Development of Experimental Cancer in the Head of the

Pancreas by Surgical Induction of Tissue Injury

Lawrence Rosenberg, MD, CM, MSc, Montreal, Quebec, Canada

Wllllam P. Duguid, MB, ChB, FRCP, Montreal, Quebec, Canada

Ftea A. Brown, MD, CM, MSc, FRCS, Montreal, Quebec, Canada

The incidence of pancreatic cancer has increased significantly since 1930 [1,2]. It ranks fourth as a cause of cancer death [3], and is now the second most common gastrointestinal malignancy. If the prog- nosis is to be improved, a better understanding of the cause and pathogenesis of pancreatic cancer is nec- essary. The majority of carcinomas of the pancreas in humans are of ductal origin and are located in the head of the gland. However, existing animal models do not accurately reflect these clinical characteristics. Proliferative changes in the epithelium of the major ducts of the pancreas are of interest in the study of qrcinogenesis, since most neoplaams originate from ducts or ductules and may therefore be preceded, as in other organs, by preneoplastic lesions [4-81. We have recently described a method for the induction of proliferative changes in the hamster pancreas in association with partial pancreatic duct obstruction [9]. Our experimental system, used in combination with exposure to an exogenous carcinogen, has led to the development of a new model of carcinoma of the head of the pancreas.

Material and Methods

One-hundred twenty-eight 8 week old female Syrian golden hamsters (CBL, Syracuse, NY) were used. They were housed in plastic cages, and fed RMH 1OOP (Charles River, Syracuse, NY) and water ad libitum. The animals were randomly allocated to four groups. Group I, con- taining 36 hamsters, received weekly subcutaneous injec- tions of N-nitrosobis (2oxopropyl) amine at 10 mg/kg (Ash Stevens, Detroit, MI) dissolved in 0.9 percent saline solu- tion for 6 weeks. Group II, containing 36 hamsters, un- derwent laparotomy and cellophane wrapping of the head of the pancreas. On the 10th postoperative day, the initial injection of N-nitrosobis(2-oxopropyl)amine (10 mg/kg)

From the DepaHmeMs of Sugary and Pathology, The Montreal General kbsoltal and McGill Mwrsitv. Montreal. Canada. Suworted in Dart bv The Natknal Cancer lnstttute G&t 1 ROl .CA33351-Oi’SRC. Silk S&t. Maryland and by The Cancer Research Society. Montreal. Quebec, Canada.

Requests for reprints should be addressed to Rea A. &own. MD. The MoMreal Gerwral Hospital. 1650 cedar Avewa. Room 9950, Uvingsbm Hall. Montreal, Quebec. Canada H3G lA4.

Presented at the 24th Annual Meeting of the Society for Surgery of the Alimentary Tract, Washington. DC, May 24-25. 1983.

146

was administered, with subsequent doses given as in Group I. Group III, containing 36 animals, underwent cellophane wrapping alone. Group IV, containing 20 animals, under- went a sham procedure consisting of laparotomy with dissection in the region of the head of the pancreas but without cellophane wrapping. Sacrifice of eight animals from Groups I and II (four from each) was carried out 5 days after the initial injection of N-nitrceobis(2-oxopropyl) amine and then at 2 week intervals. In Group III, four an- imals were sacrificed on the fifth postoperative day and then at 2 week intervals. Four animals from Group IV were sacrificed at 5 days, 2 weeks, 6 weeks, 10 weeks, and 14 weeks postoperatively.

Following intraperitoneal pentobarbital (NembutaP) anesthesia, a midline laparotomy incision was made, and the distal common bile duct and head of the pancreas were exposed. Using blunt dissection, an avascular plane was developed to allow the placement of a 0.5 mm wide strip of sterile cellophane which was wrapped around the head of the gland (Figure 1) and tied loosely in position. Care was taken to avoid crushing the pancreatic tissue or occluding the common bile duct.

At the time of sacrifice, the animals were anesthetized with intraperitoneal nembutal, and a thoracotomy was performed. The left ventricle was cannulated with a no. 19 butterfly catheter, and the right atrium was vented. The animals were then perfused with lactated Ringer’s solution until the effluent from the right atrium was clear. The perfusate was then changed to a solution of 10 percent formalin, thereby fixing the tissues in situ. A complete autopsy was performed and then the pancreas was removed en bloc with the common bile duct and duodenum. The specimens were embedded in paraffin, 5 p sections were cut, and then they were stained with hemalum and eosin.

Serum ribonuclease was used as a marker of disease in our experimental setting. Blood collected at the time of sacrifice was centrifuged at 2,000 rpm for 15 minutes and the serum separated. Determination of serum ribonuclease activity was by Walton et al [IO] modification of Reddi and Holland’s method [II]. A ribonuclease unit is defined as that amount of ribonuclease present in 0.05 ml of diluted serum which causes a 0.001 increase in the absorbance of acid solubilized assay products.

Tumor size was evaluated using software developed for the Zeiss Videoplan, a computer-based system. Statistical analysis was by chi-square analysis, Student’s t test, and by determination of the correlation coefficient (r), with p <0.05 considered statistically significant [12].

lhe American Journal of Surpy

EXPERIMENTAL MODEL

F&m 1. Hamatorpanoraaa wtth oaHophana tapa (aatarkk) to pwltkn.

Results

The surgical procedures were well tolerated by all of the animals. None of the hamsters that underwent cellophane wrapping demonstrated signs of pancre- atic insufficiency, such as diarrhea. Weight gain be- tween experimental groups was comparable until 8 weeks, at which time growth in Group II animals (N-nitrosobus amine and cellophane wrap) plateaued and thereafter declined significantly (Figure 2). Group I animals (N-nitrosobis[2-oxopropyllamine) began to experience a less severe weight loss 1 month postoperatively. Both of these groups had a demon- strable weight gain at the conclusion of the experi- ment which was attributed to the presence of ascites in some animals.

In the sham-operated hamsters (Group IV) normal pancreatic histologic characteristics were demon- strated throughout the course of the study. The ep- ithelial lining of the major ducts was cuboidal or low columnar with a few goblet cells interspersed.

Cellophane wrapping of the head of the hamster pancreas (Group III) induced an initial inflammatory response, but by 2 to 4 weeks postoperatively, there was marked fibrosis surrounding the major ducts in the head of the gland, and the inflammatory reaction was minimal. Diffuse pancreatitis never developed despite the obstructing nature of the developing fi- brosis.

After 5 days of wrapping, ductal epithelial hyper- plasia and goblet cell metaplasia in the main ducts in the head of the pancreas became increasingly ev- ident (Figure 3). These changes appeared to become maximal at 4 weeks at which time the lining of the pancreatic common duct, which drains secretions from the duodenal and gastric lobes, and the common duct, representing the confluence of the pancreatic common duct and common bile duct, was formed by a pseudostratified columnar epithelium in which goblet cells were prominent and mitotic figures were seen. Papillary proliferation of the epithelial lining

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Group I animals demonstrated histologic changes attributable to the carcinogen. The earliest alter- ations were ductular dilatation with stasis and nesi- dioblastosis. Subsequent changes consisted of ade- nomatosis followed by atypical ductuIar proliferation and dysplasia. By the end of the study, six carcino- mas of ductular or acinar origin had been identified

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Vohmo 147, January 1984 147

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in the gastric or splenic lobes. The major ducts in the head of the pancreas remained either unaffected or demonstrated only mild simple hyperplasia.

In Group II, the histologic changes produced by wrapping and by the carcinogen both occurred. These were associated with the development of 12 carci- nomas, and these lesions developed earlier than those in Group I (chi-square 5.33, p <0.05) (Figure 4). In addition, 50 percent of the tumors in Group II were of ductal origin and these were located in the head of the gland (Figure 5), whereas none of the lesions in Group I were found in this location (chi-square 4.5, p <0.05). Group II tumors were also larger (maxi- mum diameter in millimeters) than those in Group I (1.64 f 0.32 mm versus 0.91 f 0.08 mm, p <0.05), and metastases to a regional lymph node was found in one Group II animal.

The pattern of serum ribonuclease activity was similar in each group (Figure 6) until 8 weeks into the study; however, there were some notable differences: the initial peak in activity that occurred in all the animals was observed 2 weeks earlier in Group II, and at all times, ribonuclease levels in Group III hamsters were greater than those in Group IV (control) ham- sters. After 8 weeks, the ribonuclease activity in Group II animals began to increase significantly, and

140 The American Journal ol Surgery

Experimental Pancreatic Cancer

eventually reached a peak at 14 weeks and thereafter decreased. In Group I, ribonuclease levels were only beginning to increase at 14 weeks. In Group II, for tumors less than 3.2 mm in diameter, serum ribo- nuclease activity was positively correlated with size (r = 0.85, p <O.Ol). If only the tumors located in the head of the gland are considered, the correlation is even more significant (r = 0.92, p <0.005). For tumors equal to or greater than 3.2 mm, the correlation was a negative one.

Comments

Cellophane wrapping of the hamster pancreas provides a unique opportunity for the study of ductal epithelial hyperplasia in the major ducts in the set- ting of partial pancreatic duct obstruction but in the absence of diffuse inflammation. The exact manner in which cellophane wrapping induces the observed morphologic alterations is not clear; however, the primary effect of this technique is periductal fibrosis in the head of the gland leading to partial pancreatic duct obstruction. The evidence for this is the re- sulting stasis of secretions, the dilatation of ducts and ductules, and the diminution in the luminal diameter of the pancreatic common and common ducts in areas adjacent to the induced fibrosis. Recently, we have also demonstrated diminished basal and se- cretin-stimulated pancreatic secretory flow in cel- lophane wrapped animals.

Ductal obstruction has long been known to be a mitogenic stimulus [13-171 and it has been suggested that fibrosis in particular is associated with ductal epithelial proliferation and goblet cell metaplasia [18,19]. The changes in ductal stasis, ductal epithelial hyperplasia, and the initiation of nesidioblastosis, which are the principal features of this model? also occur in the setting of experimental pancreatic chemical carcinogenesis [20,21]. It is of considerable interest that these proliferative changes can be pro- duced in the absence of an exogenous carcinogen, and therefore make primary duct obstruction or stasis, and ductal hyperplasia important factors to be studied in pancreatic neoplasia. The relationship between ongoing chronic irritation and the subse- quent appearance of carcinoma has been a matter of speculation for many years. Seventeen to 33 percent of pancreatic cancers are said to be preceeded by chronic inflammation [22-261. In addition, it has been found that at least 67 percent of cases are as- sociated with partial duct obstruction [27,28].

This is the first report of an experimental model for the production of carcinoma of the head of the pancreas. The mitogenic stimulation of ductal epi- thelium in the major ducts by the technique of eel- lophane wrapping no doubt was responsible for the development of tumors in this location. This is in accordance with the multistep theory of neoplasia which suggests that cellular proliferation may be

more important than exposure to a carcinogen in initiating the neoplastic process.

Increased levels of serum ribonuclease have been reported in studies of patients with various types of cancer 129,301. An elevation of ribonuclease activity was found in the serum of many patients with pan- creatic carcinoma, although the assay sensitivity was not high [II]. The correlation between histologic characteristics or the tumor and enzyme activity has also been examined [31,32]. Serum ribonuclease may also be elevated in the setting of pancreatic necrosis, and renal impairment invalidates the assay. The origin of serum ribonuclease is controversial and al- though some studies have indicated that an elevation of ribonuclease activity represented new production by the tumor [31-331, this concept has recently been challenged [34,35]. The correlation in our model of serum ribonuclease activity with the earlier stages of carcinogenesis may explain the low clinical sensitivity of this assay in patients in whom the disease is usu- ally very advanced at the time of presentation.

Summary

The majority of carcinomas of the pancreas in humans are of ductal origin and are located in the head of the gland. These clinical characteristics however, are not affected in traditional animal models of the disease. Partial pancreatic duct ob- struction with ductal epithelial hyperplasia was produced in the Syrian golden hamster by wrapping the head of the pancreas with cellophane tape. Wrapped and unwrapped animals were then exposed to an exogenous carcinogen (N-nitrosobis[2-oxo- propyllamine). Assay of serum ribonuclease activity was used as a marker of disease. Invasive lesions de- veloped in both groups of animals. Fifty percent of the tumors in the Group II (cellophane wrap and N-nitrosobis [2-oxopropyl] amine) hamsters were located in the head of the gland and were of ductal origin. All tumors in animals receiving N-nitrosobis [%oxopropyl]amine alone (Group I) occurred pe- ripherally and were derived from ductular or acinar tissue. Elevation of serum ribonuclease activity was noted early in the course of carcinogenesis, thereafter returning to normal, which may explain the clinical controversy regarding this marker. This new model should enhance our knowledge of the interrelation- ships between etiologic factors, precusor lesions, and pancreatic cancer.

References

1. Wynder EL, hdabuchi K, Maruchi N, Fortner JG. Epidemiology of cancer of the pancreas. J Nat1 Cancer lnsi 1973;50: 645-67.

2. Krain LS. The rising incidence of carcinoma of the pan- creas-real or apparent? J Surg 0ncol 1973;2:115-24.

3. American Cancer Society. 1972 cancer facts and figures. New York: American Cancer Society, 1972: l-72.

4. Cubilla AL, Fitzgeraki PJ. hduphological lesions associated with

Volume 147, January 1964 149

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human primary invasive nonendocrine pancreas cancer. Cancer Res 1976;36:2690-8.

Kozuka S, Sassa R, Torki T, et al. Relation of pancreatic duct hyperplasia to carcinoma. Cancer 1979;43:1418-28.

Nakamura N. Untersuchungen uber das pankreas bei foten, neugeborenien, kindrernund im puberstats alter. Virchows Arch 1924;253:286-349.

7. Pour PM, Saad S, Sayed G. Hyperplasia, preneoplastic and neoplastic lesions found in 83 human pancreases. Am J Clin Pathol i982;77:137-52.

31. Cretien PB, Matthews US. Serum ribonucleases in cancer: relation to tumor histology. Cancer 1973;31: 175-9.

32. Funokoshi A, Wakasujc H, Kimura T, Matsumoto M, lbayashi H. Serum ribonucleases in pancreatic cancer: relation to

tumor histology. Gastroenterol Jpn 1978;13:390-4. 33. Renner IG, Mocka, Reitheman R, Douglas AP. An isoenzyme

of serum ribonuclease specific for pancreatic cancer. Gastroenterology 1976;74:1132.

a.

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Somrners SC, Murphy SA, Warren S. Pancreatic duct hyper- olasia and cancer. Gastroenterolwv 1954;27:629-40. r -~-

Rosenberg L, Brown RA, Duguid WPlA new approach to the induction of duct epithelial hyperplasia and nesidioblastosis by cellophane wrapping of the hamster pancreas. J Surg Res 1983;35:63-72.

34. Warshaw AL, Lee K-H. Characteristic alterations of serum isoenzymes of amylase in diseases of liver, pancreas, sali- vary glands, lung and genitalia. J Surg Res 1977;22:362- 9.

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Walton D, Nakazawa S, Kajikawam, et al: RNase levels in golden hamsters with DHPN induced pancreatic cancer. Gastroenterology 1979;14:74-9.

Reddi KK, Holland JF. Elevated serum ribonuclease in patients with pancreatic cancer. Proc Natl Acad Sci USA 1976;73: 2308-10.

35. Abramson SB, Renner IG. Catalytic evidence for nonpancreatic origin of polycytidylate-selective ribonuclease (RNase C) in the peripheral circulation. Newsletter of the National Pancreatic Cancer Project 1981;6:3.

Discussion

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Ferguson GA. Statistical analysis in psychology and education. Montreal: McGraw-Hill, 1976:1-492.

Dpie EL. Cytology of the pancreas. In: Cowdry EV, ed. Special cytology, volume 1. New York: Paul Hoeber, 1928:241- 71.

14.

15.

Courtney M. Townsend, Jr. (Galveston, TX): I would like to congratulate Dr. Rosenberg and colleagues on very nicely carrying out and presenting a study of carcinogenesis in the pancreas. It is a nice demonstration that the more cells that are undergoing mitosis at one time, the greater the chance for error, particularly when carcinogens are present.

16.

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Kirkbride MB. The islet of Langerhans after ligation of the pancreatic ducts. J Exp Med 1972;15:101-5.

Zelander T, Ekholm R, Edlund Y. The ultrastructure of rat exo- crine pancreas after experimentally occluded outflow. J Uitrastruct Res 1964;10:89-102.

Boquist L, Edstrom C. Ultrastructure of pancreatic acinar and islet parenchyma in rats at various intervals after duct liga- tion. Virchows Arch 1970;349:69-79.

Chung A, Richter WR. Early changes in the exocrine pancreas of the dog and rat after ligation of the pancreatic duct. Am J Pathol 1971;62:521-34.

Of particular importance to the study of the natural history of pancreatic cancer in the animal model may be the ability, in this particular model, to decrease the dose of carcinogen because the major problem, especially in such animals, is the occurrence of tumors at other sites beside the primary site.

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Walters MN-I. Goblet cell metapiasia in ductules and acini of the exocrine pancreas. J Path Bact 1965;89:569-72.

Roberts PF. Pyloric gland metaplasia of the human pancreas. Arch Pathol Lab Med 1974;97:92-5.

Pour P. Experimental pancreatic ductal (ductular) tumors. In: Fitzgerald PJ, Morrison AB, eds. The pancreas. Baltimore: Williams and Wilkins, 198O:ll l-39.

Pour P. Islet cells as a component of pancreatic duct neo- plasms. I. Experimental study: ductular cells including islet cell precursors as primary progenitor cells of tumors. Am J Pathol 1978;90:295-316.

Did the animals that were wrapped have tumors at other sites, and did that interfere with their survival? Was the number of animals with tumors greater in Group II or was it just the number of tumors in the animals? Finally, re- garding ribonuclease activity, it appeared that the wrap alone also increased the activity. Is that really a marker of proliferation only or of malignant proliferation since ele- vated levels disappear as tumors get larger, or is it related to the specific type of cells (pancreatic) that are prolifer- ating?

22. Paulins-Netto A, Dreiling, DA. The relationship between pan- creatic calcification and pancreatic cancer. Acta Chir Stand 1970;136:493-6.

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Grozinger K-H, Dahlenbach F, Heisler H. Correlations between chronic and malignant diseases of the pancreas. Langen- be& Arch Chir 1969;326:47-61.

Lundh G, Nordenstam H. Pancreatic calcification and pancreatic cancer. Acta Chir Stand 1970; 136:493-6.

Kaiser G, Hammel G. Morphometric-statistical analysis of pancreatic arteries in chronic pancreatitis. Virchows Arch 1975;365:103-18.

26. Becker V. Carcinoma of the pancreas and chronic pancreati- tis-a possible relationship. Acta Hepatogastroenterol 1976;25:257-9.

27.

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Kasugai T, Nobuyoshi K, Minoru K. Manometric endoscopic retrograde pancreatocholangiography: technique, signifi- cance, evaluation. Am J Dig Dis 1974;19:485-502.

Ogoshi K, Niwa M, Hara Y, et al. Endoscopic pancreatocho- langiography in the evaluation of pancreatic and blliary dis- ease. Gastroenterology 1973;64:210-6.

Migliarese JF. Serum ribonuclease In the cancer patient. Proc Am Assoc Cancer Res 1958;2:327.

Levy AL, Rottins A. Serum ribonuclease levels in malignant and

Richard II. Bell, Jr. (San Diego, CA): All of us who work with the Syrian hamster model would like it to be analogous to human pancreatic cancer, but I think some caution is appropriate. When this model was first described by Pour, it was appealing because it appeared to be a ductular cancer, perhaps more like human pancreatic cancer than previous animal tumors which were thought to be of acinar origin. However, recent studies by Bockman and by Flaks suggest that hamster tumors are not of ductular origin but, in fact, originate from acinar cells by a process of dedifferentiation. In regard to drawing an- alogies to human pancreatic cancer, one problem with your cellophane model is that tumors may ultimately develop in the tail of the gland even after discontinuing N-nitro- sobus amine. In some cases, even a single dose of N-nitro- sobus amine will cause pancreatic cancer if one waits long enough. This predilection for continued new tumor de- velopment in the tail of the pancreas may not be analogous to the human situation.

Frank Jones (Milwaukee, WI): As far as I am aware this is the first documentation supporting the two-step theory

150 The American Journal of Surgery

nonmalignant diseases. Proc Am Assoc Cancer Res 1959;3:36-7.

Experimental Pancreatic Cancer

of carcinogenesis in pancreatic carcinoma. Yesterday, Dr. O’Leary suggested that obstruction of the duct was not necessary for there to be hyperplastic changes (Am J Surg 1983;147:72-7). However, you showed some indication of at least partial ductal obstruction. Do you have any further evidence that obstruction of the duct itself is necessary? Have you totally ligated the pancreatic duct to see if this is important? Is bile contact necessary? Have you per- formed experiments that might increase bile flow or changed the concentration of various bile acids? Have you performed biliary diversion and then been able to produce your pancreatic carcinoma? What is the role of the cello- phane? Is the material itself important or is it just the nonspecific inflammatory changes that are created in that particular region of the pancreas? Did you perform a dis- section and then give the carcinogen, or did you use other materials and then give the carcinogen? I work with mice, not hamsters. What is there about the hamster, if anything, that would promote pancreatic tumors? You used females. Have you tried it in males? To repeat a question already asked, do these animals get more neoplasms elsewhere or spontaneous tumors? Lastly, to try to relate these findings to the human condition, have you tried your model in an- imals that were also given alcohol, caffeine, or some of the substances that is supposed to contribute to pancreatic carcinoma in people? Have you given anything to these animals to try to prevent it, such as antioxidants?

Howard A. Reber (Columbia, MO): I enjoyed the paper very much. You have shown that the reaction to injury produced by wrapping, which was associated with an in- creased mitotic index, made this portion of the pancreas more susceptible to carcinogenesis. That is a general phe- nomenon that has been demonstrated in other organ sys- tems, but to my knowledge, has never been shown in the pancreas before. I think that this is a major accomplish- ment. I take issue, however, with your suggestion that this model is now more relevant to the human disease because the tumor was concentrated in the head of the pancreas. I believe that if you wrapped the body of the pancreas or its tail, you would have found that the cancer developed preferentially in those areas. The pancreas in hamsters is so different from that in humans that we must be careful about making any comparisons between the two. We also have no idea of the relevance of the carcinogen used to that which causes the human disease.

Martin H. Max (Norfolk, VA): Three questions: Why do you suppose the ribonuclease activity diminished over time after the initial elevation? Why was there weight loss in these animals? Was it secondary to malabsorption be- cause of ductal obstruction or progresssive disease? If this is applicable to man, do these tumors metastasize, and if so at what rate?

Leonard Rosoff, Sr. (LX Angeles, CA): I wish to inquire about the cellophane referred to in this excellent presen- tation. Approximately 20 years ago, I was wrapping aortic aneurysms with cellophane obtained from the DuPont Company until informed by them that no more was avail- able as they had discontinued its manufacture. In the au- thors’ experiments what was the chemical structure of the cellophane wrapping and its possible carcinogenicity and, just out of curiosity, where was it obtained?

Lawrence Rosenberg (closing): In response to the questions of Drs. Bell and Reber concerning the origin of the tumors, I agree that the lesions reported by Pour and others, which are largely located peripherally, may be of acinar origin; however, I think we have demonstrated convincingly by sequential photomicrographs that the tumors in our model which were located in the head of the gland almost certainly were of ductal epithelial origin and in this respect, were similar to human pancreatic cancer. I agree with Dr. Jones that the model is a good represen- tation of the multistep theory of carcinogenesis. The evi- dence for obstruction playing a role in the development of proliferative changes in the ductal epithelium is derived in part from this study and from work to be reported else- where. In short, we have found that the obstructive nature of the fibrosis induced by wrapping with cellophane is as- sociated with a significant uptake of 3H-thymidine in ductular epithelial cells, acinar cells, and islet cells throughout the gland; that is, at sites distant from the in- flammation in the head of the gland. As serum ribonuclease activity is strongly correlated with increasing tumor size (up to 3.2 mm), it is not unreasonable to suggest that the tumor is responsible, at least in some measure, for ribo- nuclease production. The decrease in serum ribonuclease activity seen with very large lesions may therefore be at- tributable to an alteration in tumor metabolism. A similar phenomenon has been described in the experimental rat hepatoma model.

Volume 147. Jammy 1984 151