Potent Tumor Promoter Research Articles

ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway.

Pancreatic adenocarcinoma (PAAD) is one of the most aggressive digestive system tumors in the world, with a low early diagnosis rate and a high mortality. Integrin beta 5 (ITGB5) is demonstrated to be a potent tumor promoter in several carcinomas. However, it is unknown whether ITGB5 participates in the occurrence and development of PAAD. In this study, we confirmed a high expression of ITGB5 in PAAD and its role in promoting invasiveness and transitivity in PAAD. Besides, the knockdown of ITGB5 increased cell sensitivity to radiation by promoting DNA damage repair and the MEK/ERK signaling pathway. Collectively, these results show that ITGB5 plays an essential role in pancreatic cancer growth and survival.

Hypermethylation of PRKCZ Regulated by E6 Inhibits Invasion and EMT via Cdc42 in HPV-Related Head and Neck Squamous Cell Carcinoma

Simple SummaryHPV+ and HPV- HNSCC share distinct epigenetic characteristics and clinicopathological features. The aim of our study was to assess whether DNA methylation plays a role in the progression of HPV+ HNSCC. We used a HumanMethylation450 BeadChip array (Illumina) to identify PRKCZ genes exhibiting different levels of DNA methylation between HPV+ and HPV- HNSCC. PRKCZ acts as a potent tumor promoter in HPV+ HNSCC. These findings may provide a possible explanation for the differences in the clinicopathological characteristics between HPV+ and HPV- HNSCC and promising ideas for the treatment of HPV+ HNSCC.Purpose: To study the role of target genes with aberrant DNA methylation in HPV+ HNSCC. Methods: A HumanMethylation450 BeadChip array (Illumina) was used to identify differentially methylated genes. CCK-8, flow cytometry, wound healing, and cell invasion assays were conducted to analyze the biological roles of PRKCZ. Western blot, qRT-PCR, immunohistochemistry, and animal studies were performed to explore the mechanisms underlying the functions of PRKCZ. Results: We selected PRKCZ, which is associated with HPV infection, as our target gene. PRKCZ was hypermethylated in HPV+ HNSCC patients, and PRKCZ methylation status was negatively related to the pathological grading of HNSCC patients. Silencing PRKCZ inhibited the malignant capacity of HPV+ HNSCC cells. Mechanistically, HPV might promote DNMT1 expression via E6 to increase PRKCZ methylation. Cdc42 was required for the PRKCZ-mediated mechanism of action, contributing to the occurrence of epithelial-mesenchymal transition (EMT) in HPV+ HNSCC cells. In addition, blocking PRKCZ delayed tumor growth in HPV16-E6/E7 transgenic mice. Cdc42 expression was decreased, whereas E-cadherin levels increased. Conclusion: We suggest that PRKCZ hypermethylation induces EMT via Cdc42 to act as a potent tumor promoter in HPV+ HNSCC.

The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy.

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

Phorbol 12-Myristate 13-Acetate Induced Toxicity Study and the Role of Tangeretin in Abrogating HIF-1α-NF-κB Crosstalk In Vitro and In Vivo.

Phorbol 12-myristate 13-acetate (PMA) is a potent tumor promoter and highly inflammatory in nature. Here, we investigated the toxic effects of PMA on different model system. PMA (10 μg) caused chromosomal aberrations on the Allium cepa root tip and induced mitotic dysfunction. Similarly, PMA caused embryonic and larval deformities and a plummeted survivability rate on zebrafish embryo in a dose-dependent manner. Persistently, PMA treatment on immortalized human keratinocyte human keratinocyte (HaCaT) cells caused massive inflammatory rush at 4 h and a drop in cell survivability at 24 h. Concomitantly, we replicated a cutaneous inflammation similar to human psoriasis induced by PMA. Herein, we used tangeretin (TAN), as an antagonist to counteract the inflammatory response. Results from an in vivo experiment indicated that TAN (10 and 30 mg/kg) significantly inhibited PMA stimulated epidermal hyperplasia and intra-epidermal neutrophilic abscesses. In addition, its treatment effectively neutralized PMA induced elevated reactive oxygen species (ROS) generation on in vitro and in vivo systems, promoting antioxidant response. The association of hypoxia-inducible factor 1-alpha (HIF-1α)-nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) crosstalk triggered by PMA enhanced PKCα-ERK1/2-NF-κB pathway; its activation was also significantly counteracted after TAN treatment. Conclusively, we demonstrated TAN inhibited the nuclear translocation of HIF-1α and NF-κB p65. Collectively, TAN treatment ameliorated PMA incited malignant inflammatory response by remodeling the cutaneous microenvironment.

The functions and regulation of Smurfs in cancers.

Smad ubiquitination regulatory factor 1 (Smurf1) and Smurf2 are HECT-type E3 ubiquitin ligases, and both Smurfs were initially identified to regulate Smad protein stability in the TGF-β/BMP signaling pathway. In recent years, Smurfs have exhibited E3 ligase-dependent and -independent activities in various kinds of cells. Smurfs act as either potent tumor promoters or tumor suppressors in different tumors by regulating biological processes, including metastasis, apoptosis, cell cycle, senescence and genomic stability. The regulation of Smurfs activity and expression has therefore emerged as a hot spot in tumor biology research. Further, the Smurf1- or Smurf2-deficient mice provide more in vivo clues for the functional study of Smurfs in tumorigenesis and development. In this review, we summarize these milestone findings and, in turn, reveal new avenues for the prevention and treatment of cancer by regulating Smurfs.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Prostate Specific Membrane Antigen promotes prostate tumor progression and survival by conferring resistance to hypoxic stress.

Prostate cancer (PC) is the most commonly diagnosed cancer and is the second leading cause of cancer deaths among men in the United States. The ability of tumor cells to survive in the low oxygen (hypoxic) environment created by the expansion of primary tumors is fundamental to their growth in situ as well as metastatic progression that underlies the majority of disease‐related mortality. Prostate Specific Membrane Antigen (PSMA), a type II transmembrane peptidase, is progressively upregulated in ~80% of tumors during PC progression where it correlates negatively with prognosis. We have previously reported that increased PSMA expression on tumor cells alters signal transduction mechanisms downstream of growth factor receptors to promote tumor progression. In addition, we found that expression of PSMA promotes increased survival in hypoxic environments and the current study was designed to determine these PSMA‐dependent survival mechanisms. Using the CRISPR/Cas9 system, we engineered a panel of human and murine PC cell lines (LnCaP, 22rv1, TRAMP‐C1) to lack PSMA expression. Interestingly, loss of PSMA (PSMAKO) in these highly metastatic PC cell lines resulted in a significantly lower proliferation rate than PSMA expressing cells (PSMAWT), formation of smaller anchorage‐independent colonies in soft agar, a shift in the balance of RIPK3/MLKL family of necrosis proteins toward a decreased survival, and a decrease in the migration and intravasation/extravasation potential. Furthermore, in a NOD/SCID xenograft mouse model, LnCaP‐PSMAWT cells formed large, well‐vascularized tumors whereas LnCaP‐PSMAKO showed no evidence of tumor growth, indicating that PSMA is a potent tumor promoter both in vitro and in vivo. Mimicking hypoxic conditions in vitro by treating both PSMAWT and PSMAKO cells with a HiF1 inhibitor, (CoCl2), produced drastic differences in the hypoxia‐induced regulation of the calcineurin A and calpain‐2 calcium‐associated signal‐transduction pathways as well as actin regulated cytoskeletal rearrangement highlighting PSMAs role in resistance to hypoxia as well as its potential contribution to a pro‐tumor phenotype and increased metastatic potential. In support of this notion, in silico meta‐analysis of publicly available human gene expression data sets indicated that changes in PSMA and calcium associated genes correlates significantly with PC metastasis to bone and lymph. Dramatic changes in calcium levels are a primary response of many cells to hypoxia and typically stimulate cell death. These results suggest that PSMA expression on tumor cells confers resistance to hypoxia via changes in the calcium signal‐transduction cascade, thus making the complete disruption of PSMA a promising therapeutic option in management and treatment of PC.Support or Funding InformationResearch reported in this paper was supported by the National Institute of General Medical Sciences of the National Institutes of Health under linked Award Numbers RL5GM118969, TL4GM118971, and UL1GM118970. Support was also received from the National Cancer Institute of the National Institutes of Health K01 Mentored Research Scientist Award to Promote Diversity under linked Award Number K01CA188412. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The mongolian gerbil (Meriones unguiculatus) as a model for inflammation-promoted prostate carcinogenesis.

One of the recognized issues in prostate cancer research is the lack of animal models allowing the research of pathological, biochemical, and genetic factors in immunocompetent animals. Our research group has successfully employed the gerbil in several studies for prostate diseases. In the present work, we aimed to analyze the effect of chronic bacterial inflammation on N-methyl-N-nitrosourea (MNU)-induced prostate carcinogenesis in gerbils. Histopathological assessment of the prostatic complex revealed that treatment combinations with MNU plus testosterone or bacterial infection resulted in a promotion of prostate cancer, with bacterial inflammation being more effective in increasing premalignant and malignant tissular alterations than testosterone in the prostate. Furthermore, chronic bacterial inflammation itself induced premalignant lesions in the ventral lobe and increased their frequency in the dorsolateral lobe as well as malignant lesions in the ventral prostate. These animals showed a rich inflammatory microenvironment, characterized as intraluminal and periductal foci. These data indicate that chronic inflammation induced by Escherichia coli acts as a potent tumor promoter, in the early stages of carcinogenesis in the gerbil, in line with the hypothesis of inflammation supporting several steps of tumor development in the prostate gland.

Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) family signalling pathway. Similar to TGF-β, the complex roles of BMPs in development and disease are demonstrated by their dichotomous roles in various cancers and cancer stages. Although early studies implicated BMP signalling in tumour suppressive phenotypes, the results of more recent experiments recognize BMPs as potent tumour promoters. Many of these complexities are becoming illuminated by understanding the role of BMPs in their contextual role in unique cell typesof cancer and the impact of their surrounding tumour microenvironment. Here we review the emerging roles of BMP signalling in cancer, with a focus on the molecular underpinnings of BMP signalling in individual cancers as a valid therapeutic target for cancer prevention and treatment.

Repeated intra-nigrostriatal injection of phorbol myristate acetate induces microglial senescence in adult rats

Phorbol myristate acetate (PMA), as a potent tumor promoter, may induce microglial senescence. The present study investigated the effect of PMA infection on microglial senescence. From 58 male Sprague-Dawley rats, 10 were randomly selected and divided into a PMA injection group, containing five rats (0.5 µg/µl PMA) and a control group, containing five rats (commensurable 0.9% saline). Immunofluorescent staining of Iba-1 and enzyme-linked immunosorbent assay analyses of the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 β were performed in these two groups. The remaining 48 rats were randomly divided into the following three groups, each containing 16 rats: Repeated injection control group (commensurable normal saline, once a week for 4 weeks), single PMA injection group (0.5 µg/µl PMA, once in the first week) and repeated injection PMA group (0.5 µg/µl PMA, once a week for 4 weeks). The expression levels of p21, detected using double immunofluorescence staining with Iba-1, and β-galactosidase, via double immunohistochemical staining of Iba-1, were examined in these three groups. The results indicated that a single injection of PMA did not change the microglial morphology and had no significant effects on the expression levels of TNF-α and IL-1β, compared with the control group (P>0.05). Following four repeated injections of PMA, the microglia in the substantia nigra presented with features of senescence, characterized by increased expression levels of β-galactosidase (P<0.001) and p21 (P<0.001), compared with the repeated injection control group. In conclusion, repeated intra-nigrostriatal treatment with PMA induced microglial senescence with increased expression levels of β-galactosidase and p21 in the substantia nigra of the rats.

Abstract A64: Chronic allergic contact dermatitis, A potent tumor promoter of Marjolin's ulcer

Abstract Allergic contact dermatitis (ACD) is a well-recognized adverse event associated with implantable medical devices that contain allergenic materials like nickel. However, other cutaneous consequences of such chronic exposures are not well understood. Herein, we report a clinical case of Marjolin's ulcer, an invasive squamous cell carcinoma (SCC) developing at the site of chronic inflammation from a previously unreported cause: chronic ACD caused by an orthopedic implant. To determine whether chronic ACD promotes skin carcinogenesis, we utilized a standard murine model of contact hypersensitivity. The chronic application of 1-Fluoro-2,4-dinitrobenzene (DNFB) to carcinogen-treated skin led to the development of papillomas and aggressive SCC. The DNFB-driven chronic ACD was marked by type 2 inflammation that mediated the skin carcinogenesis. Importantly, we found similar tumor-promoting inflammation surrounding the SCC in our patient. Our findings demonstrate that chronic ACD caused by constant exposure to an allergen can promote tumorigenesis at skin sites with pre-existing cancer-initiated cells. This has great implication for the monitoring of implantable devices that are placed in the proximity of the skin and highlights the importance of patch testing prior to the placement of such devices. Citation Format: Shadmehr Demehri, Trevor J. Cunningham, Eva A. Hurst, Andras Schaffer, David M. Sheinbein, Wayne M. Yokoyama. Chronic allergic contact dermatitis, A potent tumor promoter of Marjolin's ulcer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A64.

Author's response to RE: Testosterone treatment is a potent tumor promoter for the rat prostate.

I am very concerned by the final statement in the comments by Dr Traish, Dr Morgentaler, and Dr Khera about my report on the carcinogenic and tumor promoting effects of testosterone treatment in male rats that “comments on T therapy based on results from rodents do not belong in this report” (1). Results from studies in rodents are used by the Food and Drug Administration and Environmental Protection Agency, as well as by their European counterparts and international organizations, such as the International Agency for Research on Cancer (World Health Organization), to evaluate the carcinogenic risk to humans of exposures to drugs and other chemicals. A statistically significant increase in the occurrence of malignant tumors in such studies is considered an indication that the drug or chemical tested may be carcinogenic to humans. Typically, drugs in development for medical use that test positive in such studies are not pursued further, and other chemicals that cause malignancies in rodent experiments are regulated on the basis of the study results. Testosterone treatment significantly increased the number of animals with malignant tumors and caused prostate carcinomas in my study and others, quoted in my article, have also found such a prostate tumor response. Prostate tumors are extremely rare in untreated aged Wistar rats, including the Cpb:WU strain used in my study, and finding rare malignancies in rodents exposed to chemicals is commonly considered a strong indication that the compound tested is a rodent carcinogen. After a single carcinogen exposure to cause DNA damage and mutations in the prostate, long-term testosterone treatment caused a massive prostate cancer response in my study, even at a dose that did not significantly elevate circulating testosterone. This tumor response of WU rats to N-methyl-N-nitrosourea plus testosterone treatment has been remarkably stable for over 25 years, indicating that “genetic drift” is not a problem. These findings, taken together, are thus clear reason to be concerned about the risk of prostate cancer in testosterone-treated men, and they form the basis for the last sentence in my report, which disturbed Dr Traish, Dr Morgentaler, and Dr Khera, who left out the beginning of that sentence: “Until adequate human studies are available.”

Testosterone treatment is a potent tumor promoter for the rat prostate.

Testosterone is increasingly prescribed to middle aged and older men, but the safety of this treatment has been called into question, and the possible risk of prostate cancer is unknown. We treated Wistar Cpb: WU rats chronically via slow-release Silastic implants with doses of testosterone that increased circulating levels in a dose-related fashion with or without a preceding single injection of the carcinogen N-nitroso-N-methylurea (MNU). Without MNU, testosterone induced prostate carcinomas in 10%-18% of rats, and after MNU injection, testosterone treatment caused prostate cancer in 50%-71% of rats with a very steep dose response, producing a 50% prostatic tumor incidence even at a testosterone dose that did not elevate circulating testosterone levels. Prostate cancers did not occur in rats given MNU or no treatment, whereas testosterone alone induced a low incidence of prostate cancer and increased the number rats bearing tumors at other sites, particularly malignant tumors. Thus, testosterone was shown to be a weak complete carcinogen and a strong tumor promoter for the rat prostate in this study. These findings have potential significant public health implications for the use of testosterone therapy in men.

Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR.

The nuclear receptors CAR (constitutive androstane receptor) and possibly PXR (pregnane X receptor) mediate the hepatic effects of phenobarbital (PB) and similar-acting compounds. Although PB is a potent nongenotoxic tumor promoter in rodent liver, epidemiological data from epilepsy patients treated with phenobarbital do not show a specific role of PB in human liver cancer risk. That points to species differences in the susceptibility to tumor promotion by PB, which might be attributed to divergent functions of the PB receptors CAR and PXR in mice and humans. In the present study, male transgenic mice expressing human CAR and PXR were used to detect possible differences between wild-type (WT) and humanized mice in their response to CAR activation in a tumor initiation/promotion experiment with a single injection of the tumor initiator N-nitrosodiethylamine preceding chronic PB treatment for 10 months. Analysis of liver tumor burden revealed that PB strongly promoted the outgrowth of hepatocellular adenoma driven by activated β-catenin in WT mice, whereas the tumor-promoting effect of PB was much less pronounced in the humanized group. In conclusion, the present findings demonstrate that human CAR and PXR support tumor promotion by PB in mouse liver, but to a significantly lesser extent than the WT murine receptors.

12-O-Tetradecanoylphorbol-13-Acetate Induces Keratin 8 Phosphorylation and Reorganization via Expression of Transglutaminase-2.

The stiffness of cancer cells is attributable to intermediate filaments such as keratin. Perinuclear reorganization via phosphorylation of specific serine residue in keratin is implicated in the deformability of metastatic cancer cells including the human pancreatic carcinoma cell line (PANC-1). 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter and protein kinase C (PKC) activator. However, its effects on phosphorylation and reorganization of keratin 8 (K8) are not well known. Therefore, we examined the underlying mechanism and effect of TPA on K8 phosphorylation and reorganization. TPA induced phosphorylation and reorganization of K8 and transglutaminase-2 (Tgase-2) expression in a time- and dose-dependent manner in PANC-1 cells. These effects peaked after 45 min and 100 nM of TPA treatment. We next investigated, using cystamine (CTM), Tgase inhibitor, and Tgase-2 gene silencing, Tgase-2’s possible involvement in TPA-induced K8 phosphorylation and reorganization. We found that Tgase-2 gene silencing inhibited K8 phosphorylation and reorganization in PANC-1 cells. Tgase-2 gene silencing, we additionally discovered, suppressed TPA-induced migration of PANC-1 cells and Tgase-2 overexpression induced migration of PANC-1 cells. Overall, these results suggested that TPA induced K8 phosphorylation and reorganization via Tgase-2 expression in PANC-1 cells.

Building Bridges toward Invasion: Tumor Promoter Treatment Induces a Novel Protein Kinase C-Dependent Phenotype in MCF10A Mammary Cell Acini

The potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) alters many cellular processes through activation of its receptor protein kinase C (PKC), including gene expression, cell cycle, and the regulation of cell morphology, raising an important question for developing targeted methods to prevent cancer: which effects of TPA are crucial for carcinogenesis? To address this question, we studied TPA action in the 3-dimensional (3D) MCF10A human breast epithelial cell system, which models important features of in vivo epithelial tissue including growth constraints, structural organization of cells, and establishment of a basement membrane. MCF10A cells, which are immortalized but nontumorigenic, form hollow, spheroid structures in 3D culture referred to as acini. The development of normal acini requires the tight spatiotemporal regulation of cellular proliferation, polarization, apoptosis, and growth arrest. Treatment of MCF10A acini with TPA caused the appearance of multi-acinar structures. Surprisingly, this phenotype did not involve an increase in cell number or major changes in cell death, and polarization. Instead, live cell and confocal microscopy revealed that TPA stimulates MCF10A acini to aggregate. TPA induces the PKC-dependent production of actin-based protrusions, which leads to the formation of cellular bridges between acini, the clustering of acini, and allows cells to move into adjacent acini. During this process, the integrity of the laminin V basement membrane is disrupted, while E-cadherin-based cell-cell contacts remain intact. Altogether, our results show that under the biochemical and structural constraints of epithelial tissue, as modeled by the 3D MCF10A system, TPA induces a novel PKC-dependent phenotype that resembles local invasion. Of the many effects caused by TPA, these studies highlight the aggressive production of actin-based cellular protrusions as a potentially important event along the pathway to carcinogenesis.

Synthesis and Biological Activities of Simplified Analogs of the NaturalPKCLigands, Bryostatin‐1 and Aplysiatoxin

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is a potent PKC activator with little tumor-promoting activity. Numerous investigations have suggested bryo-1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo-1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo-1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo-1 surrogates. We have recently identified 10-methyl-aplog-1 (26), a simplified analog of tumor-promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo-1 and ATX, to develop potential medicinal leads.

Correction: Corrigendum: A novel potent tumour promoter aberrantly overexpressed in most human cancers

The complexity and heterogeneity of tumours have hindered efforts to identify commonalities among different cancers. Furthermore, because we have limited information on the prevalence and nature of ubiquitous molecular events that occur in neoplasms, it is unfeasible to implement molecular-targeted cancer screening and prevention. Here, we found that the FEAT protein is overexpressed in most human cancers, but weakly expressed in normal tissues including the testis, brain and liver. Transgenic mice that ectopically expressed FEAT in the thymus, spleen, liver and lung spontaneously developed invasive malignant lymphoma (48%, 19/40) and lung-metastasizing liver cancer (hepatocellular carcinoma) (35%, 14/40) that models human hepatocarcinogenesis, indicating the FEAT protein potently drives tumorigenesis in vivo. Gene expression profiling suggested that FEAT drives receptor tyrosine kinase and hedgehog signalling pathways. These findings demonstrate that integrated efforts to identify FEAT-like ubiquitous oncoproteins are useful and may provide promising approaches for cost-effective cancer screening and prevention.

Canonical Wnt suppressor, Axin2, promotes colon carcinoma oncogenic activity

Aberrant activation of canonical Wingless-type MMTV integration site family (Wnt) signaling is pathognomonic of colorectal cancers (CRC) harboring functional mutations in either adenomatous polyposis coli or β-catenin. Coincident with Wnt cascade activation, CRCs also up-regulate the expression of Wnt pathway feedback inhibitors, particularly the putative tumor suppressor, Axin2. Because Axin2 serves as a negative regulator of canonical Wnt signaling in normal cells, recent attention has focused on the utility of increasing Axin2 levels in CRCs as a means to slow tumor progression. However, rather than functioning as a tumor suppressor, we demonstrate that Axin2 acts as a potent promoter of carcinoma behavior by up-regulating the activity of the transcriptional repressor, Snail1, inducing a functional epithelial-mesenchymal transition (EMT) program and driving metastatic activity. Silencing Axin2 expression decreases Snail1 activity, reverses EMT, and inhibits CRC invasive and metastatic activities in concert with global effects on the Wnt-regulated cancer cell transcriptome. The further identification of Axin2 and nuclear Snail1 proteins at the invasive front of human CRCs supports a revised model wherein Axin2 acts as a potent tumor promoter in vivo.

Saudi Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma: Technical Review and Practice Guidelines

Recognizing the significant prevalence of hepatocellular carcinoma (HCC) in Saudi Arabia, and the difficulties often faced in early and accurate diagnoses, evidence-based management, and the need for appropriate referral of HCC patients, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) formed a multi-disciplinary task force to evaluate and update the previously published guidelines by the Saudi Gastroenterology Association. These guidelines were later reviewed, adopted and endorsed by the Saudi Oncology Society (SOS) as its official HCC guidelines as well. The committee assigned to revise the Saudi HCC guidelines was composed of hepatologists, oncologists, liver surgeons, transplant surgeons, and interventional radiologists. Two members of the task force served as guidelines editors. A wide based search on all published reports on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC was performed. All available literature was critically examined and available evidence was then classified according to its strength. The whole document and the recommendations were then discussed in details by members and consensus was obtained. All recommendations in these guidelines were based on the best available evidence, but were tailored to the patients treated in Saudi Arabia. We hope that these guidelines will improve HCC patient care and enhance the multidisciplinary care needed for these patients.