Inhibition of Pancreatic Hepatocyte Induction in Hamsters Treated Sequentially with Ethionine, a Protein-free Diet and then Methionine by Prior N-nitrosobis-(2-oxopropyI)amine Administration

A 100% yield of pancreatic hepatocytes was induced in pancreas tissues of female hamsters treated with twice-repeated sequential administrations of DL-ethionine (ethionine) together with a protein-free diet and then L-methionine (methionine) for 10 weeks. The cells were also found in 40% of hamsters receiving 20mg/kg body weight of the pancreatic carcinogen, N nitrosobis(2-oxopropyl)amine (BOP) given twice at the peak of pancreatic regeneration stimulated by methionine after ethionine induced cell damage. However, BOP at doses of 30, 70, and 100 mg/kg body weight administered before the occurrence of pancreatic regeneration dose dependently inhibited their appearance, with reduction of the yield to 40%, 25%, and 8.3% respectively, and BOP per se did not induce any development of pancreatic hepatocytes. Stein iodine staining revealed bile pigments in the induced hamster pancreatic eosinophilic cell populations.     

Inhibition of pancreatic hepatocyte induction in hamsters treated sequentially with ethionine, a protein-free diet and then methionine by prior N-nitrosobis-(2-oxopropyl)amine administration

A 100% yield of pancreatic hepatocytes was induced in pancreas tissues of female hamsters treated with twice-repeated sequential administrations of DL-ethionine (ethionine) together with a protein-free diet and then L-methionine (methionine) for 10 weeks. The cells were also found in 40% of hamsters receiving 20 mg/kg body weight of the pancreatic carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP) given twice at the peak of pancreatic regeneration stimulated by methionine after ethionine-induced cell damage. However, BOP at doses of 30, 70, and 100 mg/kg body weight administered before the occurrence of pancreatic regeneration dose-dependently inhibited their appearance, with reduction of the yield to 40%, 25%, and 8.3% respectively, and BOP per se did not induce any development of pancreatic hepatocytes. Stein iodine staining revealed bile pigments in the induced hamster pancreatic eosinophilic cell populations.     

Stimulation of islet cell proliferation enhances pancreatic ductal carcinogenesis in the hamster model.

Previous studies have shown that some N-nitrosobis (2-oxopropyl)amine (BOP)-induced ductal/ductular pancreatic cancers in the hamster model develop within islets and that streptozotocin (SZ) pretreatment that caused islet degeneration and atrophy inhibits pancreatic cancer induction. Hence, it appears that in this model islets play a significant role in exocrine pancreatic carcinogenesis. To examine whether stimulation of islet cell proliferation (nesidioblastosis) enhances pancreatic exocrine cancer development, we tested the effect of the pancreatic carcinogen BOP in hamsters after induction of nesidioblastosis by cellophane wrapping. Before wrapping, hamsters were treated with SZ to inhibit pancreatic tumor induction in the unwrapped pancreatic tissues. Control groups with a wrapped pancreas did not receive SZ. Six weeks after SZ treatment, all hamsters were treated with BOP (10 mg/kg body weight) weekly for 10 weeks and the experiment was terminated 38 weeks after the last BOP treatment. Many animals recovered from their diabetes at the time when BOP was injected and many more after BOP treatment. Only nine hamsters remained diabetic until the end of the experiment. Both SZ-treated and control groups developed proliferative and malignant pancreatic ductal-type lesions primarily in the wrapped area (47%) but less frequently in the larger segments of the pancreas, including the splenic lobe (34%), gastric lobe (13%), and duodenal lobe (6%). Only a few lesions developed in the unwrapped pancreatic region of nine diabetic hamsters with atrophic islets, whereas seven of these hamsters had tumors in the wrapped area. Histologically, most tumors appeared to originate from islets, many invasive carcinomas had foci of islets, and some tumor cells showed reactivity with anti-insulin. The results show that, in the BOP hamster model, islets are the site of formation of the major fraction of exocrine pancreatic cancer and that induction of nesidioblastosis enhances pancreatic carcinogenesis.     

Early changes in islet hormone secretion in the hamster pancreatic cancer model

The diabetic state that is seen at a high frequency in association with pancreatic cancer is characterized by elevated plasma levels of several islet hormones and by marked insulin resistance. Both the diabetic state and insulin sensitivity improve after tumor removal by sub-total pancreatectomy. Impaired glucose tolerance has also been found in the hamster pancreatic cancer model, but conflicting data regarding islet function have been reported. In order to further investigate islet function and secretion during early development of pancreatic cancer, we measured the concentrations of insulin, glucagon, somatostatin, and islet amyloid polypeptide (IAPP) in plasma, pancreatic tissue, and secretin-stimulated pancreatic juice at 12 and 27 weeks after the ductal-cell-specific carcinogen, BOP had been used to induce tumors in Syrian golden hamsters. At 12 weeks after BOP, plasma glucagon levels were significantly increased. An exaggerated plasma-glucose response and concomitant hyperinsulinemia were observed at 27 but not 12 weeks after BOP. Plasma IAPP concentrations, but not glucagon or somatostatin, were elevated at 27 weeks. Tissue concentrations of IAPP were substantially reduced in BOP-treated hamsters at 27 weeks. No differences in hormone concentrations were seen in pancreatic juice from the two groups at either of the two time points investigated. The study showed that islet hormone changes accompany the early development of pancreatic tumors in the hamster pancreatic model. The hormone changes and apparent insulin resistance resemble the metabolic changes found in humans with pancreatic cancer.     

Expression of human tumor-associated antigens in pancreatic cancer induced in Syrian hamsters.

Our previous studies have shown that pancreatic cancer induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) shows remarkable similarities with the human disease in morphologic and biologic characteristics. Moreover, both human and hamster pancreatic cancer share expression of some tumor-associated antigens, such as those with blood group specificities, including A, B, H, Leb, Lex, and Ley. By examining other antigens commonly expressed in human pancreatic cancer, we have found that monoclonal antibodies CO17-1A (recognizing 17-1A antigen), OC 125 (recognizing CA 125 antigen), B72.3 (recognizing TAG-72 and DU-PAN-2 react with induced pancreatic cancer in a pattern similar to that seen in human pancreatic cancer. Remarkably, although the epitopes of the antigens recognized by these three antibodies are different, many tumor cells were reactive with all these antibodies. However, in contrast to the human cancer, none of these antigens were expressed in the normal hamster pancreatic tissue, except for 17-1A. However, all of these antigens were expressed in some hamster tissues showing the same cellular localization as pancreatic cancer cells and corresponded, to a great extent, with findings in human tissue. Expression of these antigens was diminished in vitro (cell culture) but was regained in vivo (homologous transplantation). The results emphasize the usefulness of this experimental model for studying some aspects of tissue antigenicity, particularly as it relates to pancreatic cancer.     

The role of pancreatic islets in experimental pancreatic carcinogenicity.

Our previous studies have suggested that the presence of intact islets is essential for the induction of pancreatic exocrine tumors in the Syrian hamster model. To validate this, we investigated the effect of the carcinogen, N-nitrosobis(2-oxo-propyl)amine (BOP) in hamsters, in which homologous isolated intact islets were transplanted into the submandibular gland (SMG). Freshly isolated pure islets from hamster donors were transplanted into the left SMG of 20 female host hamsters. Ten of these hamsters (group 1) received BOP (40 mg/kg) weekly for 3 weeks. Another 10 hamsters (group 2) were kept untreated. In groups 3 and 4 (10 hamsters each) the salt solution or isolated pancreatic ductal cells, respectively, was injected into the gland. In other groups (10 hamsters each) islets were transplanted into the peri-SMG connective tissue (group 5) or into the renal subcapsular space (group 6). Hamsters of group 1 (40 mg/kg, weekly for 3 weeks) as were group 7 hamsters, which served as BOP-treated controls. All BOP-treated hamsters developed pancreatic lesions. Similar hyperplastic and atypical ductal/ductular proliferation and in situ carcinoma were found in the SMG of many group 1 hamsters. No such lesions were found in the SMG, peri-SMG, or renal subcapsular space of the other groups. Islets appear to be involved in carcinogenicity of BOP. The mechanism is obscure.     

Modification of pancreatic carcinogenesis in the hamster model. 2. The effect of partial pancreatectomy.

The effect of partial pancreatectomy (PP) on the pancreatic carcinogenicity of N-nitrosobis (2-oxopropyl)amine (BOP) was investigated in Syrian golden hamsters by subcutaneous injection of a single dose of BOP (20 mg/kg, body weight) given 30 minutes after (Group 1), 1 week after (Group 2), or 1 week before 70% PP (Group 3). Additional groups consisted of animals with PP alone (Group 4), sham operation (laparotomy) followed 30 minutes later by BOP treatment (Group 5), and BOP treatment only (Group 6). The experiment was terminated 46 weeks after BOP administration in each group. The pancreas and extrahepatic bile ducts, including the common duct and gallbladder, were examined histologically. Tumor patterns were compared in hamsters with PP and in the corresponding segments of the pancreas in BOP-treated control groups. The pancreatic cancer incidence was highest (31%) in Group 2 and lowest in Group 1 (3%), a difference that was statistically significant (P less than 0.01). Also, a statistically highly significant larger number of tumors occurred in Group 2, compared with group 1, 3, or 5 (P less than 0.0005). In a comparison of the number of carcinomas per tumor-bearing hamster, there were greater numbers of carcinomas in Group 2 (2.6 carcinomas) than in Groups 1, 3, 5, and 6 (1.0, 1.0, 1.3, and 2.6 tumors, respectively). Moreover, pancreatic tumors in Group 2 hamsters were larger (average diameter, 10 mm) than in Group 1 (4 mm), Group 3 (3.5 mm), Group 5 (4 mm), and Group 6 (average, 9mm). The incidence of extrapancreatic tumors did not vary among the PP groups but was equally lower than those in BOP-treated control groups. The data indicated BOP carcinogenesis was inhibited by surgery (regardless of whether PP was per formed) when the carcinogen was given 30 minutes after the surgery but was significantly enhanced when BOP was administered 1 week after PP. The possible reasons for these conflicting results are discussed. Morphologically all tumors were of ductular, ductal, and mixed ductular-insular patterns and most developed at the resected margins, where proliferation of islets, ducts, and ductules, but not of acinar cells, occurred. The results confirm our view that the ductal and ductular cells are the progenitor cells for BOP-induced pancreatic tumors in hamsters.     

Combined hepatocellular carcinoma and osteoclast-like giant cell tumor of the liver: Possible clue to histogenesis

Hepatic giant cell tumor is extremely rare, and only five cases have been reported of overt hepatocellular carcinoma, thus its histogenesis is controversial. Herein is reported a case of simultaneous hepatocellular carcinoma and osteoclast-like giant cell tumor in a single tumor. A liver tumor was found in a 74-year-old woman. Histologically the tumor consisted of two distinct components: mononuclear and multinuclear giant cells with osteoclastic giant cells, and a conventional hepatocellular carcinoma. The boundary between the two components showed transitional features. Immunohistochemistry showed that the osteoclast-like giant cells were CD68 and vimentin positive, but cytokeratin and AFP negative, while spindle-shaped cells were positive only for vimentin. In a portion of the hepatocellular carcinoma the cells were cytokeratin-8 and AFP positive. Ki-67 positivity was 10% for the hepatocellular carcinoma, 60% for the spindle-shaped cells, and 0% for the giant cells. It is possible that the tumor might have had a hepatocellular carcinoma origin, given the more highly proliferative sarcomatous changes and reactive osteoclast-like cells. This case provides a clue to the histogenesis of hepatic giant cell tumors.     

Modification of pancreatic carcinogenesis in the hamster model. 3. Inhibitory effect of alloxan.

Alloxan, when given intravenously at a dose of 60 mg/kg body weight 2 hours prior to subcutaneous injection of the potent pancreatic carcinogen N-nitrosobis (2-oxopropyl) amine (BOP), inhibited the induction of hyperplastic and neoplastic pancreatic lesions in a statistically significant fashion (P less than 0.01). The number of lesions per animal affected was markedly less in these animals, compared with BOP-treated control animals. BOP administration 2 weeks after alloxan treatment, at which time pancreatic islet cell regeneration is considered completed, did not alter either the incidence or number of lesions. The results support our view that the pancreatic islet cells are the primary source of BOP metabolism. The concomitant inhibition of gallbladder tumors, but not of common duct neoplasms, in hamsters receiving BOP 2 hours after alloxan could indicate that alloxan's inhibitory effects on BOP carcinogenesis are not restricted to the pancreas.     

Pleomorphic (giant cell) carcinoma revisited: A historical perspective and conceptual reappraisal

The term pleomorphic "giant cell" carcinoma was coined by Sommers and Meissner in 1954 for a pancreatic carcinoma variant showing a "sarcoma-like transformation" and characterized by an admixture of undifferentiated cells with striking variation in size and shape. Based on the predominant cell type, four patterns were recognized: spindle cell (sarcomatoid), pleomorphic "giant cell", osteoclastic giant cell-rich, and anaplastic round cell. These four basic patterns frequently coexisted within same tumor, albeit to a significantly variable extent. Follow-up series further characterized the entity, expanded its topographic distribution to include almost all organ systems, and illustrated its morphological and phenotypic homology among different organs. Although resemblance of the neoplastic cells to rhabdomyoblasts was already pointed out by Stout in 1958, the term "rhabdoid" (introduced in 1978 for specific kidney tumors) was not used for carcinomas until 1993. Review of the old and recent literature indicates pleomorphic "giant cell" carcinoma is not an entity but a morphological pattern in the spectrum of undifferentiated (anaplastic) and sarcomatoid carcinoma that can originate in any organ, either in a pure form or as a dedifferentiated carcinoma component. These tumors fall into two major categories: a monomorphic (variable admixture of small or larger "gemistocyte-like" rhabdoid cells and epithelioid cells) and a pleomorphic (bizarre large polygonal, spindled, or multinucleated malignant cells) subtype. The few available genetic studies suggest close association of the monomorphic type with SWI/SNF pathway defects, while bizarre-looking pleomorphic tumors usually harbor complex and heterogeneous genetic alterations. Most tumors dominated by the pleomorphic "giant cell" pattern are extremely aggressive, resulting in death, soon after diagnosis, irrespective of treatment modalities. This review gives an historical account on the evolution of the pleomorphic "giant cell" carcinoma concept with special reference to their relationship to SWI/SNF complex alterations.     

Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways.

Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood. In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms. We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors. Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (<5%). Expression of topoisomerase II alpha is not seen in solid pseudopapillary tumors and undifferentiated carcinomas with osteoclastic-like giant cells but is focally seen in pancreatoblastomas (50%) and acinar cell carcinomas (85%). Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%). CK19, a marker of pancreatic ductal adenocarcinomas, is not expressed in pancreatic nonductal neoplasms. Expression of gamma-synuclein as well as stromal markers (fascin, hsp47 and fibronectin) is frequently seen in both. Our findings indicate pancreatic nonductal neoplasms have distinctive patterns of protein expression relative to pancreatic ductal adenocarcinomas and suggest that pancreatic nonductal neoplasms have different genetic pathways from the more common pancreatic ductal adenocarcinomas.     

Histidine decarboxylase expression in pancreatic endocrine cells and related tumors

Histidine decarboxylase (HDC) is an enzyme for decarboxylating l-histidine to histamine and is expressed in various types of cells including neuroendocrine tumors. Recent findings have demonstrated a high percentage of HDC immunoreactivity in many neuroendocrine tumors, including carcinoid tumors, small cell carcinomas of the lung, pheochromocytomas, and medullary carcinomas of the thyroid. HDC immunostaining was applied to pancreatic islet cells and related tumors to explore possible expression of HDC as a wide spectrum marker for neuroendocrine differentiation. A total of 24 cases (22 pancreatic endocrine neoplasms, one small cell carcinoma of the pancreas, and one mixed exocrine-endocrine carcinoma) along with normal pancreatic tissue were immunostained with the anti-HDC antibody. In a normal pancreas, a double immunostaining revealed possible colocalization of HDC with glucagon- or insulin-positive cells in the islets. Seventeen of 22 pancreatic endocrine neoplasms (77%) were found to be positive for HDC, and no distinct relation to hormonal activity was observed. One small cell carcinoma was strongly positive to HDC. One non-functional tumor with mixed exocrine and endocrine components showed a diffuse positive immunostaining for HDC, and some neoplastic glucagon- or somatostatin (SRIF)-positive cells coexpressed HDC. In conclusion, we demonstrated that the majority of pancreatic endocrine tumors expressed HDC, and we suggest that HDC is a wider new marker for neuroendocrine differentiation.     

Undifferentiated carcinoma with osteoclast-like giant cells: A pathologic-radiologic correlation of a rare histologic subtype of pancreatic ductal adenocarcinoma

Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) is an exceedingly rare subtype of pancreatic ductal adenocarcinoma. Histologically, UC-OGC is characterized by three cell types namely, a neoplastic mononuclear cell component, non-neoplastic osteoclast-like giant cells, and a non-neoplastic mononuclear histiocytic component. The behavior of this tumor is unpredictable; but many patients survive many years after diagnosis. UC-OGC may have a better prognosis compared to conventional pancreatic adenocarcinoma due to its slower local spread, less aggressive nature, better response to surgical resection and/or chemotherapy, and fewer metastases. Due to likely differences in prognosis and significant impact on patient management, it is important to distinguish this subtype from other types of pancreatic adenocarcinoma. We report a case of a small (<1 cm) undifferentiated carcinoma with osteoclast-like giant cells of the posterior pancreatic body discovered incidentally on magnetic resonance image (MRI) scan of a middle-aged man. The radiologic and pathologic findings are presented along with a discussion of the differential diagnosis of this exceedingly rare entity.     

Follicular dendritic cell sarcoma mimicking giant cell carcinoma of the pancreas

Extranodal follicular dendritic cell (FDC) tumors are rare. Recognition of the morphological spectrum of FDC tumors is important to clinical diagnosis. Herein is presented a case of pancreatic FDC sarcoma with unusual clinicopathological features. A 64-year-old male patient presented with weight loss, poor appetite, abdominal fullness, mild anemia and mild peripheral eosinophilia. Histologically, the tumor was composed of both epithelioid and spindle cells with abundant intracytoplasmic hyaline globules. These tumor cells were positive for CD21, CD23, CD35, S-100 protein, fascin and clusterin. Both epithelioid and spindle tumor cells independently colonized the liver and formed two tumor nodules 18 months after the initial resection. Notably, the two hepatic metastases additionally acquired patchy expression of human leukocyte antigen-DR. The epithelioid FDC in one of the hepatic lesions transformed into numerous bizarre giant cells, which could easily be confused with a metastatic giant cell carcinoma from the pancreas. FDC tumor should therefore be included in the differential diagnoses when dealing with a giant cell tumor.     

Ultrastructural study of the initial phases of pancreatic carcinoma induced by BOP in the Syrian golden hamster.

A serial study was carried out on the lesions induced by N-nitroso-bis(2-oxopropyl)amine (BOP) in the Syrian golden hamster until the appearance of pancreatic ductal carcinomas. During the initial phase, first findings were cytolysis of acinar cells close to blood vessels and other cells, together with a loss of zymogen granules from the cytoplasm, and an increase in the diameters of the acinar lumens. After week 11 a proliferation of ductule-like cells was observed. We consider that a minimum proliferation of cells at the acinus-ductule junction would give rise to pseudoductules composed of remains of acinar cells together with ductule-like cells.     

Genotoxicity of pancreatic chemical carcinogens to propagable cultured normal pancreatic epithelial cells

The cytotoxic and DNA-damaging effects of the pancreatic carcinogens azaserine, streptozotocin, and N-nitrosobis(2-oxyopropyl)amine (BOP) on propagable cultured normal rat pancreatic epithelial cells have been studied. All three chemicals in micromolar concentrations produced cytotoxicity to these cells. The concentrations that caused 50% reduction in colony formation (LD50) were approximately 0.3 mM for azaserine, 0.4 mM for BOP, and 2 mM for streptozotocin. Comparatively, the LD50 for N-methyl-N'-nitro-N-nitrosoguanidine was 3 microM. The toxicity of both azaserine and BOP did not require exogenously added S9 microsomal enzymes, indicating that the cells were capable of metabolic activation of these carcinogens. All three compounds induced unscheduled DNA synthesis, thus suggesting their mutagenic and carcinogenic potential in these cultured cells.     

Giant-cell containing neoplasms of the pancreas: an aspiration cytology study

Giant-cell containing neoplasms of the pancreas are rare with few reports documenting their cytologic appearance. Giant-cell containing neoplasms of the pancreas have been divided into two subtypes corresponding to the osteoclastic giant-cell tumor of the pancreas and the pleomorphic giant-cell carcinoma of the pancreas. Despite the better prognosis reported in some series for osteoclastic giant-cell tumors, the most recent edition of the World Health Organization classification lumps the two entities into a single category designated as undifferentiated carcinoma with osteoclast-like giant cells. Smears obtained from osteoclastic giant-cell tumors show numerous giant-cells with clustered overlapping, bland appearing nuclei containing prominent nucleoli consistent with an osteoclast-type multinucleated giant-cell. These neoplasms contain a second population of mononuclear cells showing more marked nuclear atypia. Pleomorphic giant-cell carcinomas are characterized by anaplastic giant-cells displaying marked nuclear pleomorphism. The mononuclear component is also pleomorphic with markedly atypical epithelioid and spindle shaped cells. In three reported cases, a tumor contained a mixture of the two cell patterns. Thus, undifferentiated carcinoma with osteoclast-like giant cells and pleomorphic giant cell carcinoma may represent a morphologic spectrum with pure osteoclast-like giant-cell tumors at one end and pleomorphic giant-cell carcinoma at the other. Fine-needle aspiration specimens from pure osteoclast-like giant-cell tumors will contain a population of bland multinucleated osteoclastic-like giant-cells that differ markedly from the anaplastic giant-cells of pleomorphic giant-cell carcinoma. The difference in the appearance of the giant-cells aids in distinction of the two neoplasms. When in pure form, the two neoplasms may follow different clinical courses.     

Bronchogenic sarcomatoid squamous cell carcinoma with osteoclast-like giant cells

A 60-year-old man developed a widely metastatic spindle cell neoplasm with admixed osteoclast-like giant cells indistinguishable from malignant giant cell tumor of soft parts. Autopsy revealed a bronchogenic sarcomatoid squamous cell carcinoma that was the primary source of the sarcomatoid metastases. The osteoclast-like giant cells in the metastatic lesions were negative for lysozyme on immunoperoxidase staining. This finding suggested that the multinucleated giant cells were not formed as a cellular response to hemorrhage or to cellular debris induced by the tumor. Extraosseous neoplasms with osteoclast-like giant cells are rare neoplasms that may occur in a variety of organs. This case is the second reported case of a primary neoplasm in the lung that contained these osteoclast-like giant cells. These tumors may cause considerable diagnostic confusion.     

Extensive polynucleate giant cell formation after X-irradiation or addition of colchicine in SV40 transformed Syrian hamster cells

Summary X-irradiation of Syrian hamster cells transformed by simian virus 40 which exhibited evidence of the presence of the viral genome was consistently followed by extensive polynucleate giant cell formation.With the possible exception of cells derived from an adenovirus 12-induced tumor this phenomenon has not been observed in other Syrian hamster cell systems, i.e. lines of oncogenic cells originally exposed to SV₄₀ virus but in which no evidence of the viral genome could be subsequently demonstrated; cells transformed by polyoma virus; a line of oncogenic cells not associated with virus; continuous lines and primary cultures of normal cells.Extensive post-irradiation polynucleate giant cell formation did not occur in SV₄₀-transformed lines of human cells; in primary cultures of human cells of various tissue origin; in lines of cells derived from human malignant tumors. A line of African green monkeys cells (Cercopithecus aethiops) after irradiation also failed to react in this manner.Treatment with colchicine of SV₄₀-transformed hamster and human cells induced extensive polynucleate giant cell formation only in hamster cell systems. Therefore the effect of colchicine appears to parallel that of irradiation.Various possible mechanisms to account for the phenomenon of post-irradiation and colchicine-induced polynucleate giant cell formation in hamster cells bearing the SV₄₀ genome are suggested and discussed.Dedicated to the Honor of the 60th birthday of ProfessorSven Gard. Supported in part by Grant No. AI-01992-08 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S.P.H.S. Bethesda, Maryland.Post Doctoral Research Fellow, Rockefeller Foundation.U.S.P.H.S. Research Development Career Award No.5-K3-AI-14,617,02.U.S.P.H.S. Special Fellow, No. 2-F3-CA-13,444-03, National Cancer Institute, National Institutes of Health.