Hyperplastic Lesions Research Articles

Abstract 5099: Evaluating Ago2 as an oncogene in Kras-dependent lung carcinoma

Abstract Background: Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases, and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g. KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA induced silencing complex (RISC)—physically interacts with KRAS and stabilizes it at the protein level. In NSCLC cell lines, AGO2 knockdown reduces KRAS protein level and attenuates cell proliferation. We hypothesized that AGO2 acts as an oncogene in KRASG12D-dependent NSCLC in vivo. Methods: To test the hypothesis, we generated a NSCLC model by intercrossing mice harboring a stop-floxed KRASG12D allele with animals containing a tamoxifen-responsive Cre recombinase gene driven by the (clara cell-specific) CCSP promoter. These animals, which frequently die within 10 weeks of tamoxifen treatment, display pulmonary lesions including hyperplasia, adenoma and frank adenocarcinoma. We evaluated whether concomitant ablation of one or both copies of (floxed) AGO2 influenced the NSCLC phenotype. After tamoxifen administration, we monitored mice daily and harvested tissues when mice were clinically moribund or reached 16 weeks of post-treatment. We harvested lungs for gross/ pathological examination and gene/ protein expression analysis. Results: While pathologically discernable adenocarcinoma was detectable in AGO2+/+ and AGO2f/+ animals, AGO2f/f mice were free of these lesions. Despite this, deletion of AGO2 had no impact on frequency or extent of hyperplastic or adenomatous lesions. Immunohistochemistry demonstrated absence of AGO2 in tumor tissue of AGO2f/f mice. Conclusion: AGO2 promotes progression but not initiation of cancerous lesions in a mouse model of KRASG12D-dependent NSCLC. Citation Format: Andrew E. Goodrum, Lisha Wang, Alice Xu, Kristin M. Juckette, Arul M. Chinnaiyan, Jean C. Tien. Evaluating Ago2 as an oncogene in Kras-dependent lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5099.

PO-086 BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

IntroductionLung cancer accounts for the highest rate of cancer related diagnosis and mortality worldwide. Small cell lung cancer and non-small cell lung cancer (NSCLC) make up the major subtypes of lung cancer. NSCLC patients only have a 15% five-year survival rate. The major subtypes of NSCLC are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). LUSC accounts for more than 4 00 000 deaths each year and unlike LUAD there are limited targeted therapies. Therefore, a great deal of work still needs to be done to understand the drivers for this cancer.Material and methods shRNA was utilised to modulate the levels of BCL11A and SOX2 in LUSC cell lines. In vitro 3D colony assays and xenograft mouse models were employed to understand the role of BCL11A in driving LUSC tumorigenesis. To explore the role of BCL11A in vivo, a Cre-inducible BCL11A overexpression mouse model was used. To further investigate BCL11A in LUSC, a mouse tracheal basal cells organoid assay was employed. CHIP-seq, immunoprecipitation and immunoblotting assays were designed to dissect the mechanism by which BCL11A elicits its function in LUSC. Drug dose response assays were used to test the efficacy of SETD8 inhibitors and cisplatin on an array of lung cancer cell lines.Results and discussionsAnalysis of TCGA has revealed BCL11A to be upregulated in LUSC but not LUAD. Subsequently reducing BCL11A levels in LUSC cell lines results in diminished xenograft tumour growth. Inversely, its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions which is a precursor to squamous metaplasia. Moreover, deleting Bcl11a in mouse tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres expressing markers of squamous cells.At the molecular level we found BCL11A to be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that BCL11A and SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells.ConclusionCollectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.

Histopathological Evaluation of Hyperplastic Endometrial Lesion based on New WHO classification

Histopathological Evaluation of Hyperplastic Endometrial Lesion based on New WHO classification

Distribution of biopsied non plaque-induced gingival lesions in a Chilean population according to the classification of periodontal diseases

BackgroundMany gingival lesions are not induced by plaque. The aim of this study was to analyze the frequency of biopsied non-plaque-induced gingival lesions (NPIGL) in a Chilean population.MethodsOne thousand twelve cases of biopsied gingival lesions with confirmed anatomopathologic diagnosis were included, from the records of the Oral Pathology Referral Institute (OPRI), Faculty of Dentistry, University of Chile, between years 1990 and 2009.ResultsThe most frequent non plaque-induced gingival lesions categories from biopsied cases included hyperplastic lesions, malignancies and benign neoplasms. The most frequent diagnoses in each category were fibrous hyperplasia (35.47%), squamous cell carcinoma (3.85%) and giant cell fibroma (2.08%), respectively. From all lesions, only 8.3% fitted in the specified categories of the current classification of periodontal diseases.ConclusionsThe most frequent biopsied NPIGL were hyperplastic lesions and neoplasms. These categories represent relevant lesions to be included in a future periodontal classification system to improve the care needs of the patients, as well as early diagnosis and treatment.

Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling.

Unopposed oestrogen is responsible for approximately 80% of all the endometrial cancers. The relationship between unopposed oestrogen and endometrial cancer was indicated by the increase in the number of endometrial cancer cases due to the widespread use of oestrogen replacement therapy. Approximately 30% of the endometrial cancer patients have mutations in the Wnt signalling pathway. How the unbalanced ratios of ovarian hormones and the mutations in Wnt signalling pathway interact to cause endometrial cancer is currently unclear. To study this, we have developed a uterine epithelial cell-specific inducible cre mouse model and used 3D in vitro culture of human endometrial cancer cell lines. We showed that activating mutations in the Wnt signalling pathway for a prolonged period leads to endometrial hyperplasia but not endometrial cancer. Interestingly, unopposed oestrogen and activating mutations in Wnt signalling together drive the progression of endometrial hyperplasia to endometrial cancer. We have provided evidence that progesterone can be used as a targeted therapy against endometrial cancer cases presented with the activating mutations in Wnt signalling pathway.

PO-090 Expression of the cocaine- and amphetamine-regulated transcript (CART) recruits SWI/SNF chromatin remodelling complexes to the oestrogen receptor

IntroductionLung cancer accounts for the highest rate of cancer related diagnosis and mortality worldwide. Small cell lung cancer and non-small cell lung cancer (NSCLC) make up the major subtypes of lung cancer. NSCLC patients only have a 15% five-year survival rate. The major subtypes of NSCLC are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). LUSC accounts for more than 4 00 000 deaths each year and unlike LUAD there are limited targeted therapies. Therefore, a great deal of work still needs to be done to understand the drivers for this cancer.Material and methods shRNA was utilised to modulate the levels of BCL11A and SOX2 in LUSC cell lines. In vitro 3D colony assays and xenograft mouse models were employed to understand the role of BCL11A in driving LUSC tumorigenesis. To explore the role of BCL11A in vivo, a Cre-inducible BCL11A overexpression mouse model was used. To further investigate BCL11A in LUSC, a mouse tracheal basal cells organoid assay was employed. CHIP-seq, immunoprecipitation and immunoblotting assays were designed to dissect the mechanism by which BCL11A elicits its function in LUSC. Drug dose response assays were used to test the efficacy of SETD8 inhibitors and cisplatin on an array of lung cancer cell lines.Results and discussionsAnalysis of TCGA has revealed BCL11A to be upregulated in LUSC but not LUAD. Subsequently reducing BCL11A levels in LUSC cell lines results in diminished xenograft tumour growth. Inversely, its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions which is a precursor to squamous metaplasia. Moreover, deleting Bcl11a in mouse tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres expressing markers of squamous cells.At the molecular level we found BCL11A to be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that BCL11A and SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells.ConclusionCollectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.

Vanadium quercetin complex attenuates mammary cancer by regulating the P53, Akt/mTOR pathway and downregulates cellular proliferation correlated with increased apoptotic events.

Flavonoid metal ion complexes have been deliberated in recent years and are considered as a new class of medicinal agents with enhanced therapeutic activity and low toxicity. Our study deals with chemotherapeutic effects of vanadium, when coordinated with the flavonoid quercetin on a defined model of chemically induced rat mammary carcinogenesis in vivo and on human breast cancer cell line MCF-7 in vitro. The characterization of the complex was achieved through UV-Visible, IR, and Mass spectra and antioxidant activity was assessed by DPPH, FRAP and ABTS methods. In vitro studies established that the complex upregulated the expressions of p53, Caspase 3 and 9, whereas down regulating Akt, mTOR and VEGF expressions and also induced apoptosis and DNA fragmentation in a dose dependent manner. Acute and Sub-acute toxicity was performed to determine safe doses. 7,12-Dimethylbenz(α)anthracene (0.5mg/100g body weight) was used for induction of breast cancer in female Sprague-Dawley rats via single tail vein injection. The histopathological analysis after 24weeks of carcinogenesis study depicted substantial repair of hyperplastic lesions. TUNEL assay showed an increase in apoptotic index (0.14 ± 0.03; 0.15 ± 0.01) in vanadium-quercetin treated groups as compared to the carcinogen control (0.02 ± 0.01) along with upregulation of Bcl-2 and downregulation of Bax and p53. Immunohistochemical analysis also exhibited decrease in cell proliferation in the vanadium-quercetin treated groups (11.3 ± 0.12; 11.8 ± 0.10). Thus, results from both in vivo and in vitro studies revealed that vanadium-quercetin complex could be a potential candidate for development of approved drug for breast cancer in the near future.

Efficacy of Narrow Band Imaging in Detecting Lower Gi Lesions and Its Histologic Correlation

Background: To evaluate the efficacy of Narrow band imaging (NBI) in detecting lower GI lesions and differentiation on the basis of color, vascular pattern and surface pattern findings on NBI with histopathologic correlation. Material and Methods: 94 patients of both gender, with lower GI symptoms were subjected for lower GI endoscopy by conventional   white   light   endoscopy and CLV-190 HD colonoscope having Narrow-band imaging (NBI) as standard feature after obtaining an informed consent. Patients who did not give consent, patients with severe inflammatory bowel disease and who lost during follow up were excluded from the study. All NBI findings of suspected lesions were classified according to NICE (NBI International Colorectal Endoscopic) classification, into hyperplastic lesion, adenomatous and invasive carcinoma. Biopsies were taken and stained with Haematoxylin and Eosin as well as Periodic Acid Schiff stain. Statistical analysis was done to compare NBI diagnosis with the histopathological diagnosis. Results: Majority of the patients were in the third decade of life, with a mean age of 36.22 years. Diarrhea was the commonest clinical presentation, in 60 (63.8%) patients. NBI was suggestive of ulcerative colitis/Inflammatory bowel disease (IBD) in 59 (62.8%) patients, neoplastic polypoidal lesion in 24 patients (25.5%) and polypoidal non-neoplastic lesion in 11 (11.7%) patients. Out of 59 (62.8%) cases of Ulcerative colitis (UC), 35 (37.2%) were polypoidal, among which 24 (68.6%) were suggestive of neoplastic polypoidal lesion (NICE II-III) and 11(31.4%) were non-neoplastic polypoidal lesion (NICE I). Out of 59 cases of UC, clear mucosal vascular pattern (MVP) was found in 11 (18.6%) cases and obscure MVP in 48 (81.4%) cases. Conclusions: NBI provides a unique image with contrast enhancement and can emphasize the capillary pattern and surface architecture and plays a major role in the differentiation of neoplastic and non-neoplastic colorectal lesion, with high sensitivity and specificity.

Canine Splenic Nodular Lymphoid Lesions: Immunophenotyping, Proliferative Activity, and Clonality Assessment.

Canine splenic lymphoid nodules are currently classified as indolent lymphomas (marginal zone lymphoma [MZL], mantle cell lymphoma [MCL]) or nodular hyperplasia (lymphoid [LNH] or complex [CNH] type). Their differentiation can be difficult on morphology, because of similar histologic appearance and poorly defined diagnostic criteria. Thirty-five surgical samples of splenic lymphoid nodules were reviewed in order to assess the diagnostic contribution of immunophenotyping, proliferative activity and clonality (PARR) in differentiating between hyperplastic and neoplastic lesions. Proliferative activity was evaluated by double immunolabeling for Ki-67 and CD79a, in order to separately assess the proliferative activity of B cells and non-B cells. Definitive diagnoses were MZL ( n = 11), MCL ( n = 4), LNH ( n = 10), and CNH ( n = 10). The overall concordance between histology and PARR was above 90%. Lymphomas had a significantly higher percentage of CD79a-positive areas (mean, 36.30%; P = .0004) and a higher B-cell proliferative activity (median Ki-67 index, 5.49%; P = .0012). The threshold value most accurately predicting a diagnosis of lymphoma was ≥28% of B-cell areas, with a Ki-67 index above 3%. Dogs were monitored for a median follow-up time of 870 days (IQR, 569-1225), and no relapses were documented. Overall median survival time was 1282 days. The combination of histology, immunohistochemistry and PARR can improve the diagnostic accuracy for canine splenic lymphoid nodules, although the long-term behavior of these lesions appears similar.

The gastric mucosal protective effects of astragaloside IV in mnng-induced GPL rats

Gastric Cancer is one of the most common types of cancer. And the occurrence of gastric carcinoma is an evolutionary histopathological stage. As a result, further research of GPL, which is a borderline of gastric cancer, is indispensable for preventing the formation and development of gastric carcinoma. Several studies have demonstrated a correlation between the expression of autophagy, apoptosis and Gastric cancer (GC). However, the effects of autophagy and apoptosis on human gastric cancer progression, particularly on gastric precancerous lesions (GPL), have not totally been investigated. At present, Astragaloside IV(AS-IV) is a saponin purified from Astragalus membranaceous Bge, a traditional Chinese herb that has been widely used for more than 2000 y in the treatment of cancer, cardiovascular and immune disorders. This study was designed to investigate the mechanism of AS-IV protecting gastric mucosa in N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)-induced GPL rats. The lesions of GIM and GED were significantly ameliorated compared with the model rats, especially crowded tubular glandular and back-to-back tubular structure, which were the dangerous borderline between GPL and GC. Western Blot analysis showed that the ratio of Bcl-2/Bax and the protein expression of Bcl-XL, p53, Beclin1, p62, ATG5 and ATG12 were decreased and the level of Caspase3 was increased in the group of AS-IV compared with the model group; RT-PCR analysis showed that the gene expression Ambra1, Beclin1, ATG5, LC3 and p62 were decreased in the group of AS-IV compared with the model group. This research manifested that the occurrence of gastric cancer was preceded by a prolonged precancerous stage, which could be ameliorated by the AS-IV. Meanwhile, the mild and moderate stage of precancerous lesions is similar with gastric adenocarcinoma in critical biological processes, including inflammation, cell proliferation, differentiation. But this lesion is very different from cancer, because it does not appear obvious invasion and malignant lesions in this pathologic stag. Further, AS-IV could regulate p53 expression to activate the Ambra1/Beclin1 complex in GPL, and it will protect the gastric mucosal injury, prevent and cure gastric mucosal atrophy, intestinal metaplasia and atypical hyperplastic lesions. It provided a potential therapeutic strategy in reversing intestinal metaplasia and dysplasia of gastric precancerous lesions and protecting the gastric mucosa in GPL rats.

Expression of TICAM-2 in hyperplastic lesions of the parathyroid glands.

Expression of TICAM-2 in hyperplastic lesions of the parathyroid glands.

Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype

Extensive spontaneous DNA damage from oncogene-induced replication stress is ubiquitous in precancerous lesions. While this damage induces differentiation, senescence, or apoptosis in normal cells, defects in DNA replication stress response (RSR) allow cells to continue proliferating, ultimately leading to early tumorigenesis. Using systems-level approaches, we developed a replication stress response defect gene signature that predicted riskof cancer development from hyperplastic lesions. Intriguingly, we found that replication stress response defects rewire non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. High-throughput drug screening to elucidate molecules required for survival of replication stress response defective cells identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. Moreover, MEK/ERK inhibition also depleted CSC populations. Together, these findings provide insights into the role of replication stress response defects in CSCs and an actionable pathway for therapeutic targeting.

Incidence of reactive hyperplastic lesions in the oral cavity: a 10 year retrospective study in Santa Catarina, Brazil

IntroductionReactive hyperplastic lesions develop in response to a chronic injury simulating an exuberant tissue repair response. They represent some of the most common oral lesions including inflammatory fibrous hyperplasia, oral pyogenic granuloma, giant cell fibroma, peripheral ossifying fibroma, and peripheral giant cell lesions. ObjectiveThe incidence of those lesions was investigated in an oral pathology service, and the clinical characteristics, associated etiological factors, concordance between the clinical and histopathological diagnostic was determined. MethodsA total of 2400 patient records were screened from 2006 to 2016. Clinical features were recorded from biopsy reports and patients’ files. ResultsA total of 534 cases of reactive hyperplastic lesions were retrieved and retrospectively studied, representing 22.25% of all diagnoses. The most frequent lesion was inflammatory fibrous hyperplasia (72.09%), followed by oral pyogenic granuloma (11.79%), giant cell fibroma (7.30%), peripheral ossifying fibroma (5.24%), and peripheral giant cell lesions (3.55%). Females were predominantly affected (74.19%), the gingiva and alveolar ridge were the predominant anatomical site (32.89%), and chronic traumatism was presented as the main etiological factor. The age widely ranges from the 1st decade of life to the 7th. Clinically, the reactive hyperplastic lesions consisted of small lesions (0.5–2cm) and shared a strong likeness in color to the oral mucosa. The concordance between the clinical and histopathological diagnostic was high (82.5%). ConclusionReactive hyperplastic lesions had a high incidence among oral pathologies. The understanding of their clinical features helps to achieve a clearer clinical and etiological diagnosis, and the knowledge of factors related to their development. This may contribute to adequate treatment and positive prognosis.

Prevalence and Distribution of Gingival Pyogenic Granuloma in Sulaimani population - Kurdistan Region - Iraq

Pyogenic granuloma is an inflammatory hyperplastic lesion seen in the oral cavity. It is commonly appear in the gingiva. The objectives of the research were to determine the percent of gingival pyogenic granuloma in the population of Sulaimani city -Iraq in relation to gender, age, pregnancy ,systemic diseases ,oral hygiene and site of occurrence of pyogenic granuloma. Materials and Methods: In this study the total stratified sample [1136 (568 male +568 female] and the randomly selected sample [248 (124 male and 124 female their age range (from 10 to 70 year) .They were examined orally for inspection of gingival pyogenic granuloma and determination of oral hygiene. The percent of the total sample with gingival pyogenic granuloma was (11.3%). The most of patients with gingival pyogenic granuloma was in females in their Second decade. The high percent of gingival pyogenic granuloma was found in buccal gingiva in upper jaw. Highly significant relationship was found between gingival pyogenic granuloma and its’ history. There was significant correlation between gingival pyogenic granuloma and oral hygiene status and systemic condition.

Deciphering the biochemical and molecular mechanism underlying the in vitro and in vivo chemotherapeutic efficacy of ruthenium quercetin complex in colon cancer.

Flavonoids are the most investigated phytochemicals due to their pharmacological and therapeutic activities. Their ability to chelate with metal ions has resulted in the emergence of a new category of molecules with a broader spectrum of pharmacological activities. In this study, the ruthenium quercetin complex has been synthesized and anticancer activity has been evaluated on a well-defined model of DMH followed by DSS induced rat colon cancer and on human colon cancer cell line HT-29. The characterizations accomplished through UV-visible, NMR, IR, Mass spectra and XRD techniques, and antioxidant activity was assessed by DPPH, FRAP, and ABTS methods. In vitro study confirmed that the complex increased p53 expression, reduced VEGF and mTOR expression, apoptosis induction, and DNA fragmentation in the HT-29 cells. Acute and subacute toxicity study was also assessed and results from in vivo study revealed that complex was efficient to suppress ACF multiplicity and hyperplastic lesions and elevated the CAT, SOD, and glutathione levels. Furthermore, the complex was found to decrease cell proliferation and increased apoptotic events in tumor cells correlates upregulation of p53 and Bax and downregulation of Bcl2 expression. Our findings from the in vitro and in vivo study support the continued investigation of ruthenium quercetin complex possesses a potential chemotherapeutic activity against colon cancer and was efficient in reducing ACF multiplicity, hyperplastic lesions in the colon tissues of rats by inducing apoptosis.

Human gene expression microarray analysis of the HPV 6bE7-HaCaT stable cell line

ObjectiveHuman papillomavirus (HPV) is the most common sexually transmitted agent in the world. HPV6b is a low-risk type of HPVs that causes benign verrucous hyperplastic lesions of the skin and anal genital mucosa. Previous research has indicated that HPV genotype 6 is sometimes associated with high-grade lesions and anal cancer. The pathogenesis of low-risk HPV infection and its relationship to high-risk HPV is not clear at present. The E7 protein, which is encoded by HPV early –expressing genes, plays an important role in HPV infection. The aim of this study is to investigate the human gene expression signature of the HPV6b E7-transfected HaCaT stable cell line. The identification of differentially expressed genes might provide a more comprehensive understanding of HPV6b infection and will allow us to explore the specific role of E7 protein. MethodsWe established a stable cell line transfected with the HPV6b E7 gene and analyzed the line's genome-wide expression profile by microarray. Quantitative real-time PCR (qRT-PCR) was used to verify the differentially expressed genes. GO enrichment analysis was applied for gene annotation according to functions. KEGG analysis, a system for analyzing gene function and genome information, was used to help us integrate differentially expressed genes into pathways. ResultsA total of 3519 genes were identified to be significantly differentially expressed between the HPV 6bE7-HaCaT stable cell line and a control cell line, among which 1884 genes were up-regulated and 1635 genes were down-regulated with a fold-change > 2.0 between the two groups. The expression profiles of the top 20 up-regulated and the top 20 down-regulated genes in the HPV 6bE7-HaCaT stable cell line as analyzed by qRT-PCR were consistent with the microarray data. The most significantly enhanced genes HPV 6bE7-HaCaT cells were SIMC1, S100A8 and S100A9, whereas PXDN expression was markedly down-regulated. GO analysis showed that HPV 6bE7 primarily affected biological processes and that the most significant difference was in heart induction (GO:0003129). Many differentially expressed genes were linked to histone H4-K20 demethylation (GO:0035574). KEGG analysis showed that the most significant changes in gene expression were related to primary bile acid biosynthesis, and the most diverse biological processes were related to systemic lupus erythematosus pathogenesis. ConclusionsThe global gene expression profile of the HPV 6bE7-HaCaT stable cell line was analyzed, revealing the genes regulated by E7 protein and providing insight into the pathogenesis of HPV6b infection.

Proliferative Lesions of the Endometrium of 50 Four-Toed Hedgehogs ( Atelerix albiventris).

Uteri from 50 four-toed hedgehogs ( Atelerix albiventris) with clinical signs of uterine disease were histopathologically examined. Sixteen animals (32%) were diagnosed with endometrial hyperplasia, 7 animals (14%) were diagnosed with endometrial polyp, and 27 animals (54%) were diagnosed with endometrial neoplasia. The mean ages of the animals with endometrial hyperplasia, polyp, and neoplasia were 28.7 months, 29.4 months, and 25.2 months, respectively. The neoplasms were classified into 7 endometrial mixed tumors, 12 endometrial stromal nodules, and 8 endometrial stromal sarcomas. However, the endometrial stromal nodules and endometrial stromal sarcomas often developed within or were contiguous with an endometrial polyp or mixed tumor. Interestingly, the stromal tumors and the stromal components of the endometrial polyp and mixed tumor displayed extraendometrial differentiation (eg, into adipocytes, granular cells, smooth muscle cells, and osteoid tissue). The endometrial stromal sarcomas exhibited severe cellular atypia and invaded subendometrial tissue. Immunohistochemical examinations demonstrated that the stromal cells of the hyperplastic lesions as well as the neoplastic lesions were positive for CD10, the progesterone receptor, and Wilms tumor 1. The four-toed hedgehog develops unique uterine neoplasms that are mainly composed of endometrial stromal cells and probably arise from endometrial polyps and/or mixed tumors.

Abstract P6-07-02: Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice

Abstract Breast cancer is a commonly diagnosed cancer of pregnancy. However, how endogenous and exogenous endocrine factors may contribute to the development of pregnancy-associated mammary tumorigenesis is not clear. There is growing evidence that mammary stem cells (MaSCs) may initiate neoplastic transformation when dysregulated in mouse models. We investigated the effect of the environmental endocrine disruptor bisphenol A (BPA) on mouse mammary gland morphology, epithelial cell composition, pre-neoplastic lesions, and the regenerative function of MaSCs. Pregnant FVB mice with GFP transgene on Day E8.5 were implanted with osmotic pumps that constantly release BPA at 0, 25 or 250 ng/kg/day for 28 days and the mice were euthanized one month after weaning. In agreement with the literature, we observed an abnormality of the morphology of the mammary gland after BPA treatment characterized by higher duct density and abnormal secondary and tertiary branching. Quantification of percent hyperplastic mammary ducts in H&E-stained tissue slides revealed a significant increase of ducts with hyperplastic lesions after BPA treatment, particularly with the low dose. To investigate the effects of BPA treatment on MaSCs, we used enzyme digestion to isolate the CD24hi/CD49f+ luminal epithelial cells (also termed as colony forming cell or CFC) and the CD24+/CD49fhi basal epithelial cells (also termed as mammary repopulating unit or MRU) from mammary gland tissues by FACS and found no significant difference in percent of luminal or basal cell population after BPA treatment. Because the basal cells are enriched with MaSCs that can form mammospheres in suspension culture and subsequently form solid 3D organoids when cultured in Matrigel, we transplanted the solid 3D organoids into cleared mammary fat pads of syngeneic FVB mice and immune-compromised nude mice to examine how BPA treatment might alter MaSC function. Significantly, similar to the results from the primary mammary glands, the regenerated mammary glands by MaSCs from mice treated with the low dose of BPA showed increased duct density, secondary and tertiary branching, and a significantly greater number of hyperplastic lesions. Taken together, our study demonstrated that BPA exposure at very low dose could induce pre-neoplastic lesions in the mammary gland of pregnant mice, apparently by directly targeting MaSCs and implicates BPA as an exogenous endocrine factor that may promote pregnancy-associated mammary tumorigenesis. Citation Format: Bouamar H, Zhang F, Gu X, Dong Q, Sun L. Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-07-02.

MUTYH-associated colon disease: adenomatous polyposis is only one of the possible phenotypes. A family report and literature review.

The MutY human homologue gene (MUTYH) is responsible for about a quarter of attenuated familial adenomatous polyposis. Occasionally, it has been associated with hyperplastic polyps and serrated adenoma. We report a family where the same MUTYH mutation determined four different phenotypes, including a case of hyperplastic polyposis syndrome. A family with a history of right-sided colon cancer and multiple colonic polyposis was investigated. Genetic tests were correlated with clinical findings to define phenotypic manifestations of MUTYH mutations. The pertinent English-language literature was reviewed to evaluate the risk of malignancy of MUTYH and the role of prophylactic surgery. Three male siblings carried a biallelic MUTYH mutation (G382D-exon13), while the fourth was heterozygote. One developed an isolated cecal cancer at the age of 48. Another, aged 38, was diagnosed with numerous minute colonic and rectal polyps and underwent a proctocolectomy, with final pathology showing a picture of hyperplastic and lymphoid polyposis. The third biallelic brother, 46 years old, developed four hyperplastic lesions, while the heterozygote brother had a large flat serrated adenoma of the right colon removed at the age of 50. Many aspects of MUTYH mutation still need to be clarified and one of them regards the different phenotypic expressions. Although the majority of reported cases manifested attenuated adenomatous polyposis, hyperplastic polyps and serrated adenomas appear to be more common than expected. Presenting hyperplastic polyposis syndrome is very unusual and may represent a clinical dilemma for correct management. Current evidence suggests to handle MUTYH-associated polyposis as typical FAP.

Localized Reactive Hyperplastic Lesions of the gingiva:A clinico-pathological study of 636 lesions from Iraq

This study was conducted to establish the prevalence of different reactive hyperplastic lesions of the gingiva in a university-based dental school biopsy service.Biopsy records over a 12-years period (1982-1994) were retrieved from the files of the department of Oral Pathology, College of Dentistry, University of Baghdad. The lesions were reclassified into: Fibrous lesions (like Focal Fibrous Hyperplasia FFH and Ossifying Fibrous Epulis OFE); vascular lesions (like Pyogenic granuloma) and Giant cell lesions (like Peripheral giant cell granuloma PGCG). The available clinical data regarding age, gender and location were obtained for each case.The majority of lesions were pyogenic granuloma which constituted 49.2% with female predilection. Peoples in the first and second decade of life were more prone to develop gingival lesions especially in upper anterior region.This study indicates some differences in age and gender distribution as well as in location between the different lesions.