, and leukocytes. By electron microscopy, nodular hyperplastic cells could still be seen in the areas of dark red nodules containing mixed cells in the stage that most foci of nodular hyperplasia disappeared.

DISCUSSION

It has been found that liver tumors in mice induced by chemicals such as o~-BHC continue to show dynamic macroscopic, histological, and electron microscopic changes throughout the observation period. Therefore, in studies on chemical carcinogenesis neoplastic changes must be care- fully judged by histological and electron microscopic observations, as well as by macroscopic examinations.

Tumor cells may arise as a result of both somatic mutation and abnormal differentiation of target cells induced by proximate carcinogens (17).

In carcinogenesis, various changes of the cells induced by carcinogens have been regarded as preneoplastic changes (7, 8). There is much evidence that nodular hyperplasias may be I site of origin of hepatocellular carcinomas.

(%) z00 / . . . ... o.. ~ . . . . 41--o

�9 % t

49

with o -BHC

20 ". . . . . without o -BHC " A

- I I . . I I �9 �9 I1" 16 20 74 28 72 A 4"0 44 4"8 52 58 52 72 Weeks

Char t 1. I nc i dence of l iver t u m o r s in male DDY mice t reated w i th (~-BHC, (500 ppm in diet) when administrated for 16 weeks (Group 1, 0), 20 weeks (Group 2, A), 24 weeks (Group 3, II), and 36 weeks (Group 4, �9

JULY 1976 2229



N. I to e t a l .

These p reneop las t i c les ions of the l iver have been analyzed b iochemica l l y , h is to log ica l ly , h is tochemica l l y , b io log ica l l y , and by e lec t ron m ic roscopy , and the revers ib i l i ty or irrevers ib i l i ty of p reneop las t i c changes has been d iscussed extens ive ly (2, 6, 7, 13, 18, 22, 27). The present wo rk showed c lear ly that the p reneop las t i c change of nodu la r hyperp las ia of the l iver in mice induced by (x-BHC may be e i ther reversible or i r reversib le.

Several invest igators have repor ted that ep i the l i omesen- chymal i n te rac t ions in f luence the response of the epi the- l ium in ca rc inogenes is (1, 4, 15). The present resul ts show that t u m o r g rowth or p rogress ion is in t imate ly related to the in te rac t ions of mesenchyma l e lements and l iver parenchymal cel ls. Because af ter (x-BHC admin is t ra t i on was d iscon- t i nued , many mesenchyma l cel ls in f i l t ra ted the nodu la r hyperp las t ic les ions of hepa tocy te pro l i fe ra t ion tha t were en- cased in a very th in f i b roconnec t i ve t issue compress ing s u r r o u n d i n g l iver pa renchyma (7). Also degenera ted l iver cel ls were in the co l l ec t i ons of mesenchyma l cel ls. These observa t ions ind ica te tha t mesenchyma l cell e lements may play an impor tan t role in reversing the g rowth of l iver tumors induced by (~-BHC.

However , by e lec t ron m ic roscopy , hyperp las t ic l iver cel ls wi th i r regu lar ly shaped m i t o c h o n d r i a had decreased smoo th e n d o p l a s m i c re t i cu lum and an i r regu lar ly oval nu- c leus wi th several i nden ta t ions , cou ld sti l l be seen in dark red nodu les . Thus it is poss ib le that these remain ing cel ls in the dark red nodu les showed cancer or i r revers ib i l i ty at a re lat ively ear ly stage of the exper imen t (21).

The apparen t regress ion or p rogress ion of the l iver t u m o r nodu le may be in f luenced by both in t r ins ic and ex t r ins ic fac to rs (17, 26). In t r ins ic fac tors inc lude the immuno log i ca l state of the host , ag ing, ho rmona l ef fects, and species suscept ib i l i t y , wh ich were all f ound to in f luence t umor g row th or p rogress ion . Ext r ins ic fac tors inc lude the nutr i - t iona l state of the host, ca rc i nogen i c or n o n c a r c i n o g e n i c chemica ls , v i ruses, i r rad ia t ion, and pa tho log ica l changes of the o rgans . Hepa toca rc inogenes i s was f ound to be in- h ib i ted by a h igh l ipid d iet . It was also observed that carci - nogen i c or n o n c a r c i n o g e n i c chemica ls , such as 3-methy l - c h o l a n t h r e n e , 3 ,4-benzpyrene, and cz-naphthyl i so th iocya- nate had e i ther inh ib i to ry or p romo t i ng ef fects on l iver ca rc i nogenes i s in exper imenta l an imals . Viral and chemica l i n te rac t i ons on var ious mammary t umors in mice and rats have also been repor ted by many invest igators .

The re fo re , var ious in t r ins ic and ex t r ins ic fac tors may in- f l uence the revers ib i l i ty or i r revers ib i l i ty of p reneop las t i c les ions. Fu r the r analysis of these fac tors may prov ide an ef fect ive me thod for inh ib i t ing t u m o r g rowth .

REFERENCES

1. Ashley, C. A. Epithelial and Stromal Roles in Carcinogenesis. II. Tumor Development in Internal Transplants of Skin and Epithelium Treated with 3-Methylcholanthrene. J. Natl. Cancer Inst., 26:1445-1459, 1961.

2. Bannasch, P., Hesse, J., and Angerer, H. Hepatocellul~re Glykogenose and die Genese sogenannter hyperplastischer Knoten in der Thioace- tamid-vergiffeten Rattenleber. Virchows Archly. Zellpathol., 17: 29-50, 1974.

3. Davis, K. J., and Fitzhugh, O. G. Tumorigenic Potential of Aldrin and Dieldrin for Mice. Toxicol. Appl. Pharmacol., 4: 187-189, 1962.

4. Dawe, C. J. Changes in Cell Interrelationships during Epithelial Carcino-

genesis. In: W. Nakahara, S. Takayama, T. Sugimura, and S. Odashima (eds.), Topics in Chemical Carcinogenesis, pp. 401-426. Tokyo: Univer- sity of Tokyo Press, 1972.

5. Deichmann, W. B., Keplinger, M., Sala, F., and Glass, E. Synergism among Oral Carcinogens. IV. The Simultaneous Feeding of Four Tumori- gens to Rats. Toxicol. Appl. Pharmacol., 11: 88-103, 1967.

6. Epstein, S., Ito, N., Merkow, L., and Farber, E. Cellular Analysis of Liver Carcinogenesis: The Induction of Large Hyperplastic Nodules in the Liver with 2-Fluoreylacetamide or Ethionine and Some Aspects of Their Morphology and Glycogen Metabolism. Cancer Res., 27: 1702-1711, 1967.

7. Farber, E. Hyperplastic Liver Nodules. In: H. Busch (ed.), Methods in Cancer Research, Vol. 7, pp. 345-375. New York: Academic Press, Inc., 1973.

8. Farber, E., Sarma, D. S. R., Rakalakshmi, S., and Shinozuka, H. Liver Carcinogenesis: A Unifying Hypothesis. The Biochemistry of Disease. In: F. F. Becker (ed.), The Liver: Normal and Abnormal Functions, Vol. 5, pp. 755-771. New York: Marcel Dekker, Inc., 1975.

9. Grasso, P., and Crampton, R. F. The Value of the Mouse in Carcino- genicity Testing. Food Cosmet. Toxicol., 10: 418-426, 1972.

10. Ito, N., Nagasaki, H., Aoe, H., Sugihara, O., Miyata, Y., Arai, M., and Shirai, T. Development of Hepatocellular Carcinomas in Rats Treated with Benzene Hexachloride. J. Natl. Cancer Inst., 54: 801-805, 1975.

11. Ito, N., Nagasaki, H., Arai, M., Makiura, S., Sugihara, S., and Hirao, K. Histopathologic Studies on Liver Tumorigenesis Induced in Mice by Technical Polychlorinated Biphenyls and Its Promoting Effect on Liver Tumors Induced by Benzene Hexachtoride. J. Natl. Cancer Inst., 51: 1637-1646, 1973.

12. Ito, N., Nagasaki, H., Arai, M., Sugihara, S., and Makiura, S. Histologic and Ultrastructural Studies on the Hepatocarcinogenicity of Benzene Hexachloride in Mice. J. Natl. Cancer Inst., 51: 817-826, 1973.

13. Kitagawa, T., and Pitot, H. C. The Regulation of Serine Dehydratase and Glucose-6-Phosphatase in Hyperplastic Nodules of Rat Liver during Di- ethylnitrosamine and N-2-Fluorenylacetamide Feeding. Cancer Res., 35: 1075-1084, 1975.

14. Kyriazis, A. P., Koka, M., and Vesselinovitch, S. D. Metastatic Rate of Liver Tumors Induced by Diethylnitrosamine in Mice. Cancer Res., 34: 2881-2886, 1974.

15. Main, J. H. P., and Washeed, M. A. Epitheliomesenchymal Interactions in the Proliferative Response Evoked by Polyoma Virus in Odontogenic Epithelium in Vitro. J. Natl. Cancer Inst., 47: 711-726, 1971.

16. Nagasaki, H., Kawabata, H., Miyata, Y., Inoue, K., Hirao, K., Aoe, H., and Ito, N. Effect of Various Factors on Induction of Liver Tumors in Animals by the e-Isomer of Benzene Hexachloride. Gann, 66: 185-191, 1975.

17. Pitot, H. C. Neoplasia: A Somatic Mutation or a Heritable Change in Cytoplasmic Membranes? J. Natl. Cancer Inst., 53: 905-911, 1974.

18. Reuber, M. D., and Firminger, H. I. Morphologic and Biologic Correla- tion of Lesions Obtained in Hepatic Carcinogenesis in A • C Rats given 0.025% N-2-Fluorenylacetamide. J. Natl. Cancer Inst., 31: 1407-1429, 1963.

19. Roe, F. J. C., and Grant, G. A. Inhibition of Germ Free Status of Develop- ment of Liver and Lung Tumors in Mice Exposed Neonatally to 7,12- Dimethylbenz(a)anthracene: Implications in Relation to Tests for Carci- nogenicity. Intern. J. Cancer, 6: 133-144, 1970.

20. Schulte-Hermann, P., Leberl, D., Landgraf, H., and Koransky, W. Liver Growth and Mixed-Function Oxidase Activity: Dose-Dependent Stimula- tory and Inhibitory Effects of e-Hexachlorocyclohexane. Naunyn- Schmiedebergs Arch. Pharmacol., 285: 355-366, 1974.

21. Sugihara, R., Hiasa, Y., and Ito, N. Ultrastructural Changes in Nuclei and Nucleoli of Rat Liver Cells Treated with Hepatocarcinogens. Gann, 63: 419-426, 1972.

22. Teebor, G. W., and Becker, F. F. Regression and Persistance of Hyper- plastic Hepatic Nodules Induced by N-2-Fluorenylacetamide and Their Relationship to Hepatocarcinogenesis. Cancer Res., 31: 1-3, 1971.

23. Terracini, B., Testa, M. C., Cabral, J. R., and Day, N. The Effects of Long- Term Feeding of DDT to BALB/c Mice. Intern. J. Cancer, 11: 747-764, 1973.

24. Thorpe, E., and Walker, A. I. T. The Toxicology of Dieldrin (HEOD). I1. Comparative Long-Term Oral Toxicity Studies in Mice with Dieldrin, DDT, Phenobarbitone, /3-BHC and 7-HBC. Food Cosmet. Toxicol., 11: 433-442, 1973.

25. Tomatis, L., Turusov, V., Day, N., and Charles, R. T. The Effect of Long- Term Exposure to DDT on CF-1 Mice. Intern. J. Cancer, 10: 489-506, 1972.

26. Weisburger, J. H., Madison, R. M., Ward, J. M., Viguera, C., and Weis- burger, E. K. Modification of Diethylnitrosamine Liver Carcinogenesis with Phenobarbital but Not with Immunosuppression. J. Natl. Cancer Inst., 54: 1185-1188, 1975.

27. Yasuzumi, G., Sugihara, R., Ito, N., Konishi, Y., and Hiasa, Y. Fine Structure of Nuclei as Revealed by Electron Microscopy. VII. Hyperplas- tic Liver Nodules in Rat by 3'-Methyl-4-Dimethylaminoazobenzene, 2- Fluorenylacetamide and DL-Ethionine. Exptl. Cell Res., 63: 83-95, 1970.

2230 CANCER RESEARCH VOL. 36



o~-BHC Carcinogenesis

Fig. 1. Symmetrical cell hypertrophy in the liver of a mouse treated with cx-BHC for 16 weeks. H & E, x 100. Fig. 2. Nontumorous~area of the liver in a mouse fed ot-BHC diet for 24 weeks and then a diet without e-BHC for 12 weeks. H & E, x 100. Fig. 3. Nodular hyperplasia induced by e-BHC diet for 24 weeks. Note compression of surrounding liver parenchymal tissue. H & E, x 100. Fig. 4. Well-differentiated hepatocellular carcinoma in a mouse treated with e-BHC for 36 weeks. H & E, x 100. Fig. 5. Area o f a dark red nodule in a mouse 8 weeks after discontinuation of e-BHC diet. Many mesenchymal cell elements, macrophages, and

lymphocytes are seen infiltrating the hyperplastic nodular area. H & E, x 100. Fig. 6. Higher magnification of a dark red nodule, showing nuclear irregularities of liver cells and macrophages or giant cells, H & E, • 200. Fig. 7. Typical hepatocellular carcinoma in a mouse fed e-BHC diet for 24 weeks and then basal diet for 36 weeks. Dilation of sinusoidal spaces and an

increased number of nuclei in cell cords are seen with hemorrhagic necrosis. H & E, x 100. Fig. 8. Higher magnification of typical hepatocellular carcinoma. Tumor cells and nuclei are irregular in size and shape. H & E, x 200. Fig. 9. Liver o f a mouse fed ~x-BHC diet for 24 weeks and then basal diet for 4 weeks. Mesenchymal cells (MC) and phagocytic cells (PC) are seen. Many

lysosomes are seen in the cytoplasm of macrophages. Degenerated liver cells (DC) are also seen. x 5000. Fig. 10. Cells in a remaining area of nodular hyperplasia (NHC) in a mouse fed o~-BHC diet for 24 weeks. The amount of smooth endoplasmic reticulum is

decreased. Some degenerated cells are seen. x 5000.

JULY 1976 2 2 3 1



N. Ito et al.




o~-BHC Carcinogenesis

JULY 1976 2233



N. lto et al.




1976;36:2227-2234. Cancer Res Nobuyuki Ito, Motoo Hananouchi, Seiichi Sugihara, et al. 1,2,3,4,5,6-Hexachlorocyclohexane

Isomer ofαInduced by the Reversibility and Irreversibility of Liver Tumors in Mice

Updated version

http://cancerres.aacrjournals.org/content/36/7_Part_1/2227

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/36/7_Part_1/2227To request permission to re-use all or part of this article, use this link

http://cancerres.aacrjournals.org/content/36/7_Part_1/2227http://cancerres.aacrjournals.org/cgi/alertsmailto:[email protected]://cancerres.aacrjournals.org/content/36/7_Part_1/2227http://cancerres.aacrjournals.org/

Reversibility and Irreversibility of Liver Tumors in Mice ... · Nobuyuki Ito, Motoo Hananouchi,...

Documents

Transcript of Reversibility and Irreversibility of Liver Tumors in Mice ... · Nobuyuki Ito, Motoo Hananouchi,...