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Studies in preclinical models support that the gut microbiota play a critical role in the development and progression of colorectal cancer (CRC). Specific microbial species and their corresponding virulence factors or associated small molecules can contribute to CRC development and progression either via direct effects on the neoplastic transformation of epithelial cells or through interactions with the host immune system. Induction of DNA damage, activation of Wnt/β-catenin and NF-κB proinflammatory pathways, and alteration of the nutrient's availability and the metabolic activity of cancer cells are the main mechanisms by which the microbiota contribute to CRC. Within the tumor microenvironment, the gut microbiota alter the recruitment, activation, and function of various immune cells, such as T cells, macrophages, and dendritic cells. Additionally, the microbiota shape the function and composition of cancer-associated fibroblasts and extracellular matrix components, fashioning an immunosuppressive and pro-tumorigenic niche for CRC. Understanding the complex interplay between gut microbiota and tumorigenesis can provide therapeutic opportunities for the prevention and treatment of CRC. [ABSTRACT FROM AUTHOR]

Specifying the role of genetic mutations in cancer development is crucial for effective screening or targeted treatments for people with hereditary cancer predispositions. Our goal here is to find the relationship between a number of cancerogenic mutations and the probability of cancer induction over the lifetime of cancer patients. We believe that the Avrami–Dobrzyński biophysical model can be used to describe this mechanism. Therefore, clinical data from breast and ovarian cancer patients were used to validate this model of cancer induction, which is based on a purely physical concept of the phase-transition process with an analogy to the neoplastic transformation. The obtained values of model parameters established using clinical data confirm the hypothesis that the carcinogenic process strongly follows fractal dynamics. We found that the model's theoretical prediction and population clinical data slightly differed for patients with the age below 30 years old, and that might point to the existence of an ancillary protection mechanism against cancer development. Additionally, we reveal that the existing clinical data predict breast or ovarian cancers onset two years earlier for patients with BRCA1/2 mutations. [ABSTRACT FROM AUTHOR]

Summary: A 13‐year‐old Thoroughbred/Oldenburg gelding presented as a tertiary referral for a 6‐year history of immune‐mediated keratitis (IMMK) after the development of corneal and limbal nodules in the presence of medical therapy. A keratectomy extending to the limbus was performed to remove the affected cornea and limbal nodules. Two corneal‐limbal samples were submitted for histopathology and initially diagnosed as marked lympho‐histiocytic stromal keratitis with epithelial hyperplasia, keratinisation and keratinocyte apoptosis consistent with IMMK. Additional testing with immunohistochemical staining for CD3, CD20, PAX5 and IBA1 revealed large, atypical B‐lymphocytes on a background of histiocytes and mature T‐lymphocytes, with concern for T‐cell‐rich large B‐cell lymphoma. PCR antigen receptor rearrangement clonality testing was also performed and was diagnostic for large B‐cell lymphoma. Polymerase chain reaction (PCR) for equine herpesvirus 5 (EHV‐5) was positive. Following keratectomy, a short course of neomycin/polymyxin B/dexamethasone ophthalmic ointment was prescribed; no other treatment nor adjunct therapy was performed. Eighteen months post‐operation, the case remains visual and comfortable on no medications. [ABSTRACT FROM AUTHOR]

Free radicals define oxidative stress as the condition in which the body's antioxidant repair systems cannot keep up with the rate of cell oxidation. Oxidative stress and reactive oxygen species (free radicals) work together to damage cellular components, encourage cell neoplastic transformation, and actively affect all three stages of carcinogenesis. The most prevalent potentially cancerous conditions on the Indian subcontinent are leukoplakia and oral submucous fibrosis, which are mostly brought on by cigarette use and areca nut consumption. Assessment of 8-OHDG, SOD, and GPx levels in saliva of OPMD and OSCC patients with and without diabetes mellitus. ELISA ASSAY was used for finding the levels of 8-OHDG, SOD, and GPx. Add salivary samples and diluent 40 µL into the testing sample. Then add some 10 µL sample into the testing sample well, Cover it properly, and incubate for some 45 minutes at 37 °C. Aspirate each well and wash, repeat the process four times for a total of five washes, 1-3 minutes per time. HRP-conjugated detection antibody is added to each well. This study is one of the first attempts to find the Assessment of 8-OHDG, SOD, and GPx levels in the saliva of OPMD and OSCC patients with and without diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Although intestinal smooth muscle cells (ISMCs) play an important role in the remodeling of the intestinal structure, considerably less is known about the molecular mechanisms that mediate the development and growth of ISMCs. A possible reason for this lag is the lack of cell lines that recapitulate ISMCs in vivo. Methods: In this study, we separated the primary ISMCs from the rat intestinal tract and integrated the Simian Vacuolating virus 40 Large T antigen (SV40 LT) gene into the genome of the primary ISMC to construct an immortalized cell line named ISMC‐Hc. Key Results: ISMC‐Hc proliferated persistently without any signs of senescence up to 50 passages and without neoplasticity. Analysis of the genome isolated from ISMC‐Hc confirmed that the SV40LT gene recombined in the genome, and mRNA reverse transcription PCR suggested that SV40LT could be expressed normally. In addition, ISMC‐Hc had few morphological differences compared with the primary ISMC. Furthermore, ISMC‐Hc showed the expression of the specific protein markers (alpha‐smooth muscle actin and desmin) through immunofluorescence analysis. Further studies showed that ISMC‐Hc had enhanced contractility and expressed the glial‐derived neurotrophic factor, nerve growth factor, ciliary neurotrophic factor, and leukemia inhibitory factor after co‐stimulation with IL‐1 beta and TNF‐alpha. Conclusions and Inferences: ISMC‐Hc showed characteristics similar to that of primary ISMC and can be used as an in vitro model to explore the cellular and molecular mechanisms of ISMC. Additionally, the immortalized ISMCs could help investigate the basic functional mechanisms of intestinal diseases. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre-dendritic cells (pre-DC) play a significant role. Remarkably, we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting the mTOR pathway at the initial stages of monocyte differentiation to LC-like fosters the pathognomonic LCH program, highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway. • Expansion of circulating CD11c+/AXL+/CD207+ cells as strong pathognomonic marker in LCH. • AXL tyrosine kinase receptor is highly induced in monocyte-derived LC-like under inflammatory stimuli. • mTOR inhibition at the initial stages of mLC-like differentiation release CD207 and NOHTCH1 expression. [ABSTRACT FROM AUTHOR]

Adenomatoid Odontogenic Tumour (AOT) is a relatively uncommon benign odontogenic tumour composed of odontogenic epithelium in a variety of histoarchitectural patterns. Conventional AOT is predominantly seen in females in second decade of life exhibiting predilection for anterior region of maxilla. Very few cases of AOT associated with dentigerous cyst have been reported till date. The present case is unique associated with an impacted lower first premolar in the front region of the mandible of an 18-year-old female patient. The patient reported to the institute with gradually increasing swelling. The orthopantomogram revealed a unilocular radiolucency with displaced premolar. Histopathological examination confirmed 4×2.5×2 cm lesion in dimension, brownish black in colour, firm in consistency with a smooth surface grossly while cut surface revealed a cystic lumen with an impacted premolar embedded into the lining, cystic wall being nodular. Microscopic evaluation revealed a well encapsulated lesion with a thin 2-3 cell layered non keratinised stratified epithelial lining in patterns such as nests, rosette like structures and duct like structures. Thus the diagnosis of AOT arising from dentigerous cyst was confirmed. Patient's six month follow-up was uneventful. Literature search of similar cases with the review of hypothesised aetiopathogenesis is discussed in brief. The available data can help researchers resolve the uncertainty whether the AOT derived from dentigerous cyst could represent a distinct hybrid variety. [ABSTRACT FROM AUTHOR]

• Chemerin is a potent chemoattractant and modulator of immune response. • Chemerin affects gastrointestinal pathophysiology. • Chemerin regulates immune response in the gastrointestinal diseases. • Chemerin is involved in cell proliferation, migration and invasion of gastrointestinal cells. Chemerin is a multifunctional protein involved among others in adipogenesis, angiogenesis and lipid as well as glucose metabolism. Chemerin is an essential factor in promotion of chemotaxis of numerous immune cell types and plays an important role in several pathophysiologic conditions. Chemerin receptors are present on monocytes/macrophages, T cells, natural killer and dendritic cells as well as neutrophils. However, the role of chemerin and chemerin receptors in immune response and gastrointestinal diseases is still poorly understood. Accumulating, clinical and experimental studies observed disturbation of chemerin and chemerin receptors in a number of disorders including Barrett's esophagus, esophageal cancer, gastric cancer, hepatic dysfunction, irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. Moreover, chemerin and chemerin receptors have been shown to regulate proliferation, migration and invasion of gastrointestinal and immune cells as well as cancer-associated fibroblasts. In this review we present the current state of knowledge about the contribution of chemerin to immune response and gastrointestinal disorders. [ABSTRACT FROM AUTHOR]

The origin and subsequent maintenance of sex and recombination are among the most elusive and controversial problems in evolutionary biology. Here, we propose a novel hypothesis, suggesting that sexual reproduction not only evolved to reduce the negative effects of the accumulation of deleterious mutations and processes associated with pathogen and/or parasite resistance but also to prevent invasion by transmissible selfish neoplastic cheater cells, henceforth referred to as transmissible cancer cells. Sexual reproduction permits systematic change of the multicellular organism's genotype and hence an enhanced detection of transmissible cancer cells by immune system. Given the omnipresence of oncogenic processes in multicellular organisms, together with the fact that transmissible cancer cells can have dramatic effects on their host fitness, our scenario suggests that the benefits of sex and concomitant recombination will be large and permanent, explaining why sexual reproduction is, despite its costs, the dominant mode of reproduction among eukaryotes. [ABSTRACT FROM AUTHOR]

Actin plays an important role in cellular adhesion, muscle and non-muscle contractility, migration, polarization, mitosis, and meiosis. Investigation of specific mechanisms underlying these processes is essential not only for fundamental research but also for clinical applications, since modulations of actin isoforms are directly or indirectly correlate with severe pathologies. In this review we summarize the isoform-specific functions of actin associated with adhesion structures, motility and division of normal and tumor cells; alterations of the expression and structural organization of actin isoforms in normal and tumor cells. Selective regulation of cytoplasmic β- or γ-actin expression determines functional diversity between isoforms: β-actin plays the predominant role in contraction and intercellular adhesion, and γ-actin is responsible for the cellular plasticity and motility. Similar data were obtained in different epithelial and mesenchymal neoplastic cell cultures, as well as in immunomorphological comparison of normal human tissues with tumor analogues. Reorganization of the actin cytoskeleton and cell–cell contacts is essential for proliferation control and acquisition of invasiveness in epithelial tumors. [ABSTRACT FROM AUTHOR]

Giant cell tumors of bone (GCTB) are semi-malignant tumors associated with extensive osteolytic defects and massive bone destructions. They display a locally aggressive behavior and a very high recurrence rate. Recently, a single mutation has been identified in GCTB affecting the H3F3A gene coding for the histone variant H3.3 (H3.3-G34W). The aim of this study was to investigate whether H3.3-G34W is sufficient to drive tumorigenesis in GCTB. Initially, we confirmed the high frequency of this mutation in 94% of 84 analyzed tissue samples. Using a siRNA based approach we could selectively knockdown H3.3-G34W in primary neoplastic stromal cells isolated from tumor tissue (GCTSC). H3.3-G34W knockdown caused a significant inhibition of cell proliferation, migration and colony formation capacity in vitro. Xenotransplantation of GCTSCs onto the chorioallantoic membrane of fertilized chicken eggs further demonstrated a significant impact of H3.3-G34W knockdown on tumor engraftment and growth in vivo. Our data indicate that H3.3-G34W is sufficient to drive tumorigenesis in GCTB. Apart from the application of H3.3-G34W screening as diagnostic tool, our data suggest that H3.3-G4W represents a promising target for the development of new GCTB therapies. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) is a fundamental process of morphogenesis whereby epithelial cells acquire the mesenchymal phenotype. Multiple data suggest a critical role of EMT in tumor progression. In carcinomas, EMT can be initiated and promoted by many oncogenic signaling pathways, hypoxia, and signals of tumor microenvironment resulting in epithelial cells losing their cell polarity and cell-cell adhesion and gaining the migratory and invasive properties. Downregulation of expression of the cell adhesion protein E-cadherin is considered a poor prognostic factor in cancer. Many tumors are characterized by incomplete EMT, where tumor cells acquire mesenchymal characteristics but retain their epithelial markers, in particular, E-cadherin. In cells with the hybrid epithelial-mesenchymal phenotype, E-cadherin is accumulated in adherens junctions which are less stable than adherens junctions in normal epithelial cells. E-cadherin-based adherens junctions are essential for efficient collective migration and invasion of carcinoma cells, and their survival in metastases. The plasticity of the hybrid epithelial-mesenchymal phenotype improves adaptive capabilities of cancer cells. By undergoing EMT, carcinoma cells become resistant to chemotherapy and acquire the ability to suppress immune response. Emergence of cancer stem cells after EMT activation has been observed in many types of carcinoma. [ABSTRACT FROM AUTHOR]

Background: Second malignant neoplasm is one of the most devastating late effects of childhood cancers. This study aimed to evaluate the incidence and survival outcomes of patients developing second malignant neoplasms (SMNs) after surviving childhood cancer in Korea. Methods: Medical data of childhood cancer patients diagnosed between 1993 and 2012 were obtained from the Korea Central Cancer Registry. The risk of developing SMNs was calculated using standardized incidence ratio (SIR), excess absolute risk (EAR), and cumulative risk. Kaplan-Meier survival curves were estimated, stratified by SMN status. Results: A total of 28,405 childhood cancer patients were diagnosed in the study period, and 337 (1.2%) developed SMN. The total follow-up period was 197,359 person-years at risk (PYR), with a median follow-up duration of 5.6 years. Overall SIR was 20.0, which was 23.2 in women, and 17.6 in men. The overall EAR was 16.4 per 10,000 PYR. The most common types of SMNs, in order of incidence, were other malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. The cumulative incidence of developing SMNs was 0.7% at 5 years, 1.2% at 10 years, and 2% at 15 years. After primary cancer diagnosis, the 10-year overall survival rate of patients with SMNs was 65.1%, which was lower than the 73.4% in patients without SMN. After SMN diagnosis, the 10-year overall survival rate was 55.8%. Conclusion: Through this registry-based study of 5.6 years of follow up, childhood cancer survivors were found to be at 20-fold higher risk of developing a malignant neoplasm compared to the general population. The majority of malignant neoplasms are malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. Continued surveillance for assessing long-term risks, and guidance for appropriate long-term follow up of childhood cancer survivors, are needed. [ABSTRACT FROM AUTHOR]

Primary organoid cultures generated from patient biopsies comprise a novel improved platform for disease modeling, being genetically stable and closely recapitulating in vivo scenarios. Barrett esophagus (BE) is the major risk factor for esophageal adenocarcinoma. There has been a dearth of long-term in vitro expansion models of BE neoplastic transformation. We generated a long-term virus-free organoid expansion model of BE neoplasia from patient biopsies. Both wild-type and paired APC-knockout (APCKO) BE organoids genome-edited by CRISPR-Cas9 showed characteristic goblet cell differentiation. Autonomous Wnt activation was confirmed in APCKO organoids by overexpression of Wnt target genes and nuclear-translocated β-catenin expression after withdrawal of Wnt-3A and R-spondin-1. Wnt-activated organoids demonstrated histologic atypia, higher proliferative and replicative activity, reduced apoptosis, and prolonged culturability. Wnt-activated organoids also showed sustained protrusive migration ability accompanied by disrupted basement membrane reorganization and integrity. This CRISPR-Cas9 editing human-derived organoid model recapitulates the critical role of aberrant Wnt/β-catenin signaling activation in BE neoplastic transformation. This system can be used to study other 'driver' pathway alterations in BE-associated neoplasia, avoiding signaling noise present in immortalized or cancer-derived cell lines. [ABSTRACT FROM AUTHOR]

Background: The grading of oral epithelial dysplasia is not possible in the atrophic epithelium of oral submucous fibrosis (OSMF). Recently, we found that features such as increased basal cell layer hyperplasia, abnormal superficial mitosis, increased nuclear-cytoplasmic ratio, increased nuclear size, and hyperchromasia represent transformation-relevant dysplastic features in the atrophic epithelium of OSMF. The presence of these features can be considered a high-risk feature for patients. However, these findings have not been tested and authenticated using markers relevant to oral carcinogenesis. Method: Paraffin-embedded tissues from 30 normal oral mucosa (NOM) and 50 OSMF were retrieved from 2008 to 2016 and subjected to immunohistochemical expression using Ki67, CD105 and α-SMA antibodies. Results: Ki67 LI showed significant increases from NOM (12.47±2.34) to LRED (23.47±3.75) to HRED (34.31±7.31) (<0.0001). Similarly, MVD was increased significantly from NOM (3.53±5.17) to LRED (27.57±12.25) to HRED (46.18±12.55) (p<0.0001). The expression of α-SMA was significantly increased from LRED (0.21±0.41) to HRED (1.13±0.56) (<0.0001). The Ki67 LI and α-SMA; MVD and α-SMA; and Ki67Ki67 LI and MVD in NOM, LRED and HRED showed a statistically significant positive correlation (P<0.0001). The increase in Ki67 LI was directly proportional to MVD and α-SMA expression from NOM to LRED to HRED (P<0.0001). The connective tissue stroma of NOM lacks α-SMA expression. Mild myofibroblast expression was noted in 4 cases of LRED (14.28%) and in 18 cases of HRED (81.81%). Moderate expression was noted only in 4 cases of HRED (22.22%). Conclusion: Ki67 LI, CD105, and α-SMA expression showed significant differences between normal, LRED and HRED. These findings further support that features such as increased basal cell layer hyperplasia, abnormal superficial mitosis, increased nuclear-cytoplasmic ratio, and hyperchromasia could be transformation-relevant dysplastic features. [ABSTRACT FROM AUTHOR]

Red ginseng oil (RGO) has been shown to possess anti-inflammatory and hepatoprotective activity. In this study, we evaluated the inhibitory effect of RGO on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated neoplastic transformation of JB6 P+ cells. RGO pretreatment abolished the transformation of JB6 P+ cells challenged by TPA. RGO suppressed the transactivation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) transcription factors as well as protein levels of cyclooxygenase-2, cyclin D1, cyclin E, and Bcl-2 in the TPA-treated cells. Additionally, TPA-induced phosphorylations of extracellular signal-regulated kinases, 90 kDa ribosomal S6 kinase 2, c-Jun N-terminal kinases, and glycogen synthase kinase 3β were downregulated in the presence of RGO. Furthermore, RGO induced the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzyme heme oxygenase-1 (HO-1) expression, and effectively blocked the overproduction of TPA-induced reactive oxygen species. These results suggest that RGO exerts a potent chemopreventive activity in skin cell model. [ABSTRACT FROM AUTHOR]

While dietary polyphenols are widely recognized for cancer-preventing characteristics, the relative effectiveness and mechanisms of action of different polyphenols is not clear. In the present study, we investigated the protective effects of six different polyphenols against benzo[a]pyrene (B[a]P)-induced oxidative stress and neoplastic transformation in the Bhas 42 cell carcinogenesis assay. All of the polyphenols completely prevented the increased intracellular ROS generation by B[a]P at 12 h, and most inhibited after 3 days. B[a]P increased mitochondrial superoxide generation at 12 h, which was inhibited by the anthocyanins and berberine. B[a]P increased expression of genes related to oxidative stress and inflammation (Nrf2, UCP2, and TNF-α) after 24 h. Polyphenols strongly inhibited the increase in TNF-α and also several polyphenols inhibited the increase in UCP2. At 21 days after 72 h treatment, B[a]P produced a large increase in the number of neoplastic colonies. This transformation was inhibited by most polyphenols, and strongly by resveratrol. In summary, all tested polyphenols were able to inhibit B[a]P-induced increases in markers of oxidative stress and inflammation, and to inhibit cellular transformation, with resveratrol being notable for the strongest preventive effect on cell transformation. The results support a role for dietary polyphenols in protecting against B[a]P-induced carcinogenesis. [ABSTRACT FROM AUTHOR]

Gliomas are the most frequent type of primary brain tumours. Low grade gliomas (LGGs, WHO grade II gliomas) may grow very slowly for the long periods of time, however they inevitably cause death due to the phenomenon known as the malignant transformation. This refers to the transition of LGGs to more aggressive forms of high grade gliomas (HGGs, WHO grade III and IV gliomas). In this paper we propose a mathematical model describing the spatio-temporal transition of LGGs into HGGs. Our modelling approach is based on two cellular populations with transitions between them being driven by the tumour microenvironment transformation occurring when the tumour cell density grows beyond a critical level. We show that the proposed model describes real patient data well. We discuss the relationship between patient prognosis and model parameters. We approximate tumour radius and velocity before malignant transformation as well as estimate the onset of this process. [ABSTRACT FROM AUTHOR]

In the past, increases in childhood cancer incidence were reported in Europe and North America. The aim of this study is to show updated patterns of temporal behavior using data of the Childhood Cancer Registry of Piedmont (CCRP), a region with approximately 4.5 million inhabitants in North-West Italy. CCRP has been recording incident cases in children (0–14 years) since 1967 and in adolescents (15–19) since 2000. Time trends were estimated as annual percent change (APC) over the 1976–2011 period for children, and over 2000–2011 for both children and adolescents. CCRP registered 5020 incident cases from 1967 to 2011. Incidence rates were 157 per million person-years for children (1967–2011) and 282 for adolescents (2000–2011). From 1976–2011, increasing trends were observed in children for all neoplasms (APC 1.1, 95%CI: 0.8; 1.5) and for both embryonal and non-embryonal tumors: 1.1%, (0.5; 1.6) and 1.2%, (0.7; 1.6), respectively. Increases were observed in several tumor types, including leukemia, lymphoma, central nervous system tumors and neuroblastoma. In 2000–2011, incidence rates showed mostly non statistically significant variations and large variability. The observation of trends over a long period shows that the incidence of most tumors has increased, and this is only partially explained by diagnostic changes. Large rate variability hampers interpretation of trend patterns in short periods. Given that no satisfying explanation for the increases observed in the past was ever found, efforts must be made to understand and interpret this peculiar and still ununderstood pattern of childhood cancer incidence. [ABSTRACT FROM AUTHOR]

Mycoplasma infection has been reported in immunocompromised cancer patients; nevertheless, it is not clear if persistent Mycoplasma infection could facilitate the proliferation of cancer cells in immunocompromised organisms. The aim of this study was to examine the relationship between persistent Mycoplasma infection and malignant transformation in an immunodeficient host model. Immunodeficient mouse model was established using cyclophosphamide and mice gastric mucosal cells were infected with Mycoplasma penetrans (Mpe). After 18 weeks, mice were sacrificed and gastric mucosal Mpe infected cells were identified by fluorescence in situ hybridization (FISH). Moreover, pathological and ultrastructural changes in mice gastric mucosa were evaluated and the expression of multiple proto-oncogenes was examined by Western blot. Our data show that Mpe infection was detected in the blood of immunodeficient mice and Mpe persistent infection in mice gastric mucosa was confirmed by FISH. There were pathological and ultrastructural malignant transformation occurred in the gastric mucosa of infected mice compared to control mice. Mpe infected mice showed lower expression of p53 and p21 and higher H-ras expression compared to the control group. Moreover, expression of NF-κB p65 subunit increased in Mpe infected mice, similar to the TNF-α expression. Bax expression in gastric mucosa of Mpe infected mice was lower while Bcl-2 expression was higher than in the uninfected control group. Collectively these data demonstrate that persistent Mpe infection is associated with aberrant expression of multiple proto-oncogenes in gastric mucosa of immunodeficient mice which potentially facilitate the malignant transformation. [ABSTRACT FROM AUTHOR]

Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the “maximum dose in minimum time” principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient’s life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor’s proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme. [ABSTRACT FROM AUTHOR]

Overexpression of DEK oncogene is associated with increased proliferation of carcinoma cells and it is observed in several solid tumors due to the amplification of the 6p22.3 chromosomal region where DEK locates. Although the same chromosomal amplification occurs in multiple myeloma (MM), a plasma cell neoplasm, whether the expression and the copy number of the DEK gene are affected in MM remains elusive. We show that despite the increased copy number in CD138positive MM cells (4 out of 41 MM samples), DEK mRNA expression was down-regulated compared with that in CD138negative bone marrow (BM) cells of the same patients (P<0.0001). DEK protein was not detectable by immunohistochemistry (IHC) in CD138positive normal plasma cells or in malignant plasma cells of MM patients (n = 56) whereas it was widely expressed in normal and neoplastic B-cells. Stable knockdown or overexpression of DEK in CD138positive MM cell lines did not affect the proliferation and viability of the cells profoundly in the presence or absence of chemotherapeutic agent melphalan whereas knockdown of DEK moderately but significantly increased the expression level of CD138 (p<0.01). Decreased DEK expression in plasma cells suggests a potential role of this gene in plasma cell development and lack of detectable DEK protein by IHC could be used as a biomarker for normal and malignant plasma cells. [ABSTRACT FROM AUTHOR]

The interior of cells is a highly complex medium, containing numerous organelles, a matrix of different fibers and a viscous, aqueous fluid of proteins and small molecules. The interior of cells is also a highly dynamic medium, in which many components move, either by active transport or passive diffusion. The mobility and localization of proteins inside cells can provide important insights into protein function and also general cellular properties, such as viscosity. Neoplastic transformation affects numerous cellular properties, and our goal was to investigate the diffusional and binding behavior of the important mismatch repair (MMR) protein MSH2 in live human cells at various stages of neoplastic transformation. Toward this end, noncancerous, immortal, tumorigenic, and metastatic mammary epithelial cells were transfected with EGFP and EGFP-tagged MSH2. MSH2 forms two MMR proteins (MutSα and MutSβ) and we assume MSH2 is in the complex MutSα, though our results are similar in either case. Unlike the MutS complexes that bind to nuclear DNA, EGFP diffuses freely. EGFP and MutSα-EGFP diffusion coefficients were determined in the cytoplasm and nucleus of each cell type using fluorescence recovery after photobleaching. Diffusion coefficients were 14–24 μm2/s for EGFP and 3–7 μm2/s for MutSα-EGFP. EGFP diffusion increased in going from noncancerous to immortal cells, indicating a decrease in viscosity, with smaller changes in subsequent stages. MutSα produces an effective diffusion coefficient that, coupled with the free EGFP diffusion measurements, can be used to extract a pure diffusion coefficient and a pseudo-equilibrium constant K*. The MutSα nuclear K* increased sixfold in the first stage of cancer and then decreased in the more advanced stages. The ratio of nuclear to cytoplasmic K*for MutSα increased almost two orders of magnitude in going from noncancerous to immortal cells, suggesting that this quantity may be a sensitive metric for recognizing the onset of cancer. [ABSTRACT FROM AUTHOR]

Background: The cytological analysis of peritoneal effusions serves as a diagnostic and prognostic aid for either primary or metastatic diseases. Among the different cytological preparations, liquid based cytology (LBC) represents a feasible and reliable method ensuring also the application of ancillary techniques (i.e immunocytochemistry-ICC and molecular testing). Methods: We recorded 10348 LBC peritoneal effusions between January 2000 and December 2014. They were classified as non-diagnostic (ND), negative for malignancy-NM, atypical-suspicious for malignancy-SM and positive for malignancy-PM. Results: The cytological diagnosis included 218 ND, 9.035 NM, 213 SM and 882 PM. A total of 8048 (7228 NM, 115SM, 705 PM) cases with histological follow-up were included. Our NM included 21 malignant and 7207 benign histological diagnoses. Our 820 SMs+PMs were diagnosed as 107 unknown malignancies (30SM and 77PM), 691 metastatic lesions (81SM and 610PM), 9 lymphomas (2SM and 7PM), 9 mesotheliomas (1SM and 8SM), 4 sarcomas (1SM and 3PM). Primary gynecological cancers contributed with 64% of the cases. We documented 97.4% sensitivity, 99.9% specificity, 98% diagnostic accuracy, 99.7% negative predictive value (NPV) and 99.7% positive predictive value (PPV). Furthermore, the morphological diagnoses were supported by either 173 conclusive ICC results or 50 molecular analyses. Specifically the molecular testing was performed for the EGFR and KRAS mutational analysis based on the previous or contemporary diagnoses of Non Small Cell Lung Cancer (NSCLC) and colon carcinomas. We identified 10 EGFR in NSCCL and 7 KRAS mutations on LBC stored material. Conclusions: Peritoneal cytology is an adjunctive tool in the surgical management of tumors mostly gynecological cancers. LBC maximizes the application of ancillary techniques such as ICC and molecular analysis with feasible diagnostic and predictive yields also in controversial cases. [ABSTRACT FROM AUTHOR]

An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis—p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA) nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies. [ABSTRACT FROM AUTHOR]

Mature teratomas are common ovarian tumors. Malignant transformation of dermoid cysts is a very rare phenomenon observed in only 0.17-2% of patients. Squamous cell carcinoma is the most common form of malignant transformation within ovarian dermoid tumors, accounting for more than 80% of cases. Adenocarcinomas, fibrosarcomas, carcinoid and mixed tumors also occur. Peritoneal gliomatosis is a rare condition, which also should be considered in patients diagnosed with teratoma. There are no sensitive and specific methods for the preoperative differential diagnosis of malignant vs. benign tumors arising in teratomas. Higher risk of malignancy is seen in large tumors, in women over 45 years of age, at elevated tumor markers (CA-125, CA 19-9, CEA, SCC-Ag in particular) and in the case of the presence of solid fragments in cysts. Extended diagnostic imaging using magnetic resonance or positron emission tomography is helpful in such cases. The treatment of mature teratoma, regardless of whether there is a suspicion of focal malignancy, involves surgical excision of the tumor. In the case of suspected malignant transformation in a perimenopausal woman, unilateral salpingooophorectomy in accordance with the principles of oncological aseptics should be considered as the minimum therapeutic management. Sparing surgery can be considered in young patients, nulliparas in particular, due to the very low risk of malignant transformations. [ABSTRACT FROM AUTHOR]

Objective: Here, we retrospectively investigate the value of voxel-wisely plotted diffusion tensor-derived (DTI) axial, radial and mean diffusivity for the early detection of malignant transformation (MT) in WHO II glioma compared to contrast-enhanced images. Materials and Methods: Forty-seven patients underwent brain magnetic resonance imaging follow-up between 2006–2014 after gross-tumor resection of intra-axial WHO II glioma. Axial/Mean/Radial diffusivity maps (AD/MD/RD) were generated from DTI data. ADmin/MDmin/RDmin values were quantified within tumor regions-of-interest generated by two independent readers including tumor contrast-to-noise (CNR). Sensitivity/specificity and area-under-the-curve (AUC) were calculated using receiver-operating-characteristic analysis. Inter-reader agreement was assessed (Cohen’s kappa). Results: Eighteen patients demonstrated malignant transformation (MT) confirmed in 8/18 by histopathology and in 10/18 through imaging follow-up. Twelve of 18 patients (66.6%) with MT showed diffusion restriction timely coincidental with contrast-enhancement (CE). In the remaining six patients (33.3%), the diffusion restriction preceded the CE. The mean gain in detection time using DTI was (0.8±0.5 years, p = 0.028). Compared to MDmin and RDmin, ROC-analysis showed best diagnostic value for ADmin (sensitivity/specificity 94.94%/89.7%, AUC 0.96; p<0.0001) to detect MT. CNR was highest for AD (1.83±0.14), compared to MD (1.31±0.19; p<0.003) and RD (0.90±0.23; p<0.0001). Cohen’s Kappa was 0.77 for ADmin, 0.71 for MDmin and 0.65 for RDmin (p<0.0001, respectively). Conclusion: MT is detectable at the same time point or earlier compared to T1w-CE by diffusion restriction in diffusion-tensor-derived maps. AD demonstrated highest sensitivity/specificity/tumor-contrast compared to radial or mean diffusivity (= apparent diffusion coefficient) to detect MT. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex Class I-related chain A/chain B (MICA/MICB) is stress-inducible, highly polymorphic ligands whose expression at the transcript level has been detected in all tissues except the central nervous system. However, their restricted protein expression is due to their regulation at the posttranslational level. Its levels are elevated in virally infected and neoplastically transformed cells. Membrane expression of this NKG2DL marks the aberrant cells for elimination by those immune effector cells that express the cognate NKG2D receptor. Among the evasion strategies developed by tumors, the metalloprotease-dependent shedding of MICA/MICB from tumors (either the free or the exosome form) can contribute to the inhibition of cytolysis by the immune effector cells (all NK cells, most NKT cells; γδ CD8+ T cells and αβ CD8+ T cells, as well as some αβ CD4+ T cells). There are micro-RNA clusters that regulate surface expression and shedding. Polymorphic variants can be used as susceptibility/associative markers and can also possibly be used to correlate with tumor survival as well as staging/grading of tumors. Variations in the expression level require quantification of this marker for diagnostic/prognostic and therapeutic purposes. Mechanism-based studies would provide a better tumor-specific understanding of their relative roles in the processes of tumor cell elimination versus growth and progression. Last but not least, conventional, interlaboratory validated assays (for, e.g., antibody-based methods) should be replaced by robust, reproducible, feasible biophysics-based methods using tumor biopsies. Further, correlative DNA polymorphism-based studies can be done using biological fluids (for, e.g., human saliva) that can be sampled by minimally invasive means. [ABSTRACT FROM AUTHOR]

The neoplastic transformation of cells and inflammation are processes that contribute to tumor initiation. Recently, emerging evidence has suggested that epigenetic alterations are also implicated in the early stages of carcinogenesis. Therefore, potent small molecules targeting epigenetic regulators have been developed as novel cancer therapeutic and preventive strategies. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play key roles at the interface between chromatin modification and transcriptional regulation. In this study, we investigated the effect of the BET inhibitor JQ-1 on malignant transformation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin epidermal JB6 P+ cells. Treatment with JQ-1 effectively impaired TPA-induced colony formation in vitro . At the molecular level, the expression of several key TPA-induced pro-survival and pro-proliferative genes (Bcl2, Cyclin D1, and c-Myc) decreased rapidly after BET inhibition. In addition, JQ-1 treatment attenuated the activation of inflammatory NF-κB signaling triggered by TPA. Luciferase reporter assays using plasmids carrying different elements from the COX2 or IL6 promoters demonstrated that JQ-1 does not directly inhibit interactions between NF-κB and its binding sequence; rather, it affects CRE-element-associated transcriptional enhancement. Through siRNA gene silencing, we found that JQ-1 inhibits the p300-dependent transcriptional activation of COX2, which correlates with the results of the luciferase assay. Chromatin immunoprecipitation assays showed that TPA elevated H3K27Ac enrichment in the COX2 promoter region, which is mediated by p300, and Brd4. JQ-1 treatment did not change H3K27Ac levels but decreased the recruitment of Brd4 and RNA Polymerase II. Collectively, our study reveals that the BET inhibitor JQ-1 exerts potent anti-cancer and anti-inflammatory effects by interfering with the core transcriptional program of neoplastic transformation. [ABSTRACT FROM AUTHOR]

Estrogens play a crucial role in the regulation of physiological and pathophysiological processes. These hormones act through specific receptors, most notably the canonical estrogen receptors α and β (ERα and ERβ) and their truncated forms as well as the G protein-coupled estrogen receptor (GPER). Several studies have shown that GPER is expressed in many normal and cancer cells, including those of the breast, endometrium, ovary, testis and lung. Hormonal imbalance is one possible cause of cancer development. An accumulating body of evidence indicates that GPER is involved in the regulation of cancer cell proliferation, migration and invasion, it may act as a mediator of microRNA, and is believed to modulate the inflammation associated with neoplastic transformation. Furthermore, used in various treatment regimens anti-estrogens such as tamoxifen, raloxifen and fulvestrant (ICI 182.780), antagonists/modulators of canonical estrogen receptors, were found to be GPER agonists. This review presents the current knowledge about the potential role of GPER in neoplastic transformation. [ABSTRACT FROM AUTHOR]

Cadmium is a carcinogenic metal, the mechanisms of which are not fully understood. In this study, human bronchial epithelial cells were transformed with sub-toxic doses of cadmium (0.01, 0.05, and 0.1 μM) and transformed clones were characterized for gene expression changes using RNA-seq, as well as other molecular measurements. 440 genes were upregulated and 47 genes were downregulated in cadmium clones relative to control clones over 1.25-fold. Upregulated genes were associated mostly with gene ontology terms related to embryonic development, immune response, and cell movement, while downregulated genes were associated with RNA metabolism and regulation of transcription. Several embryonic genes were upregulated, including the transcription regulator SATB2. SATB2 is critical for normal skeletal development and has roles in gene expression regulation and chromatin remodeling. Small hairpin RNA knockdown of SATB2 significantly inhibited growth in soft agar, indicating its potential as a driver of metal-induced carcinogenesis. An increase in oxidative stress and autophagy was observed in cadmium clones. In addition, the DNA repair protein O6-methylguanine-DNA-methyltransferase was depleted by transformation with cadmium. MGMT loss caused significant decrease in cell viability after treatment with the alkylating agent temozolomide, demonstrating diminished capacity to repair such damage. Results reveal various mechanisms of cadmium-induced malignant transformation in BEAS-2B cells including upregulation of SATB2, downregulation of MGMT, and increased oxidative stress. [ABSTRACT FROM AUTHOR]

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed. [ABSTRACT FROM AUTHOR]

Background: To investigate the diagnostic and prognostic performances of 18F-FDG PET/CT measures of metabolic tumour burden in patients with neurofibromatosis type-1 (NF1), suspect of malignant transformation. Methods: This retrospective study included 49 patients (15–60 years old, 30 women) with a diagnosis of NF1, followed in our Reference Centre for Rare Neuromuscular Diseases, who presented clinical signs of tumour progression (pain, neurological deficit, tumour growth). Quantitative metabolic parameters were measured on 149 tumoral targets, using semi-automatic software and the best cut off values to predict transformation was assessed by Receiver Operating Characteristics (ROC) analysis. Prognostic value of PET/CT metabolic parameters was assessed by Kaplan-Meier estimates of overall survival. Results: Lesions were histologically documented in 40 patients: a sarcomatous transformation was found in 16, a dysplastic neurofibroma (NF) in 7, and a benign NF in 17; in the remaining 9 patients, a minimal follow-up of 12 mo (median 59 mo) confirmed the absence of transformation. The optimal cut off values for detection of malignant transformation were, in decreasing order of area under the ROC curves, a tumour-to-liver (T/L) ratio >2.5, SUVmax > 4.5, total lesion glycolysis (TLG) > 377, total metabolic tumour volume (TMTV) > 88 cm3, and heterogeneity index (HIsuv) > 1.69. The best prognostic marker was the TLG: the 4-y estimates of survival were 97% [95% CI, 90% - 100%] in patients with TLG ≤ 377 vs. 27% [95% CI, 5% - 49%] in patients with TLG > 377 (P < 0.0001; χ2 27.85; hazard ratio 13.27 [95% CI, 3.72–47.35]). T/L ratio, SUVmax and TMTV demonstrated slightly lower performance to predict survival, with χ2 ranging 14.41–19.12. The HIsuv index was not predictive of survival. Conclusion: Our study demonstrates that TLG and TMTV, as PET/CT measures of metabolic tumour burden, may be used clinically to identify sarcomatous transformation in patients with NF1 and predict overall survival, with a higher specificity for the TLG. Conventional measures such as the SUVmax, and T/L ratio also demonstrate high prognostic value. [ABSTRACT FROM AUTHOR]

In classic Hairy cell leukaemia (HCLc), a single case has thus far been interrogated by whole exome sequencing (WES) in a treatment naive patient, in which BRAF V(600)E was identified as an acquired somatic mutation and confirmed as occurring near-universally in this form of disease by conventional PCR-based cohort screens. It left open however the question whether other genome-wide mutations may also commonly occur at high frequency in presentation HCLc disease. To address this, we have carried out WES of 5 such typical HCLc cases, using highly purified splenic tumour cells paired with autologous T cells for germline. Apart from BRAF V(600)E, no other recurrent somatic mutation was identified in these HCLc exomes, thereby excluding additional acquired mutations as also prevalent at a near-universal frequency in this form of the disease. These data then place mutant BRAF at the centre of the neoplastic drive in HCLc. A comparison of our exome data with emerging genetic findings in HCL indicates that additional somatic mutations may however occur recurrently in smaller subsets of disease. As mutant BRAF alone is insufficient to drive malignant transformation in other histological cancers, it suggests that individual tumours utilise largely differing patterns of genetic somatic mutations to coalesce with BRAF V(600)E to drive pathogenesis of malignant HCLc disease. [ABSTRACT FROM AUTHOR]

Although generally benign, giant cell tumors of bone (GCTB) display an aggressive behavior associated with significant bone destruction and lung metastasis in rare cases. This and the very high recurrence rate observed after surgical resection ranging from 20 to 55% necessitates the development of more effective treatment strategies. To identify valuable therapeutic targets, we screened a previously identified microRNA signature consisting of 23 microRNAs predominantly down-regulated in GCTB. We preselected eight candidate microRNAs and analyzed the impact of their restored expression on the neoplastic phenotype of GCTB stromal cells (GCTSC). A consistent and significant inhibition of cell proliferation, migration, colony formation and spheroid formation could be induced by transfection of primary GCTSC cell lines with miR-127-3p and miR-376a-3p, respectively. Genome wide expression analysis of miR-127-3p and miR-376a-3p transfected cells revealed four novel target genes for each microRNA. Luciferase reporter assays demonstrated direct interactions of miR-127-3p with COA1 and direct interaction of miR-376a-3p with GLE1 and PDIA6, suggesting a pivotal role of these genes in the molecular etiology of GTCB. Interestingly, both microRNAs are located within a chromosomal region frequently silenced in GCTB and many other types of cancers, indicating that these microRNAs and their target genes are valuable therapeutic targets for the treatment of GCTB and possibly other tumor entities. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved and lysosome-dependent degradation process which assists in cell survival and tissue homeostasis. Although previous reports have shown that deletion of the essential autophagy gene disturbs stem cell maintenance in some cell types such as hematopoietic and neural cells, it remains unclear how autophagy-deficiency influences hepatic progenitor cells (HPCs). Here we report that Atg5-deficiency in HPCs delays HPC-mediated rat liver regeneration in vivo. In vitro researches further demonstrate that loss of autophagy decreases the abilities of colony and spheroid formations, and disrupts the induction of hepatic differentiation in HPCs. Meanwhile, autophagy-deficiency increases the accumulations of damaged mitochondria and mitochondrial reactive oxygen species (mtROS) and suppresses homologous recombination (HR) pathway of DNA damage repair in HPCs. Moreover, in both diethylnitrosamine (DEN) and CCl4 models, autophagy-deficiency accelerates neoplastic transformation of HPCs. In conclusion, these findings demonstrate that autophagy contributes to stemness maintenance and reduces susceptibility to neoplastic transformation in HPCs. [ABSTRACT FROM AUTHOR]

Nm23H1 and H2 are prototypical metastasis suppressors with diverse functions, but recent studies suggest that they may also regulate tumorigenesis. Here, we employed both cellular and in vivo assays to examine the effect of Nm23H1 and H2 on tumorigenesis induced by oncogenic Ras and/or p53 deficiency. Co-expression of Nm23H1 but not H2 in NIH3T3 cells effectively suppressed neoplastic transformation and tumorigenesis induced by the oncogenic H-Ras G12V mutant. Overexpression of Nm23H1 but not H2 also inhibited tumorigenesis by human cervical cancer HeLa cells with p53 deficiency. However, in human non-small-cell lung carcinoma H1299 cells harboring N-Ras Q61K oncogenic mutation and p53 deletion, overexpression of Nm23H1 did not affect tumorigenesis in nude mice assays, while overexpression of Nm23H2 enhanced tumor growth with elevated expression of the c-Myc proto-oncogene. Collectively, these results suggest that Nm23H1 and H2 have differential abilities to modulate tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Most studies have found that osteopontin (OPN) expression level is related to the poor prognosis of gastric cancer. However, few studies have examined the relationship between OPN expression and gastric precancerous diseases, and the potential role of OPN in the formation and development of GC. We investigated the relationships between serum OPN levels and the risks of gastric cancer (GC) and its precancerous disease, to explore the diagnostic efficacy of serum OPN level for GC and atrophic gastritis and its influencing factors. Methods: A total of 1,452 patients were enrolled, including 609 with mild superficial gastritis (SG), 594 with atrophic gastritis (AG) and 249 with GC. The levels of serum OPN and serum Helicobacter pylori IgG antibody were detected by enzyme-linked immunosorbent assay. Results: Serum OPN levels increased from mild SG (1.99±1.91 ng/ml) to AG (2.37±2.27 ng/ml) to GC (5.94±4.52 ng/ml) (P≤0.002), along with increasing severity of gastric disease. OPN levels were significantly higher in patients with GC compared with the non-cancer population (2.17±2.10, P<0.0001). Serum OPN level was positively correlated with age and was higher in men than women, but was not correlated with H. pylori infection status. The area under the receiver operating characteristic curve was 0.805, the optimal cutoff was 2.56 ng/ml and the sensitivity and specificity were 74.3% and 71.8%, respectively, for the ability of serum OPN to discriminate GC. Conclusions: Serum OPN expression was closely related to the risks of GC and AG, and it might be a useful marker for the discrimination of GC. OPN level was positively correlated with age and male sex, but was not affected by H. pylori infection, and it was promoted by smoking and drinking, in patients with mild SG. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is a significant health problem in rural areas of Africa and the Middle East where Schistosoma haematobium is prevalent, supporting an association between malignant transformation and infection by this blood fluke. Nevertheless, the molecular mechanisms linking these events are poorly understood. Bladder cancers in infected populations are generally diagnosed at a late stage since there is a lack of non-invasive diagnostic tools, hence enforcing the need for early carcinogenesis markers. Methodology/Principal Findings: Forty-three formalin-fixed paraffin-embedded bladder biopsies of S. haematobium-infected patients, consisting of bladder tumours, tumour adjacent mucosa and pre-malignant/malignant urothelial lesions, were screened for bladder cancer biomarkers. These included the oncoprotein p53, the tumour proliferation rate (Ki-67>17%), cell-surface cancer-associated glycan sialyl-Tn (sTn) and sialyl-Lewisa/x (sLea/sLex), involved in immune escape and metastasis. Bladder tumours of non-S. haematobium etiology and normal urothelium were used as controls. S. haematobium-associated benign/pre-malignant lesions present alterations in p53 and sLex that were also found in bladder tumors. Similar results were observed in non-S. haematobium associated tumours, irrespectively of their histological nature, denoting some common molecular pathways. In addition, most benign/pre-malignant lesions also expressed sLea. However, proliferative phenotypes were more prevalent in lesions adjacent to bladder tumors while sLea was characteristic of sole benign/pre-malignant lesions, suggesting it may be a biomarker of early carcionogenesis associated with the parasite. A correlation was observed between the frequency of the biomarkers in the tumor and adjacent mucosa, with the exception of Ki-67. Most S. haematobium eggs embedded in the urothelium were also positive for sLea and sLex. Reinforcing the pathologic nature of the studied biomarkers, none was observed in the healthy urothelium. Conclusion/Significance: This preliminary study suggests that p53 and sialylated glycans are surrogate biomarkers of bladder cancerization associated with S. haematobium, highlighting a missing link between infection and cancer development. Eggs of S. haematobium express sLea and sLex antigens in mimicry of human leukocytes glycosylation, which may play a role in the colonization and disease dissemination. These observations may help the early identification of infected patients at a higher risk of developing bladder cancer and guide the future development of non-invasive diagnostic tests. [ABSTRACT FROM AUTHOR]

Aim: Deregulation of FOXM1 has been documented in various cancers. The aim of this study was to evaluate the role of FOXM1 in ovarian cancer tumorigenesis and paclitaxel resistance. Experimental Design: Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological parameters. Effects of FOXM1 knockdown on ovarian cancer cell migration, invasion and mitotic catastrophe were also studied. qPCR and ChIP-qPCR were used to establish KIF2C as a novel FOXM1 target gene implicated in chemoresistance. Results: High nuclear FOXM1 expression in ovarian cancer patient samples was significantly associated with advanced stages (P = 0.035), shorter overall (P = 0.019) and disease-free (P = 0.014) survival. Multivariate analysis confirmed FOXM1 expression as an independent prognostic factor for ovarian cancer. FOXM1 knockdown significantly inhibited migration and invasion of ovarian cancer cells and enhanced paclitaxel-mediated cell death and mitotic catastrophe in a p53-independent manner. Bioinformatics analysis suggested a number of potential transcription targets of FOXM1. One of the potential targets, KIF2C, exhibited similar expression pattern to FOXM1 in chemosensitive and chemoresistant cells in response to paclitaxel treatment. FOXM1 could be detected at the promoter of KIF2C and FOXM1 silencing significantly down-regulated KIF2C. Conclusion: Our findings suggest that FOXM1 is associated with poor patient outcome and contributes to paclitaxel resistance by blocking mitotic catastrophe. KIF2C is identified as a novel FOXM1 transcriptional target that may be implicated in the acquisition of chemoresistance. FOXM1 should be further investigated as a potential prognostic marker and therapeutic target for ovarian cancer. [ABSTRACT FROM AUTHOR]

Myxoid/round-cell liposarcoma (MLS/RCLS) is characterized by either the fusion gene FUS-DDIT3 or the less commonly occurring EWSR1-DDIT3 and most cases carry few or no additional cytogenetic changes. There are conflicting reports concerning the status and role of TP53 in MLS/RCLS. Here we analysed four MLS/RCLS derived cell lines for TP53 mutations, expression and function. Three SV40 transformed cell lines expressed normal TP53 proteins. Irradiation caused normal posttranslational modifications of TP53 and induced P21 expression in two of these cell lines. Transfection experiments showed that the FUS-DDIT3 fusion protein had no effects on irradiation induced TP53 responses. Ion Torrent AmpliSeq screening, using the Cancer Hotspot panel, showed no dysfunctional or disease associated alleles/mutations. In conclusion, our results suggest that most MLS/RCLS cases carry functional TP53 genes and this is consistent with the low numbers of secondary mutations observed in this tumor entity. [ABSTRACT FROM AUTHOR]

High mortality in ovarian cancer patients is primarily caused through rapid metastasis of the tumour, but the underlying mechanisms are poorly understood. Glycosaminoglycans, are abundantly present in tumours and chondroitin sulfate-E (CSE), a highly 4,6-sulfated glycosaminoglycan, has been indicated to play a role in carcinogenesis. In this study we investigated the presence of CSE in ovarian cancer metastasis and studied its role in tumour cell adhesiveness and migration. CSE was studied immunohistochemically in primary ovarian carcinomas and abdominal metastases using the single chain antibody GD3G7. The role of CSE was studied in 2D (scratch assays) and 3D (collagen matrices, spheroids) systems using SKOV3 cells applying 1: overexpression of CSE by stable transfection with DNA encoding GalNAc4S-6 sulfotransferase, 2: enzymatic removal of CS, and 3: addition of CSE. In ovarian cancer tissue, CSE expression was predominantly seen in the stromal compartment of both primary ovarian carcinomas and metastases, with a comparable degree of intensity and extent. Overexpression of CSE disaccharide units by tumour cells increased their adhesive properties which was especially seen in tumour spheroid formation. Increased expression of CSE reduced cell migration. Addition of free CSE had similar effects. The data presented here indicate that CSE is associated with metastatic lesions and that it provides tumours with adhesive properties. CSE rich motifs are put forward as a potential target for ovarian cancer therapy. [ABSTRACT FROM AUTHOR]

It is well known that the microenvironment plays a major role in breast cancer progression. Yet, the mechanism explaining the transition from normal fibroblasts to cancer-stimulated fibroblasts remains to be elucidated. Here we report a FTIR imaging study of the effects of three different breast cancer cell lines on normal fibroblasts in culture. Fibroblast activation process was monitored by FTIR imaging and spectra compared by multivariate statistical analyses. Principal component analysis evidenced that the fibroblasts stimulated by these cancer cell lines grouped together and remained distinctly separated from normal fibroblasts indicating a modified different chemical composition in the cancer-stimulated fibroblasts. Similar changes in fibroblasts were induced by the various breast cancer cell lines belonging to different sub-types. Most significant changes were observed in the region of 2950 and 1230 cm−1, possibly related to changes in lipids and in the 1230 cm−1 area assigned to phosphate vibrations (nucleotides). Interestingly, the cancer-cell induced changes in the fibroblasts also occurred when there was no possible direct contact between the two cell lines in the co-culture. When contact was possible, the spectral changes were similar, suggesting that soluble factors but not direct cell-cell interactions were responsible for fibroblast activation. Overall, the results indicate that IR imaging could be used in the future for analyzing the microenvironment of breast tumors. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens. [ABSTRACT FROM AUTHOR]

Cell lines recapitulate cancer heterogeneity without the presence of interfering tissue found in primary tumor. Their heterogeneous characteristics are reflected in their multiple genetic abnormalities and variable responsiveness to drug treatments. In order to understand the heterogeneity observed in Asian gastric cancers, we have performed array comparative genomic hybridization (aCGH) on 18 Asian gastric cell lines. Hierarchical clustering and single-sample Gene Set Enrichment Analysis were performed on the aCGH data together with public gene expression data of the same cell lines obtained from the Cancer Cell Line Encyclopedia. We found a large amount of genetic aberrations, with some cell lines having 13 fold more aberrations than others. Frequently mutated genes and cellular pathways are identified in these Asian gastric cell lines. The combined analyses of aCGH and expression data demonstrate correlation of gene copy number variations and expression profiles in human gastric cancer cells. The gastric cell lines can be grouped into 2 integrative clusters (ICs). Gastric cells in IC1 are enriched with gene associated with mitochondrial activities and oxidative phosphorylation while cells in IC2 are enriched with genes associated with cell signaling and transcription regulations. The two clusters of cell lines were shown to have distinct responsiveness towards several chemotherapeutics agents such as PI3 K and proteosome inhibitors. Our molecular integrative clustering provides insight into critical genes and pathways that may be responsible for the differences in survival in response to chemotherapy. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients. [ABSTRACT FROM AUTHOR]

Mounting evidence suggests that the FAK N-terminal (FERM) domain controls FAK phosphorylation and function; however, little is known regarding the role of the C terminal (FAT) domain in FAK regulation. We identified a patient-derived FAK mutant, in which a 27-amino acid segment was deleted from the C-terminal FAT domain (named FAK-Del33). When FAK-Del33 was overexpressed in specific tumor cell lines, Y397 phosphorylation increased compared with that observed in cells expressing FAK-WT. Here, we attempt to unveil the mechanism of this increased phosphorylation. Using cell biology experiments, we show that FAK-Del33 is incapable of co-localizing with paxillin, and has constitutively high Y397 phosphorylation. With a kinase-dead mutation, it showed phosphorylation of FAK-Del33 has enhanced through auto-phosphorylation. It was also demonstrated that phosphorylation of FAK-Del33 is not Src dependent or enhanced intermolecular interactions, and that the hyperphosphorylation can be lowered using increasing amounts of transfected FERM domain. This result suggests that Del33 mutation disrupting of FAT's structural integrity and paxillin binding capacity leads to incapable of targeting Focal adhesions, but has gained the capacity for auto-phosphorylation in cis. [ABSTRACT FROM AUTHOR]

The detachment of epithelial cells, but not cancer cells, causes anoikis due to reduced energy production. Invasive tumor cells generate three splice variants of the metastasis gene osteopontin, the shortest of which (osteopontin-c) supports anchorage-independence. Osteopontin-c signaling upregulates three interdependent pathways of the energy metabolism. Glutathione, glutamine and glutamate support the hexose monophosphate shunt and glycolysis and can feed into the tricarboxylic acid cycle, leading to mitochondrial ATP production. Activation of the glycerol phosphate shuttle also supports the mitochondrial respiratory chain. Drawing substrates from glutamine and glycolysis, the elevated creatine may be synthesized from serine via glycine and supports the energy metabolism by increasing the formation of ATP. Metabolic probing with N-acetyl-L-cysteine, L-glutamate, or glycerol identified differential regulation of the pathway components, with mitochondrial activity being redox dependent and the creatine pathway depending on glutamine. The multiple skewed components in the cellular metabolism synergize in a flow toward two mechanisms of ATP generation, via creatine and the respiratory chain. It is consistent with a stimulation of the energy metabolism that supports anti-anoikis. Our findings imply a coalescence in cancer cells between osteopontin-a, which increases the cellular glucose levels, and osteopontin-c, which utilizes this glucose to generate energy. [ABSTRACT FROM AUTHOR]

Estimates of cancer risks posed to space-flight crews by exposure to high atomic number, high-energy (HZE) ions are subject to considerable uncertainty because epidemiological data do not exist for human populations exposed to similar radiation qualities. We assessed the carcinogenic effects of 300 MeV/n 28Si or 600 MeV/n 56Fe ions in a mouse model for radiation-induced acute myeloid leukemia and hepatocellular carcinoma. C3H/HeNCrl mice were irradiated with 0.1, 0.2, 0.4, or 1 Gy of 300 MeV/n 28Si ions, 600 MeV/n 56Fe ions or 1 or 2 Gy of protons simulating the 1972 solar particle event (1972SPE) at the NASA Space Radiation Laboratory. Additional mice were irradiated with 137Cs gamma rays at doses of 1, 2, or 3 Gy. All groups were followed until they were moribund or reached 800 days of age. We found that 28Si or 56Fe ions do not appear to be substantially more effective than gamma rays for the induction of acute myeloid leukemia. However, 28Si or 56Fe ion irradiated mice had a much higher incidence of hepatocellular carcinoma than gamma ray irradiated or proton irradiated mice. These data demonstrate a clear difference in the effects of these HZE ions on the induction of leukemia compared to solid tumors, suggesting potentially different mechanisms of tumorigenesis. Also seen in this study was an increase in metastatic hepatocellular carcinoma in the 28Si and 56Fe ion irradiated mice compared with those exposed to gamma rays or 1972SPE protons, a finding with important implications for setting radiation exposure limits for space-flight crew members. [ABSTRACT FROM AUTHOR]

Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45–60 years were excluded to help define “young” and “old” groups. Thirty-nine cases of sporadic EOCRC (patients≤45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease. [ABSTRACT FROM AUTHOR]