BRCA1-associated mammary tumorigenesis is dependent on estrogen rather than progesterone signaling.

Hereditary breast cancers in BRCA1 mutation carriers are mostly estrogen receptor α (ERα)-negative and progesterone receptor (PR)-negative; however, hormone depletion via bilateral oophorectomy does result in a marked reduction in breast cancer risk, suggesting that BRCA1-associated breast tumorigenesis is dependent on hormone signaling. We used geneticaly engineered mouse models to determine the individual influences of ERα and PR signaling on the development of BRCA1-deficient breast cancer. In line with the human data, BRCA1-deficient mouse mammary tumors are ERα-negative, and bilateral ovariectomy leads to abrogation of mammary tumor development. Hormonal replacement experiments in ovariectomized mice showed that BRCA1-deficient mammary tumor formation is promoted by estrogen but not by progesterone. In line with these data, mammary tumorigenesis was significantly delayed by the selective ERα downregulator fulvestrant, but not by the selective PR antagonist Org33628. Together, our results illustrate that BRCA1-associated tumorigenesis is dependent on estrogen signaling rather than on progesterone signaling, and call into question the utility of PR antagonists as a tumor prevention strategy for BRCA1 mutation carriers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cutaneous squamous cell carcinomas (SCC) associated with cosmetic skin whitening: 8 cases reported in Senegal.

BACKGROUND: The cosmetic use of bleaching products is common among women from sub-Saharan Africa. The most frequently used products are highly potent corticosteroids (clobetasol propionate) and hydroquinone. Herein, we report 8 cases of SCC in women using skin bleaching products for cosmetic purposes. Our aim is to describe the epidemiological, clinical and pathological aspects of the carcinomas observed during the course of skin lightening. METHODS: We conducted a descriptive multicentre study from August 2005 to January 2016 in three dermatology units in Senegal. We included all patients consulting for cutaneous squamous cell carcinoma associated with skin bleaching. Sociodemographic, clinical, paraclinical and therapeutic data were recorded. RESULTS: A total of 8 female patients were included. The mean age was 48.1 years (37-63 years). Topical hydroquinone and highly potent corticosteroids were the main products used over the whole body, for an average duration of 20.3 years. No pre-neoplastic skin disease was found in our patients. The clinical aspects of tumours were as follows: cauliflower-like (n=4), ulcerated (n=3) and nodular (n=1). The average development time before consultation was 6.75 months. All the cutaneous squamous cell carcinomas were localized to lichenoid lesions or exogenous ochronotic lesions on photo-exposed areas: face (n=1), neck (n=3) or upper back (n=4). The most common histopathological type was the infiltrating form and there was one case of in situ carcinoma. The outcome was favourable in six of eight patients after surgical resection. Two deaths occurred: one through tumour recurrence and the other through haemorrhagic shock. CONCLUSIONS: From 2005 to 2016, eight cases of cutaneous squamous cell carcinomas associated with cosmetic use of bleaching products were reported in Senegal. The mechanism was not fully elucidated and further studies are necessary. These observations provide an additional argument for combating this practice and including skin bleaching among known risk factors for squamous cell carcinoma.

Anthocyanins Prevent Colorectal Cancer Development in a Mouse Model.

BACKGROUND: Colorectal cancer is the main leading cause of cancer-related deaths worldwide. Present data suggest that plant-derived anthocyanins have anti-inflammatory and chemopreventive properties. This study was aimed at evaluating the effect of an anthocyanin-rich extract from bilberries on colorectal tumour development and growth in the administration of azoxymethan (AOM)/dextran sodium sulfate (DSS) mouse model. METHODS: Colonic carcinogenesis was induced by AOM and DSS 3 or 5%, respectively, in 50 female Balb/c mice. Mice received either normal food (controls) or a diet containing either 10 or 1% anthocyanin-rich bilberry extract. Colonoscopy took place at week 4 and 9 after initiation of carcinogenesis. After termination at week 9, colon samples were analysed macroscopically and microscopically. RESULTS: Mice receiving 10% anthocyanins showed significantly (p < 0.004) less reduced colon length (12.1 cm [8.5-14.4 cm]) as compared to controls (11.2 cm [9.8-12.3]) indicating less inflammation. Mice fed with 10% anthocyanin-rich extract revealed significantly less mean tumour numbers (n = 1.2) compared to control (n = 14) and anthocyanin 1% treated mice (n = 10.6, p < 0.001). CONCLUSION: Anthocyanins prevented the formation and growth of colorectal cancer in AOM/DSS-treated Balb/c mice. Further studies should investigate the mechanisms of how anthocyanins influence the development of colorectal cancer.

The role of Ly49E receptor expression on murine intraepithelial lymphocytes in intestinal cancer development and progression.

Ly49E is a member of the Ly49 family of NK receptors and is distinct from other members of this family on the basis of its structural properties, expression pattern and ligand recognition. Importantly, Ly49E receptor expression is high on small intestinal and colonic intraepithelial lymphocytes (IELs). Intestinal IELs are regulators of the mucosal immune system and contribute to front-line defense at the mucosal barrier, including anti-tumor immune response. Whereas most Ly49 receptors have MHC class-I ligands, we showed that Ly49E is instead triggered by urokinase plasminogen activator (uPA). uPA has been extensively implicated in tumor development, where increased uPA expression correlates with poor prognosis. As such, we investigated the role of Ly49E receptor expression on intestinal IELs in the anti-tumor immune response. For this purpose, we compared Ly49E wild-type mice to Ly49E knockout mice in two established tumor models: ApcMin/+-mediated and azoxymethane-induced intestinal cancer. Our results indicate that Ly49E expression on IELs does not influence the development or progression of intestinal cancer.

Mutations in the p16 gene in DMBA-induced pancreatic intraepithelial neoplasia and pancreatic cancer in rats.

BACKGROUND: 7, 12-dimethylbenzanthracene (DMBA)-induced pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer. However, this model has not been characterized genetically, and in particular, the major genetic alterations in the p16 gene are unknown. METHODS: Lesions of PanIN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozygous deletions and point mutations of the p16 (exons 1 and 2) gene were detected by PCR amplification and direct sequencing. RESULTS: DMBA implantation in the 40 rats induced 26 PanINs and 9 carcinomas. The overall frequency of p16 alterations in the pancreatic tissue of these rats was 42.86% (15/35), and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% (8/26) of the rats with PanIN and 77.78% (7/9) of the rats with carcinoma (P<0.05). The increasing incidence of p16 alterations was detected in 20.00% (1/5) of PanIN-1, 28.57% (2/7) of PanIN-2 and 35.71% (5/14) of PanIN-3 lesions. CONCLUSION: Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.

Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model.

Previous studies in the field of cancer research have suggested a possible role for statins in the reduction of risk in certain malignancies. The purpose of these studies was to examine the chemopreventive effects of pravastatin alone and in combination with pineal hormone melatonin in the N-methyl-N-nitrosourea-induced mammary carcinogenesis model. Pravastatin was given orally (1 00 mg/kg) and melatonin was added to the water (20 µg/ml). Chemoprevention began seven days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, angiogenesis and proliferation) and side effects after long-term treatment in animals were assessed. Pravastatin alone suppressed tumour frequency by 20.5% and average tumour volume by 15% compared with controls. Combined administration of the drugs decreased tumour frequency by 69% and lengthened tumour latency by nine days compared with control animals. The ration between high and low grade carcinomas was apparently reduced in both treated groups. The analysis of carcinoma cells showed significant expression increase in caspase-3 and caspase-7 after pravastatin treatment; however, combined treatment even more pronounced increase in the expression of both caspases. Regarding VEGFR-2 expression, a small effect in carcinomas of both treated groups was found. In plasma metabolism evaluation, pravastatin alone significantly decreased levels of glucose and triacylglycerols. Our results suggest a mild anti-neoplastic effect of pravastatin in this rat mammary gland carcinoma model. Statins co-administered with other suitable drug (e.g. melatonin) should be further evaluated for tumour-preventive properties.

An unusual cause of cancer mimicry following liver transplantation.

Sirolimus is an approved anti-rejection agent following liver or kidney transplantation that works through inhibition of the mammalian target of rapamycin (mTOR). As sirolimus functions through a pathway independent of calcineurin inhibition, it may have less potential for nephrotoxicity and carcinogenesis. That being said, there are a myriad of potential adverse effects reported with sirolimus, many of which are severe and unknown or poorly understood. Herein we present a case of sirolimus causing a serious but uncommon adverse event in an adult liver transplant recipient; the adverse event in this instance unfortunately resulted in significant medical testing and morbidity. The adverse event profile of sirolimus is summarized through review of available evidence.

Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous intraepithelial lesions.

BACKGROUND: The complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond. METHODS: Biopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning. RESULTS: The immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1+/type 1 Tbet+), M1-like macrophages (CD68+CD163-) and dendritic cells (CD11c+) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3+FOXP3+ regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4+ T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p<0.0001). CONCLUSION: The capacity of cHSIL patients to respond to imiquimod is associated with a pre-existing coordinated local immune process, fostering an imiquimod-mediated increase in local T cell infiltration. The CIBI immunohistochemical biomarker has strong potential to select cHSIL patients with a high likelihood to experience a complete response to imiquimod immunotherapy.

Fluorescent imaging of high-grade bladder cancer using a specific antagonist for chemokine receptor CXCR4.

We previously reported that the expression of CXC chemokine receptor-4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high-grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative-control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive-stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high-grade superficial bladder cancer.

Diet synergistically affects helicobacter pylori-induced gastric carcinogenesis in nonhuman primates.

BACKGROUND & AIMS: Gastric cancer results from a combination of Helicobacter pylori (H pylori) infection, exposure to dietary carcinogens, and predisposing genetic make-up. Because the role of these factors in gastric carcinogenesis cannot be determined readily in human beings, the present study examined the role of an oral carcinogen and H pylori infection in rhesus monkeys. METHODS: Gastroscopies were performed in 23 monkeys assigned to 4 groups: controls; nitrosating carcinogen ethyl-nitro-nitrosoguanidine administration alone; inoculation of a virulent H pylori strain alone (H); and ethyl-nitro-nitrosoguanidine in combination with H pylori (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for 5 years for pathologic and molecular studies. RESULTS: Postinoculation, H and EH groups showed persistent infection and antral gastritis. Starting at 2 and 5 years, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in 3 EH monkeys but in no other groups. Transcriptional analysis of biopsy specimens at 5 years revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in nonneoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer. CONCLUSIONS: Gastric intraglandular neoplasia is induced in primates when H pylori infection is associated with consumption of a carcinogen similar to the nitrosamines found in pickled vegetables, suggesting that H pylori and the carcinogen synergistically induce gastric neoplasia in primates.

Computer-assisted morphometric analysis of lymphatic vessel changes in hamster tongue carcinogenesis.

BACKGROUND: To characterize lymphangiogenesis in early-stage hamster tongue carcinoma development, morphological features and spatial relationships of lymphatic vessels. METHODS: Lymphatic vessels were examined histochemically, using 5'-Nase-ALPase enzyme and combined light and electron microscopy to measure lymphatic vessel area (LVA) and lymphatic vessel density (LVD). RESULTS: In atypical hyperplastic tissues, LVA was found to be 1429.97 and LVD was found to be 39, in carcinoma in situ LVA was 2538.33 and LVD was 48, and in micro-invasive carcinoma LVA was 5733.74 and LVD was 59. Increased lymphangiogenesis was seen in pre-neoplastic states and in early-stage oral squamous cell carcinoma (OSCC). Small regular lymphatic vessels predominated in atypical hyperplasia, and large, irregular lymphatic vessels in early-stage OSCC. Lymphatic endothelial vessels were stretched and porous over large areas. CONCLUSIONS: Newly formed lymphatics and patulous intercellular junctions may be optimally suited for tumor cell metastasis through lymphatic channels in early- and middle-phase carcinogenesis. Lymphatic capillary LVA and LVD became enlarged, and positively correlated, with malignancy, but show no correlation with 7,12-dimethylbenz[a]anthracene-induced time.

The association between oral contraceptive use and lobular and ductal breast cancer in young women.

Recent reports indicate that the incidence of lobular breast cancer is increasing at a faster rate than ductal breast cancer, which may be due to the differential effects of exogenous hormones by histology. To address this issue, we examined whether the relationship between oral contraceptive use and incident breast cancer differs between lobular and ductal subtypes in young women. A population-based sample of in situ and invasive breast cancer cases between ages 20 and 44 were recruited from Atlanta, GA; Seattle-Puget Sound, WA and central New Jersey. Controls were sampled from the same areas by random-digit dialing, and were frequency matched to the expected case age distribution. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. Among the 100 lobular cancers, 1,164 ductal cancers, and 1,501 controls, the odds ratios for oral contraceptive ever use were 1.10 (95% CI = 0.68-1.78) for lobular cancers and 1.21 (95% CI = 1.01-1.45) for ductal cancers, adjusted for study site, age at diagnosis, and pap screening history. Our results suggest that the magnitude of the association between ever use of oral contraceptives and breast cancer in young women does not vary strongly by histologic subtype. These results are similar to previous studies that report little difference in the effect of oral contraceptive use on breast cancer by histology.

N-(4-hydroxyphenyl)all-trans-retinamide (4-HPR) high dose effect on DMBA-induced hamster oral cancer: a histomorphometric evaluation.

N-(4-hydroxyphenyl)all-trans-retinamide (4-HPR) has shown cancer chemoprevention activity in many experimental and clinical situations. The purpose of this research is to evaluate the in vivo efficacy of 4-HPR in preventing 7,12-dimethylbenz(alpha)antracene (DMBA)-induced oral carcinogenesis and to study histomorphometric changes. 76 Syrian hamsters were separated into four groups: group 1, untreated controls (16 animals); group 2, 4-HPR controls (16 animals); group 3, DMBA-treated animals (28); group 4, animals treated with DMBA and 4-HPR (16). Hamsters were painted with a 0.5% solution of DMBA three times a week in their left buccal pouch. A diet of 2 mmol of 4-HPR/kg was administered. At week 9, 50% of the animals were killed; the remainder were killed at week 12. Pathology and histomorphometric tests were performed on epithelium, dysplasia and carcinomas. At week 9, 5 carcinomas were found in group 3, and 13 in group 4. Cancers in group 4 were more numerous, endophytic and infiltrating than those in group 3 animals. At week 12, 16 carcinomas were detected in group 3 animals, but group 4 developed more carcinomas per animal than group 3. Using these experimental concentrations, 4-HPR cannot express its best chemopreventive effect.

A breast cancer patient with pelvic and gastric malignancy after adjuvant tamoxifen treatment for breast cancer.

As is known, tamoxifen therapy is related to endometrial proliferation, hyperplasia, polyp formation, invasive carcinoma and uterine sarcoma. In this study, we present a 75-year-old woman who had five children. Gastric tumor, endometrial carcinoma and cervical adenocarcinoma in situ were detected after treatment with tamoxifen for breast cancer. It seems that being aware of the undesirable affects of tamoxifen treatment during the chemotherapy and post-chemotherapy period is very important.

Environment, testicular dysgenesis and carcinoma in situ testis.

The testicular dysgenesis syndrome (TDS) hypothesis proposes that a proportion of the male reproductive disorders-cryptorchidism, hypospadias, infertility and testicular cancer-may be symptoms of one underlying developmental disease, TDS, which is most likely a result of disturbed gonadal development in the embryo. TDS may be caused by genetic factors, environmental/life-style factors, or a combination of both. Some rare disorders of sex development of genetic origin are among the best-known examples of severe TDS. Among the environmental and life-style factors that are suspected to influence the hormonal milieu of the developing gonad are the endocrine disrupters. A prenatal exposure to commonly used chemicals, e.g. phthalates, may result in a TDS-like phenotype in rats. Currently, this animal model is the best model for TDS. In humans the situation is much more complex, and TDS exists in a wide range of phenotypes: from the mildest and most common form, in which impaired spermatogenesis is the only symptom, to the most severe cases, in which the patient may develop testicular cancer. It is of great importance that clinicians in different specialties treating patients with TDS are aware of the association between the different symptoms.

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure.

Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast cancer during adult life. Fetal exposure to low doses of the xenoestrogen bisphenol A resulted in long-lasting effects in the mouse mammary gland that were manifested during adult life. It enhanced sensitivity to estradiol, decreased apoptosis, increased the number of progesterone receptor-positive epithelial cells at puberty and increased lateral branching at 4 months of age. We now report that fetal exposure to 2.5, 25, 250 and 1000 microg bisphenol A/kg body weight/day induces the development of ductal hyperplasias and carcinoma in situ at postnatal day 50 and 95 in rats. These highly proliferative lesions have an increased number of estrogen receptor-alpha positive cells. Thus, fetal bisphenol A exposure is sufficient to induce the development of preneoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumor development.

Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues.

This study characterizes the morphologic features and the endogenous fluorescence in the stratified squamous epithelia of the 7,12-dimethylbenz(a)anthracene-treated hamster cheek pouch model of carcinogenesis using multiphoton laser scanning microscopy (MPLSM). MPLSM allows high-resolution, three-dimensional image data to be collected deeper within thick tissue samples with reduced phototoxicity compared with single-photon imaging. Three-dimensional image stacks of normal (n = 13), precancerous (dysplasia, n = 12; carcinoma in situ, n = 9) and cancerous tissue [nonpapillary squamous cell carcinoma (SCC), n = 10, and papillary SCC, n = 7] sites in the hamster cheek pouch were collected in viable, unsectioned tissue biopsies at a two-photon excitation wavelength of 780 nm. Five features were quantified from the MPLSM images. These included nuclear density versus depth, keratin layer thickness, epithelial thickness, and the fluorescence per voxel in the keratin and epithelial layers. Statistically significant differences in all five features were found between normal and both precancerous and cancerous tissues. The only exception to this was a lack of statistically significant differences in the keratin fluorescence between normal tissues and papillary SCCs. Statistically significant differences were also observed in the epithelial thickness of dysplasia and carcinoma in situ, and in the keratin layer thickness of dysplasia and SCCs (both nonpapillary and papillary). This work clearly shows that three-dimensional images from MPLSM of endogenous tissue fluorescence can effectively distinguish between normal, precancerous, and cancerous epithelial tissues. This study provides the groundwork for further exploration into the application of multiphoton fluorescence endoscopy in a clinical setting.

Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine.

PURPOSE: To evaluate the effects of alcohol and caffeine in a pancreatic carcinogenesis mouse model induced by 7,12-dimethylbenzantracene (DMBA), according to the PanIN classification system. METHODS: 120 male, Mus musculus, CF-1 mice were divided into four groups. Animals received either water or caffeine or alcohol or alcohol + caffeine in their drinking water. In all animals, 1 mg of DMBA was implanted into the head of the pancreas. After 30 days, euthanasia was performed; excised pancreata were then fixed in formalin, stained with hematoxylin-eosin and categorized as follows: normal ducts, reactive hyperplasia, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 or adenocarcinoma. RESULTS: PanIN lesions were verified in all groups. Adenocarcinoma was detected in 15% of animals in the caffeine group, 16.6% in the water group, 23.8% in the alcohol + caffeine group and 52.9% in the alcohol group (P<0.05). CONCLUSIONS: The experimental pancreatic carcinogenesis mouse model using DMBA effectively induces PanIN lesions and pancreatic adenocarcinoma. This study verified the association between alcohol use and pancreatic adenocarcinoma; caffeine did not present the same effect.

Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice.

BACKGROUND: Pancreatic ductal adenocarcinoma has a poor long-term prognosis. Experimental models are necessary to understand not only its biologic behavior, but also the early pancreatic lesions known as pancreatic intraepithelial neoplasia (PanIN) and to develop new treatments. The aim of this study was to evaluate pancreatic carcinogenesis induced by 7,12-dimethyl-1,2-benzanthracene (DMBA) implantation in mice according to the PanIN classification system. METHODS: Ninety male, Mus musculus, CF-1 mice underwent a median laparotomy and 1 mg of DMBA was implanted into the proximal pancreas held in place by a purse-string suture. Mice were killed after 30 and 60 days after which the excised pancreata were fixed in formalin, embedded in paraffin, and stained with hematoxylin-eosin for histologic analysis. The specimens were evaluated blind by 2 pathologists for the presence of the following histology: normal ducts, reactive hyperplasia, PanIN-1A, PanIN-1B, PanIN-2, and PanIN-3, and adenocarcinoma. RESULTS: In the 30-day group, pathologic evaluation showed 4 (17%) reactive hyperplasia, 16 (67%) PanIN lesions, and 4 (17%) adenocarcinomas. In the 60-day group, there were 10 (27%) specimens with reactive hyperplasia, 13 (35%) with PanIN lesions, and 14 (38%) with adenocarcinomas. The difference between groups was statistically significant (P<.05). All pancreata with adenocarcinoma had concomitant PanIN lesions. CONCLUSIONS: The DMBA experimental model in mice induces PanIN lesions and ductal adenocarcinoma that have similar histology to that of human pancreatic cancer. This model may be useful for study of pancreatic carcinogenesis, particularly the molecular progression of early pancreatic ductal lesions.

Effect of the co-administration of phenobarbital, quercetin and mancozeb on nitrosomethylurea-induced pancreatic tumors in rats.

UNLABELLED: We have previously shown that a single i.p. injection of nitrosomethylurea (NMU) in 3-day-old rats orally treated with the pesticide mancozeb (MZ), the flavonoid quercetin (Q) or in combination (MZ-Q) induces hyperplasia, atypical acinar cell proliferation and carcinoma in situ (CIS) in the pancreas. This work studies the effect of oral administration of phenobarbital (PB) on this model of pancreatic carcinogenesis. The animals were fed on a diet supplemented by MZ or/and Q from the 10th day of pregnancy, thorough lactation and as pups after weaning until being sacrificed at week 24. Saline injection with non-supplemented diet was used for the control group (SAL). The experimental groups were (1) SAL (control), (2) SAL-PB, (3) NMU, (4) NMU-PB, (5) MZ-NMU, (6) MZ-NMU-PB, (7) Q-NMU, (8) Q-NMU-PB, (9) MZ-Q-NMU and (10) MZ-Q-NMU-PB. Acinar cell hyperplasia was found in all groups of NMU-treated rats. Dysplastic foci (DYS) were seen in groups 3-10 at the following percentages: 19, 48, 71, 27, 71, 35, 100 and 30, respectively. CIS were recorded in groups 4 to 10 at percentages: 4, 36, 13, 11, 0, 16, 5, respectively. CONCLUSION: Although PB, Q or MZ given alone enhance DYS lesions in NMU-treated rats, the MZ/Q/PB combined treatments may increase (mainly in males) or decrease (mainly in female) the DYS and CIS proportion. Because PB, MZ and Q influence P450 enzymes, we suggest that these enzymes play a role in the carcinogenesis process.