Induction and expression of cyclin D3 in human pancreatic cancer.

PURPOSE: Cyclins play a key role in the control and regulation of the cell cycle. The role of cyclins in the pathogenesis of pancreatic cancer is largely unknown. METHODS: Using Northern blot analysis, polymerase chain reaction (PCR) and immunohistochemistry, we examined the expression of cyclins D1, D2, and D3 in human pancreatic cancer and studied the induction of these cyclins by growth factors in pancreatic cancer cell lines. RESULTS: We now report that cyclin D1 and D3 mRNAs are expressed in human pancreatic cancer cell lines, and that the expression of cyclin D3 is enhanced in pancreatic cancer cells by amphiregulin, a member of the epidermal growth factor family. Cyclins D1 and D3 are also expressed in normal and malignant pancreatic tissues. However, while the normal pancreas and pancreatic cancers express cyclin D2 as determined by reverse-transcriptase PCR, we could not detect cyclin D2 mRNA by either Northern blot analysis or reverse transcriptase PCR in the two pancreatic cancer cell lines. Immunohistochemical analysis revealed the expression of cyclin D3 in pancreatic cancer cells. CONCLUSIONS: These findings suggest that D-type cyclins are differentially expressed in pancreatic cancer and that the aberrant activation of the EGF receptor in human pancreatic cancer by amphiregulin may lead to the progression of the cell cycle via induction of cyclin D3 expression, thus contributing to the growth advantage of these transformed cells.

Differentiation of islet cells in long-term culture.

Our previous studies in the hamster pancreatic cancer model have shown that exocrine pancreatic cancer arises from ductal/ductular cells, as well as from within the islets, most probably from islet precursor (stem) cells. To identify and characterize these cells, we established a long-term culture from isolated hamster islets and investigated their growth, differentiation, and expression of biomarkers. Islets maintained their original form and structure within the first 14 days in culture. However, beginning at day 7, ductular structures began to form within the islets. At day 21 in culture, acinar cells, intermediary cells, oncocytes, and cells comparable to pancreatic hepatocytes also appeared between ductular and endocrine cells. The number of duct-like cells gradually increased, whereas the number of hormone-producing cells decreased. After 35 days in culture, the exocrine cells disappeared, and undifferentiated cells formed a monolayer. These cells expressed cytokeratins, alpha1-antitrypsin, transforming growth factor-alpha, epidermal growth factor receptor, carbonic anhydrase II, vimentin, laminin, and showed binding to tomato lectin and Phaseolus vulgaris leukoagglutinin. They did not express the regulatory transcriptional factors, insulin-promoting factor 1, NKx6.1, Pax6, and NeuroD. The results thus indicate that islet cells have potential to form exocrine cells. At present, it is not clear whether these cells originate from preexisting stem cells or from transdifferentiated islet cells.

Overexpression of platelet-derived growth factor (PDGF) B chain and type beta PDGF receptor in human chronic pancreatitis.

Platelet-derived growth factors (PDGF) are mitogenic polypeptides that are involved in cellular proliferation and tissue repair. The expression of PDGFs and type beta PDGF receptor was examined in the normal human pancreas and in chronic pancreatitis, a fibrotic disease associated with fibroblastic proliferation, atrophy, and acinar cell dedifferentiation. In the normal human pancreas, PDGF A chain mRNA levels were relatively abundant, whereas PDGF B chain mRNA levels were not detected, and type beta PDGF receptor mRNA transcripts were present at low levels. In the normal pancreas, PDGF immunoreactivity was present in islet cells, whereas type beta PDGF receptor immunoreactivity was present in acinar cells. In chronic pancreatitis, PDGF A chain mRNA transcripts were also abundant, and 11 of 19 samples exhibited the PDGF B chain mRNA transcript. In addition, there was a significant increase in the mRNA levels of type beta PDGF receptor in the pancreatitis samples by comparison with the normal pancreas (P < 0.001). In chronic pancreatitis tissues, PDGF and type beta PDGF receptor immunoreactivity were present in acinar, ductal, islet, and endothelial cells, fibroblasts, and leukocytes. The concomitant overexpression of PDGFs and of the type beta PDGF receptor points to the existence of autocrine and paracrine PDGF-dependent loops in human chronic pancreatitis.

Risk of nervous system cancer among workers exposed to lead.

Experimental animal studies suggest that lead compounds may increase the risk of gliomas. To study whether occupational exposure to lead increases the risk, we followed nervous system cancer incidence among 20,741 employees biologically monitored for their blood lead (B-Pb) concentrations. We also performed a nested case-referent study, comprising 26 male cases of nervous system cancer (16 of which had gliomas). Those cases a B-Pb > or = 1.4 mumol/L had a twofold increase in the odds ratio of nervous system cancer as compared with those employees whose B-Pb had not exceeded 0.7 mumol/L. The excess was confined to gliomas (odds ratio 11, 95% confidence interval 1.0 to 630 for B-Pb > or = 1.4 mumol/L; overall P value for trend, 0.037). We obtained lifetime information on exposure and potential confounders for 58% of the cases. The odds ratio of glioma was associated with indices of lifetime exposure to lead, and potential confounders seemed not to explain the effects. The results suggest that there may be an association between occupational lead exposure and the risk of gliomas. No firm conclusions can be drawn because of the small number of cases and loss of material.

Excess lung cancer among workers exposed to lead.

OBJECTIVE: Studies on experimental animals suggest that inorganic lead is a carcinogen. The purpose of the study was to examine whether occupational exposure to lead increases the risk of cancer. METHODS: The study population comprised 20,700 workers who had been biologically monitored for their blood lead (B-Pb) concentrations during 1973-1983. The mortality and cancer incidence rates were followed among the monitored workers and compared with those of the Finnish general population. An internal comparison of the cancer incidence rates was also done between subcohorts formed according to individual B-Pb levels. Questionnaire-based information was also collected on lifetime occupational history and potential confounders, and exposure history was assessed on an individual basis with a nested case-referent design for lung cancer. RESULTS: The internal comparison within the cohort showed a 1.4-fold increase in the overall cancer incidence and a 1.8-fold increase in the incidence of lung cancer among those who had ever had a blood lead level of > or = 1.0 mumol.l-1. In the case-referent study, an increased odds ratio for lung cancer was found for concomitant exposure to lead and engine exhaust. The odds ratio for squamous-cell carcinoma of the lung was increased even when the blood lead level had been slightly elevated. Bias or confounding did not explain the risks. CONCLUSIONS: The results suggest that exposure to lead increases the risk of lung cancer. Co-exposure to engine exhaust and lead may be associated with the risk.

Cancer incidence among Finnish workers exposed to halogenated hydrocarbons.

Epidemiologic studies and long-term carcinogenicity studies in experimental animals suggest that some halogenated hydrocarbons are carcinogenic. To investigate whether exposure to trichloroethylene, tetrachloroethylene, or 1,1,1-trichloroethane increases carcinogenic risk, a cohort of 2050 male and 1924 female workers monitored for occupational exposure to these agents was followed up for cancer incidence in 1967 to 1992. The overall cancer incidence within the cohort was similar to that of the Finnish population. There was an excess of cancers of the cervix uteri and lymphohematopoietic tissues, however. Excess of pancreatic cancer and non-Hodgkin lymphoma was seen after 10 years from the first personal measurement. Among those exposed to trichloroethylene, the overall cancer incidence was increased for a follow-up period of more than 20 years. There was an excess of cancers of the stomach, liver, prostate, and lymphohematopoietic tissues combined. Workers exposed to 1,1,1-trichloroethane had increased risk of multiple myeloma and cancer of the nervous system. The study provides support to the hypothesis that trichloroethylene and other halogenated hydrocarbons are carcinogenic for the liver and lymphohematopoietic tissues, especially for non-Hodgkin lymphoma. The study also documents excess of cancers of the stomach, pancreas, cervix uteri, prostate, and the nervous system among workers exposed to solvents.

Mortality and cancer morbidity of Finnish chlorophenoxy herbicide applicators: an 18-year prospective follow-up.

An 18-year follow-up for mortality and cancer morbidity was conducted in a cohort of 1,909 men who had started spraying chlorophenoxy herbicides (mixture of 2,4-dichlorophenoxyacetic acid [2,4-D] and 2,4,5-trichlorophenoxyacetic acid [2,4,5-T]) in 1955 through 1971. In all, 384 persons had died during the follow-up, and there was a slight deficit in natural deaths (standardized mortality ratio [SMR] 0.84; 95% confidence interval [CI] 0.75-0.94). By contrast, there was a small, nonsignificant increase in accidental and violent deaths. The overall cancer mortality was slightly less than in the general population (SMR 0.83; 95% CI 0.65-1.02), and not a single case of death of non-Hodgkin's lymphomas (NHL) or soft tissue sarcomas (STS) was detected. With regard to cancer morbidity, the incident cases showed a slight deficit compared to the population figure (standardized incidence ratio [SIR] 0.81; 95% CI 0.67-0.97). One case of NHL was found (2.4 expected with 10 years of latency), but not a single case of STS (0.8 expected with 10 years of latency). While our study does not support the contention that spraying of 2,4-D and 2,4,5-T containing herbicides carries any significant risk of cancer, the medium to low statistical power of the study does not allow any far reaching negative conclusions regarding the carcinogenicity of the agents.

Pancreatic cancer in industrial branches and occupations in Finland.

An examination of the risk of pancreatic cancer associated with occupation, by industrial branch and job title, was undertaken in a nationwide case-referent study in Finland. The results are based on job history information from the next-of-kin of 625 incident cases of primary malignant exocrinic pancreatic neoplasms, and of 1,700 cancer referents (stomach, colon, and rectum). All cases and referents were between 40 and 74 years at diagnosis. The diagnoses were made in 1984-87, and both cases and referents were known to be dead by April 1, 1990. The source of the cases and referents was the Finnish Cancer Registry. Increases in risk of pancreatic cancer were suggested for a small number of industrial branches and job titles, including stone mining (odds ratio 3.7), cement and building materials (11.1), pharmacists and sales associates in pharmacies (12.9), male wood machinists (4.1), male gardeners (6.7), female textile workers (5.4), and male transport inspectors and supervisors (9.4). The exposures potentially implicated are discussed. In agreement with the overall results of epidemiologic studies conducted elsewhere, direct occupational determinants probably do not account for a substantial share of the etiology of pancreatic cancer, at least in conditions resembling Finnish working environments some 15-40 years ago.

Chemical exposures and respiratory cancer among Finnish woodworkers.

A case-control study of respiratory cancer, nested within a cohort of male woodworkers, was updated in Finland. The update extended the initial follow up of 3805 workers from 19 plants to 7307 workers from 35 plants. Each case of respiratory cancer (n = 136) diagnosed between 1957 and 1982 within the cohort was matched by year of birth with three controls (n = 408) from the cohort. Chemical exposures were assessed for the cases and the controls by a plant and period specific job exposure matrix. An excess of respiratory cancer was associated with phenol. Concomitant exposures to several other agents occurred as well, however, and no exposure-response relation for phenol was seen. An excess risk and an increasing exposure-response relation were found for engine exhaust from petrol and diesel driven factory trucks. The excess risk associated with pesticides was lower than in our previous study, an indication of qualitative and quantitative differences in exposure between the initial and augmented cohorts. Slightly increased risks were found for terpenes and mould spores, which may be due to chance although the contribution of occupational exposure cannot be ruled out. Exposure to wood dust, mainly from pine, spruce and birch, at a level of about 1 mg/m3, was not associated with lung cancer, upper respiratory cancer, or adenocarcinoma of the lung.

Primary liver cancer and occupational exposure.

In a dynamic population-based case-referent study on primary liver cancer and occupational exposure, the work histories of 344 cases and 861 referents, derived from the follow-up of the whole Finnish population in 1976-1978 and 1981, were analyzed by industry, occupation, and agent. After adjustment for alcohol consumption, elevated odds ratios were found for the categories other agricultural workers (mainly milkmaids), clerical workers, persons exposed to welding fumes and those exposed to other inorganic dusts (mainly silica). One possible explanation for the excess among milkmaids was exposure to dust from cattle feed contaminated with aflatoxins. The excess among clerical workers was probably due to nonoccupational factors or chance because occupational exposure was generally rare. The excesses for welding fumes and inorganic dusts, although compatible with occupational etiology, contradict the results of many previous studies carried out among workers exposed to silica dust and welders.

Renal cell cancer and occupational exposure to chemical agents.

A case-referent study of occupational risk indicators of renal cell adenocarcinoma was conducted. Each incident case in Finland in 1977-1978 was matched with two population referents. Lifelong job histories were collected and translated into indicators of industry, occupation, and occupational exposures. The analyses of 338 sets of cases and referents revealed elevated risks for a history of employment in white-collar occupations; the printing industry; the chemical industry; the manufacturing of metal products; mail, telephone, and telegraph services; and iron and metalware work. A decreased risk was observed for male farmers. An elevated risk and an exposure-response relationship were found for gasoline exposure. The excess risk was highest at a latency period of approximately 30 years. The findings support the hypothesis that exposure to some constituent(s) of gasoline increases the incidence of renal adenocarcinoma in humans. Suggestions of elevated risks appeared for exposures to inorganic lead, cadmium, and nonchlorinated solvents.

Formaldehyde exposure and respiratory cancer among woodworkers--an update.

Respiratory cancer was examined in relation to occupational formaldehyde exposure in a case-referent study (136 cases, 408 referents) nested in a woodworker cohort. Plant- and time-specific job-exposure matrices were constructed for formaldehyde exposure. Over 3 ppm-months of formaldehyde exposure was associated with an odds ratio of 1.4 [90% confidence interval (90% CI) 0.5-4.1]. The odds ratios for lung cancer were near unity, the excess risk concentrating on the upper respiratory tract. That for combined exposure to formaldehyde-phenol exposure (all respiratory cancers) was 1.6 (90% CI 0.6-4.4) but 1.0 for formaldehyde only. No consistent exposure-response patterns emerged for the level, duration, or cumulative exposure. The results are hardly more than debatable support for the hypothesis concerning formaldehyde as a carcinogen in humans, the possible risk seemingly concentrating on the upper respiratory tract rather than the lung.

Increased risk for primary liver cancer among women exposed to solvents.

An earlier case-referent study by the same authors [Int Arch Occup Environ Health 54 (1984) 147-153] reported that solvent-exposed women, but not men, had an increased risk for primary liver cancer. The present study was undertaken to verify these results. The relatives of deceased patients, ie, 377 liver cancer cases, 385 coronary infarction referents, and 476 stomach cancer referents, responded to a questionnaire on past employment and potentially relevant covariables, the response rates being 71.7, 72.7, and 69.0%, respectively. The information was assessed for solvent exposure by two occupational hygienists without knowledge of the patients' diagnoses. Seven male and seven female liver cancer cases had been exposed to solvents, the odds ratio being less than 1 for the men but greater than 3 for the women irrespective of the reference group used for comparison. The results confirm the authors' earlier findings. When both materials were combined, the odds ratio was 7.8 for the female liver cancer cases as compared with the infarction referents. In the combined material, nine female liver cancer cases, two stomach cancer referents, but no infarction referent had had at least probable exposure to chlorinated hydrocarbons. Such exposure was rare among all of the men in the study. This finding may explain why the increased liver cancer risk occurred only for the women, although a sex difference in sensitivity cannot be completely ruled out.

Respiratory cancers and chemical exposures in the wood industry: a nested case-control study.

A cohort of 3805 men who had worked for at least one year in the particleboard, plywood, sawmill, or formaldehyde glue industries between 1944 and 1965 was followed up until 1981. From within the cohort the 57 patients with verified "respiratory" cancer (ICD 7 codes: 160-162.1, 141, 143-8) were defined as "cases," and 171 men without respiratory cancer from within the cohort were matched on birth year and used as controls. The comparison of exposures was carried out according to work histories and job exposure matrices for each plant. The odds ratio for exposure to wood dust was 1.03 (32 exposed cases) without provision for any latent period, and 0.97 (27 exposed cases) when provision for a minimum latent period of ten years was applied. The odds ratios were 1.60 and 1.68, respectively, when smoking was controlled by stratification. These results did not differ significantly from unity. The estimated average level of exposure to wood dust among the exposed was 1-2 mg/m3 and the mean duration of exposure about ten years. Significantly (one sided test, 5% level) raised odds ratios were observed for exposure to pesticides and phenol. No single pesticide could be identified as "causative" because of frequent multiple exposures. The raised odds ratios for phenol were partly explained by smoking and exposure to pesticides which confounded the observed associations for phenol exposure. Exposure to terpenes and other heating products of coniferous woods was significantly associated with a risk of respiratory cancer when the duration of exposure exceeded five years.

Formaldehyde exposure and respiratory and related cancers. A case-referent study among Finnish woodworkers.

A case-referent study was undertaken to investigate the associations between formaldehyde exposure and respiratory and related cancers. Fifty-seven such cancers from a retrospective cohort of male woodworkers formed the case group. They were matched by year of birth with 171 referents. Exposure to formaldehyde was assessed with job-exposure matrices. The median of the time-weighted average concentration was about 1 ppm, and the mean duration of exposure was 10 years among the exposed. Odds ratios (OR) were calculated for formaldehyde exposure (1.44), peak exposure to formaldehyde (1.26), and exposure to formaldehyde-containing wood dust (1.22). None of the values exceeded unity with statistical significance. Allowance was also made for a 10-year period from the onset of exposure. Birth year, cigarette smoking and exposure to wood dust, chlorophenols, pesticides, and terpenes were controlled by stratification. The adjusted ORs did not change appreciably. The highest OR was 1.95 for formaldehyde exposure without allowance for minimum latency, adjusted for exposure to terpenes. No exposure-response relation was observed for the level, duration, or dose (ppm-years) of formaldehyde exposure. The result is nonpositive and may be explained by absence of effect, by too short a follow-up, or by insufficient power for detecting a mild excess risk.

Congenital malformations, mortality and styrene exposure.

The prevalence of congenital malformations among children born to styrene-exposed male and female workers, as well as the mortality of the exposed workers, was studied. A cohort of 2,209 workers (1,698 men, 511 women) was selected from the personnel files of 160 workplaces using styrene in the manufacture of reinforced plastic products. The earliest exposure histories began in 1960, but the majority of workers had been exposed after 1967. The data on children born to the exposed workers were linked with those of the Register of Congenital Malformations. The number of malformations of children born to the workers was, both before and during the styrene exposure, below the expected values. In the cohort there were 37 observed deaths (expected 74.0), six of which were due to cancer (expected 13.0). The cancer sites were the stomach (2 cases), bronchus (1), breast (1), ovary (1), and kidney (1 case). There were no cases of lymphatic or haematopoietic cancer. Most of the cancers appeared after short exposure times and soon after the commencement of exposure.