Central Role In Carcinogenesis Research Articles

Environmental and Metabolic Risk Factors Linked to Gallbladder Dysplasia.

Gallbladder disorders encompass a spectrum from congenital anomalies to inflammatory and neoplastic conditions, frequently requiring surgical intervention. Epithelial abnormalities like adenoma and metaplasia have the potential to progress to carcinoma, emphasizing the importance of histopathological assessment for early detection of malignancy. Gallbladder cancer (GBC) may be incidentally discovered during cholecystectomy for presumed benign conditions, underscoring the need for a thorough examination. However, the lack of clarity regarding the molecular mechanisms of GBC has impeded diagnostic and therapeutic advancements. Timely detection is crucial due to GBC's aggressive nature and poor prognosis. Chronic inflammation plays a central role in carcinogenesis, causing DNA damage and oncogenic alterations due to persistent insults. Inflammatory cytokines and microRNAs are among the various mediators contributing to this process. Gallbladder calcifications, particularly stippled ones, may signal malignancy and warrant preemptive removal. Molecular pathways involving mutations in oncogenes and tumor suppressor genes drive GBC pathogenesis, with proposed sequences such as gallstone-induced inflammation leading to carcinoma formation. Understanding these mechanisms, alongside evaluating mucin characteristics and gene mutations, can deepen comprehension of GBC's pathophysiology. This, in turn, facilitates the identification of high-risk individuals and the development of improved treatment strategies, ultimately enhancing patient outcomes. Thus, in this review, our aim has been to underscore the primary mechanisms underlying the development of gallbladder dysplasia and neoplasia.

Abstract A028: Alcohol induces DNA damage and genomic instability in MCF-7 breast cancer cells and primary mammary tissues

Abstract Alcohol consumption has been associated with increased breast cancer risk. Previous studies indicated that alcohol-induced DNA damage plays a central role in carcinogenesis. However, the underlying molecular mechanisms remain unclear. This study aimed to examine the effect of alcohol exposure on key DNA damage/repair pathways in both in vitro and in vivo settings. When MCF-7 breast cancer cells were exposed to 0.1 ~ 0.8% alcohol, the treatment induced concentration-dependent DNA damage, as indicated by the increased 8-OHdG (8-hydroxy 2 deoxyguanosine) production and p-H2AX foci formation. Signal transduction analysis showed that alcohol induced DNA damage signals, including p53, p21, E2F-1 and CHK1, and the markers in DNA repair pathways, including XLF, Rad50 and DNA-PK. p53 knockdown in MCF-7 cells resulted in enhanced DNA damage and DNA repair responses, which underscores the role of p53 in alcohol-induced cellular regulation. We also demonstrated that alcohol induces sister chromatid exchanges (SCEs) in MCF-7 cells, and ALDH2 knockout enhanced alcohol induced SCEs, which suggests that alcohol-induced acetaldehyde (AA) is a key mediator in this process. Moreover, we examined the DNA damage markers in mammary tissues of FVB/N mice exposed to alcohol and showed that alcohol exposure in vivo induced similar patterns of DNA damage and repair responses. Taken together, our data highlights the contribution of alcohol-induced DNA damage in cellular injury and the consequent tumorigenesis, which provide fundamental support for further studies on alcohol-induced DNA damage and carcinogenesis. Citation Format: Xiaohe Yang. Alcohol induces DNA damage and genomic instability in MCF-7 breast cancer cells and primary mammary tissues [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A028.

Tumor-associated macrophages in canine visceral hemangiosarcoma.

Canine hemangiosarcoma (HSA) is a highly malignant tumor derived from hematopoietic stem cells and commonly occurs in visceral organs or skin. Visceral HSAs are particularly aggressive and progress rapidly despite multimodal treatment. Tumor-associated macrophages (TAMs) play a central role in carcinogenesis, tumor progression, and metastasis in humans and murine models. In this retrospective study, we investigated the prevalence and phenotype of TAMs in privately owned, treatment-naïve dogs with naturally occurring HSA. We used CD204 as a general macrophage marker and CD206 as a marker for M2-polarized macrophages. Formalin-fixed paraffin-embedded tissues from HSAs in the spleen (n = 9), heart (n = 6), and other locations (n = 12) from 17 dogs were sectioned and immunohistochemically labeled with CD204 and CD206 antibodies. The mean number of log(CD204)- and log(CD206)-positive cells and the ratio of log(CD206/CD204)-positive cells were compared with normal surrounding tissues and between tumor locations. There were significantly more macrophages and M2 macrophages, and a higher ratio of M2 macrophages to total macrophages in tumor hot spots (P = .0002, P < .0001, and P = .0002, respectively) and in tumor tissues outside of hot spots (P = .009, P = .002, and P = .007, respectively) than in normal surrounding tissues. There were no significant differences between tumor locations, but there was a trend toward higher numbers of CD204-positive macrophages within the splenic tumors. There was no association between histological parameters or clinical stage and TAM numbers or phenotype. As in humans, TAMs in dogs with HSA have a predominantly M2-skewed phenotype. Dogs with HSA could serve as excellent models to evaluate new TAM-reprogramming therapies.

Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed.

Carcinogenic N-nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens—widely detectable in relatively low levels in food, water, cosmetics, and drugs—are well-established and powerful animal carcinogens. The electrophiles resulting from the cytochrome P450-mediated metabolism of N-nitrosamines can readily react with DNA and form covalent addition products (DNA adducts) that play a central role in carcinogenesis if not repaired. In this review, we aim to provide a comprehensive and updated review of progress on the metabolic activation and DNA interactions of 10 carcinogenic N-nitrosamines to which humans are commonly exposed. Certain DNA adducts such as O6-methylguanine with established miscoding properties play central roles in the cancer induction process, whereas others have been linked to the high incidence of certain types of cancers. We hope the data summarized here will help researchers gain a better understanding of the bioactivation and DNA interactions of these 10 carcinogenic N-nitrosamines and facilitate further research on their toxicologic and carcinogenic properties.

Molecular mechanism of EGFR signaling evoked by environmental pollutant 1,2-naphthoquinone

The epidermal growth factor receptor (EGFR) is the most extensively examined receptor tyrosine kinase. Several EGFR mutations and modifications have been shown to induce self-activation, which plays a central role in carcinogenesis. Recently, environmental chemicals such as PM2.5 can also activate EGFR and become risk factors for cancer. Although, the detailed mechanism remains unknown. In this study, we focused on 1,2-naphthoquinone (1,2-NQ) which is a secondary metabolite of naphthalene. Humans are exposed to 1,2-NQ through the combustion of fossil and diesel fuel and from tobacco smoke and PM2.5. Here, we demonstrate that 1,2-NQ is a novel EGFR-specific activator. We found that 1,2-NQ forms a covalent bond called N-arylation with EGFR Lys80 which is in the extracellular domain by LC-MS/MS. This modification activates the EGFR-Akt signaling pathway, which inhibits serum deprivation-induced apoptosis in A549 cells. Our study reveals an original mode of EGFR activation via covalent binding. We propose the correlation between EGFR activation without ligands and environmental pollutant-associated diseases such as cancer.

Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management.

The epidermal growth factor receptor (EGFR) family is a class of receptor tyrosine kinase playing a central role in carcinogenesis and cancer progression. The members of this family, particularly EGFR and human epidermal growth factor receptor 2 (HER2), are the most extensively studied drug targets for malignancy. Today, numerous tyrosine kinase inhibitors targeting EGFR family have been developed to combat non-small-cell lung cancer and breast cancer. However, severe gastrointestinal (GI) toxicity leading to dose reduction and treatment discontinuation hampers the therapeutic outcome of EGFR inhibitors. Diarrhea is one of the most frequent GI side effects, especially when it comes to second-generation EGFR inhibitors. Enterocytes apoptosis and increased inflammation accompany with many oral EGFR inhibitors. Loperamide and budesonide are the first-line treatment to manage such adverse effects. However, current prophylaxis and management are all empirical interventions to relieve the symptom. They do not specifically target the toxicological mechanism of EGFR inhibitors. Hereby, those anti-diarrhea agents do not work well when used in cancer patients experiencing EGFR inhibitor-induced diarrhea. On the other hand, the toxicological mechanism of EGFR inhibitor-induced diarrhea is poorly understood. Thus, determining the mechanism behind such diarrhea is urgently in need for developing genuinely effective anti-diarrhea agents. This review aims to call attention to EGFR inhibitor-induced diarrhea, a highly occurring and devastating cancer drug toxicity.

Correct Identification of Cell of Origin May Explain Many Aspects of Cancer: The Role of Neuroendocrine Cells as Exemplified from the Stomach.

Cancers are believed to originate from stem cells. Previously, the hypothesis was that tumors developed due to dedifferentiation of mature cells. We studied the regulation of gastric acid secretion and showed that gastrin through the gastrin receptor stimulates enterochromaffin-like (ECL) cell histamine release and proliferation. In animal and human studies, we and others showed that long-term hypergastrinemia results in ECL cell-derived tumor through a sequence of hyperplasia, dysplasia, neuroendocrine tumors (NETs), and possibly neuroendocrine carcinomas (NECs) and adenocarcinomas of diffuse type. Perhaps, other cancers may also have their origin in differentiated cells. Knowledge of the growth regulation of the cell of origin is important in cancer prophylaxis and treatment. Physiology plays a central role in carcinogenesis through hormones and other growth factors. Every cell division implies a small risk of mutation; thus mitogens are also mutagens. Moreover, metastasis of slow proliferating cells may also explain so-called tumor dormancy and late recurrence.

Exploring targets of TET2-mediated methylation reprogramming as potential discriminators of prostate cancer progression

BackgroundGlobal DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, the identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology.ResultsUsing a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes—ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX—exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n = 423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n = 50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n = 19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site.ConclusionsOur study identifies seven genes governed by TET2 loss in PCa which exhibit an association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.

The functional roles of exosomal long non-coding RNAs in cancer.

Exosomes are extracellular membranous vesicles that are secreted by various cell types. Exosomes have become indispensable facilitators in the exchange of information between cells. More importantly, exosomes perform a crucial role in a variety of diseases including cancers. Long non-coding RNAs (lncRNAs) are over 200 nucleotides long transcripts that exhibit no or limited protein-coding potentials. LncRNAs are an emerging group of regulatory RNAs and can be selectively packaged into exosomes. Exosomal lncRNAs play a central role in carcinogenesis and cancer progression by modulating tumor growth, metastasis, angiogenesis and chemoresistance. Moreover, exosomal lncRNAs function as messengers in cell-to-cell communication, and thus remodel the tumor microenvironment. Their function relevance in cancer biology hints at the possibility of employing exosomal lncRNAs as promising, non-invasive biomarkers for further cancer therapy. In this review, we provide an overview of current research on the functional roles of exosomal lncRNAs in cancer and discuss their potential clinical applications as diagnostic biomarkers and therapeutic targets for cancers.

Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer.

Mitochondrial dysfunction plays a central role in carcinogenesis in numerous cancer-related diseases. We examined the copy number variation of mitochondrial DNA (mtDNA) and the expression of energy-producing genes in relation to ulcerative colitis (UC)-associated carcinogenesis. We studied 17 patients with UC-associated adenocarcinoma (UC-Ca) and 16 without UC-associated adenocarcinoma (UC-nonCa). The copy number of mtDNA in non-dysplastic mucosa in both groups was quantified by an array-based digital polymerase chain reaction (PCR) assay. Simultaneously, gene expression related to mitochondrial energy metabolism was determined by a PCR array. We observed a higher copy number of mtDNA in non-dysplastic mucosa in the UC-Ca group compared to the UC-nonCa group (484.2 vs. 747.7 copies/cell, p=0.022). The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of UC-associated adenocarcinoma by mtDNA copy number were 43.8%, 100%, 100%, and 60.9%, respectively. We observed an increased expression of mitochondrial genes related to energy metabolism together with an increased copy number of mtDNA. Mitochondrial function and its metabolic process play essential roles in UC carcinogenesis and are possible risk markers for the development of colitic cancer.

H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance

Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer.

Transforming growth factor β2 promotes transcription of COX2 and EP4, leading to a prostaglandin E2-driven autostimulatory loop that enhances virulence of Theileria annulata-transformed macrophages.

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-β consequently plays a central role in carcinogenesis, and a dampened TGF-β2 response by Theileria annulata-infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-β2 production, there is ablated expression of COX2 and EP4, which leads to a drop in cyclic AMP (cAMP) levels and, consequently, reduced activation of protein kinase A (PKA) and EPAC. This ablated phenotype can be rescued in attenuated macrophages by the addition of exogenous TGF-β2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-β2 therefore promotes the adhesion and invasiveness of virulent macrophages by modulating COX2, EP4, and PKIG transcription to initiate a prostaglandin E2 (PGE2)-driven autostimulatory loop that augments PKA and EPAC activities. A virulence phenotype stemming from the double activation of PKA and EPAC is the induction of a CREB-mediated transcriptional program and the upregulation of JAM-L- and integrin 4αβ1-mediated adhesion of Theileria-infected macrophages.

Expression of nicotinamide phosphoribosyltransferase-influenced genes predicts recurrence-free survival in lung and breast cancers.

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide biosynthesis. NAMPT protein is a secreted plasma biomarker in inflammation and in cancer. The NAMPT enzymatic inhibitor, FK866, acts as an inducer of apoptosis and is a cancer therapeutic candidate, however, little is known regarding the influence of NAMPT on cancer biological mechanisms or on the prognosis of human cancers. We interrogated known microarray data sets to define NAMPT knockdown-influenced gene expression to demonstrate that reduced NAMPT expression strongly dysregulates cancer biology signaling pathways. Comparisons of gene expression datasets of four cancer types generated a N39 molecular signature exhibiting consistent dysregulated expression in multiple cancer tissues. The N39 signature provides a significant and independent prognostic tool of human recurrence-free survival in lung and breast cancers. Despite the absence of clear elucidation of molecular mechanisms, this study validates NAMPT as a novel “oncogene” with a central role in carcinogenesis. Furthermore, the N39 signature provides a potentially useful tool for prediction of recurrence-free survival in lung and breast cancer and validates NAMPT as a novel and effective therapeutic target in cancer.

Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma

The epithelial to mesenchymal transition (EMT) is a crucial process in tumor progression. EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. Serum response factor (SRF) is a transcription factor that plays a central role in carcinogenesis and tumor progression in several types of cancers. We investigated the effect of EMT-related SRF, focusing on its promotion of chemoresistance against sorafenib in hepatocellular carcinoma (HCC). We examined SRF and Snail expression in 146cases of HCCs by immunohistochemistry. We also examined the chemoresistance effect of SRF in HCC cells by transfecting HLE cells with SRF cDNA and SH-J1 cells with SRF antisense cDNA. Expression of SRF and Snail were detected in 37.6% (55 of 146 cases) and in 12.3% (18 of 146 cases) of the HCCs, respectively. None of the tumor-free liver tissues showed SRF or Snail expression. SRF expression was closely correlated with the expression of Snail (p<0.001) and expression of both SRF and Snail showed significant correlation with the high histological grade (p=0.015 and 0.003, respectively). Overexpression of SRF in HLE cells led to increased expression of mesenchymal markers, as well as increased cell growth and colony formation. Overexpression of SRF also led to a significant reduction in the cytotoxic effect of sorafenib in HLE cells. Conversely, inhibition of SRF expression in the SH-J1 cells significantly enhanced the apoptotic effects of sorafenib, along with the reduced expression of mesenchymal markers and restored the expression of E-cadherin. These results suggest that SRF is critical for HCC to acquire a mesenchymal phenotype, which leads to resistance against a sorafenib-mediated apoptotic effect.

P53 gene: major mutations in neoplasias and anticancer gene therapy

The p53 gene encodes a protein that has molecular weight of 53kD and is also called p53 protein, being constantly studied for its classic concept of "genome guardian". This gene plays a range of essential functions to ensure the cell cycle control, in addition to playing a central role in carcinogenesis. With respect to neoplasias, it prevents the neoplastic transformation through three intricate mechanisms. Depending on the extent of the mutation, different responses may be sent by p53 and those range since the disruption of the cell cycle, the correction of the mutation through the activation of repair proteins or still, the induction of senescence or cell death by apoptosis. This review aims to address the structural and functional aspects of the p53 gene and protein, and also reaffirm their participation in the carcinogenesis control, approaching their major mutations and the anticancer gene therapy involving this gene.

Genetic polymorphisms of EGF 5'-UTR and NAT2 857G/A associated with glioma in a case control study of Malaysian patients

Studies of genetic mutations that have been used in predicting glioma prognosis have revealed a complex relationship between clinical and genetic factors. Epidermal growth factor (EGF) and the NAT2 gene play a central role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the 5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production, and the mutations in the NAT2 gene have been postulated as a risk factor for cancer. We investigated EGF and the NAT2 gene in 13 glioma tissue samples and 12 normal controls. In the EGF 5'-UTR 61G polymorphism, the heterozygote GA was the most common genotype in the glioma patients. In the NAT2 polymorphism at nucleotide position 857G/A, the G allele and the GG genotype were the most prevalent forms in both the glioma and normal samples. We did not find any homozygous AA genotypes in the glioma patients. Based on this preliminary evidence, the EGF 5'-UTR at position 61 and the NAT2 SNP at position 857 polymorphisms are associated with increased risk for glioma.

FTS (fused toes homolog) a novel oncoprotein involved in uterine cervical carcinogenesis and a potential diagnostic marker for cervical cancer

The high incidence and fatality rate of uterine cervical cancer warrant effective diagnostic and therapeutic target identification for this disease. Here, we have found a novel oncoprotein FTS (Fused Toes Homolog), which is involved in cervical cancer pathogenesis. Immunohistochemical analysis of human cervical biopsy samples revealed that the expression of FTS is absent in normal cervical epithelium but progressively overexpressed in human cervical intraneoplastic lesions (CIN-I to CIN-III), this characteristic phenomenon put this protein, a potential diagnostic marker for the screening of early neoplastic changes of cervix. Using FTS-specific small hairpin RNA (shRNA) in cervical cancer cells, we determined a specific role for FTS protein in, cervical neoplasia. Targeted stable knock down of FTS in HeLa cells led to the growth inhibition, cell-cycle arrest, and apoptosis with concurrent increase in p21 protein. FTS effectively represses the p21 mRNA expression in dual luciferase assay which indicates that p21 is transcriptionally regulated by this oncoprotein which in turn affect the regular cell-cycle process and its components. Consistent with this we found a reciprocal association between these proteins in early cervical neoplastic tissues. These data unraveled the involvement of new oncoprotein FTS in cervical cancer which plays a central role in carcinogenesis. Targeted inhibition of FTS lead to the shutdown of key elemental characteristics of cervical cancer and could lead to an effective therapeutic strategy for cervical cancer.

Islet Cells Contribute to Pancreatic Carcinogenesis in an Animal Model

In the hamster model, pancreatic ductal adenocarcinoma develops after treatment with N-nitrosobis-(2-oxopropyl)amino (BOP). In this model, Langerhans islets play a central role in carcinogenesis. In contrast, treatment with BOP in rats and mice did not result in cancer development. We investigated whether pancreatic tumors develop after orthotopic implantation of hamster islets into severe combined immunodeficiency mouse pancreases and subsequent treatment with BOP. This occurrence would suggest that pancreatrophic carcinogens are metabolized by islet cells. Twenty-four severe combined immunodeficiency mice were separated into 2 groups of 12 animals. Five hundred hamster islets were implanted in the splenic lobe of the mouse pancreases in the treatment group, whereas animals of the control group received a sham operation. All animals were treated with BOP for 5 weeks. One year later, the animals were killed and investigated for tumors. Carcinomas developed in 3 animals in the treatment group and none in the control group. The tumors displayed the histomorphological phenotype pancreatic ductal adenocarcinoma. Islet cells seem to play a role in pancreatic carcinogenesis in this animal model and therefore represent useful targets for future investigations on the putative role of islet cells during pancreatic ductal adenocarcinoma tumorigenesis.

S92 Epithelial mesenchymal transition occurs earlier than previously thought in the development of squamous cell carcinoma of the lung

IntroductionSquamous cell carcinoma is believed to develop in a step-wise fashion from squamous metaplasia (SqMet), through low- and high-grade dysplasia (LGDys; HGDys) and carcinoma-in-situ (CIS) to invasive disease (InvSCC). Epithelial...

BAMBI is overexpressed in ovarian cancer and co-translocates with Smads into the nucleus upon TGF-ß treatment

Objective Transforming growth factor beta (TGF-ß) signaling via Smads plays a central role in carcinogenesis. Bmp and activin membrane-bound inhibitor ( BAMBI) was initially described as a pseudoreceptor antagonizing TGF-ß receptor activation, thus impairing signaling. Here we wanted to estimate the role of BAMBI in ovarian cancer. Methods The function of BAMBI was studied using a cell line model and intracellular localization experiments. The impact of BAMBI expression on patient outcome was estimated by real-time PCR and immunohistochemistry. Results We demonstrate for the first time a nuclear co-translocation of BAMBI with Smad2/3 upon TGF-ß treatment. Moreover, overexpression of BAMBI in an in vitro model led to significantly increased proliferation (doubling time − 37.0%, P = 0.010), migration (+ 581.2%, P = 0.004) and resistance to TGF-ß-mediated apoptosis (decrease of apoptosis from 30% in the control cells to 7% in the BAMBI-overexpressing cells). Although— prima facie—this fits to the thesis of BAMBI as a pseudoreceptor, it may also be explained by modulation of TGF-ß signaling in the nucleus, leading to the observed pro-oncogenic properties. The tumor promoting impact of BAMBI mRNA overexpression in vitro could not be confirmed in primary tumor samples, and while nearly all tumor samples showed up-regulation of BAMBI (37.3% 1+, 39.2% 2+, and 16.7% 3+, respectively) compared to undetectable BAMBI in healthy pre- and post-menopausal ovarian epithelia, no impact of BAMBI expression on recurrence free and overall survival could be observed. Conclusion These findings provide new insights into the Smad-mediated pathway by inferring that BAMBI is a novel modulator of TGF-ß signaling.