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1. Introduction The high intake of nitrate has led to growing con- cern about the health risks, based on the risk of the metabolite of nitrate, nitrite. This concern focuses mainly on the risk of gastric cancer [l]. Nitrate is a natural compound of foods like vegetables and pota- toes and in the Netherlands it is used as food additive in cheese and cured meats. It is also present in drink- ing water [2]. The proposed mechanism by which nitrate can be converted to carcinogenic N-nitroso compounds contains the following steps. After inges- tion and absorption in the stomach, nitrate is secreted in the saliva in concentrated form. Oral bacteria can then reduce nitrate to nitrite. About 25% of ingested nitrate is recirculated into the saliva and about 20% of the salivary nitrate is reduced to nitrite by oral bac- teria. Next, nitrite can react with nitrosatable com- pounds like amines, amides and aminoacids to N- nitroso compounds [3]. Ascorbic acid acts as inhibitor ~

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Upon investigation, it was discovered that 5 figures contain fabrication. Figures 1C, 3D, 5C, 5D, and 6G contain manipulated and/or duplicated data. The authors requested a corrigendum be published, however, due to the large number of corrections applied (Figs. 3, 6, 7, 8 and S3), it cannot be concluded that these changes would not alter the conclusions of the paper. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

The crosstalk between the transformed tumoral cells and their microenvironment is a key aspect for pancreatic ductal adenocarcinoma (PDAC) progression. This molecular dialog is intensively studied because it may result in an efficient therapeutic target. Contrary to this near microenvironment, the stromal portion in direct contact with the transformed cells, a far microenvironment, placed at the periphery of the tumor mass, produces factors signaling tumors. Among these factors, REG3β, produced by this part of the pancreas, is an important factor in promoting tumor progression. This paper demonstrated that targeting REG3β protein with specific antibodies limits the PDAC tumor growth in an orthotopic, syngeneic mice model induced by injection of Panc02 cells. Then, we showed that CTGF is over-expressed in response to REG3β in PDAC-derived cells. Moreover, inactivation of REG3β by treating tumors with anti-REG3β antibodies results in a strong decrease of CTGF in PDAC tumors. Lastly, we demonstrated that forced expression of CTGF in xenografted Panc02 cells abolishes the therapeutic effect of the anti-REG3β antibody treatment. Altogether, these results indicate that the effect of REG3β in promoting PDAC progression is mediated by CTGF over-activation. Thus, REG3β is a promising therapeutic target to treat PDAC with an original rationale. In conclusion, we demonstrated that the far microenvironment is essential for PDAC progression by producing active secretory factors, and some of them could be used as therapeutic targets., This work was supported by La Ligue Contre le Cancer, INCa, Canceropole PACA, and INSERM.

The authors regret not having included the following funding in the paper “Spanish Society of Neumology and Thoracic Surgery”. Project number 848. 2019 call. The authors would like to apologise for any inconvenience caused.

The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas provided recommendations for diagnostic and therapeutic procedures. The Panel covered all fields of expertise in neuro-oncology, i.e. neurosurgeons, neurologists, neuropathologists, neuroradiologists, radiation and medical oncologists and clinical trial experts. The task made clearer and more transparent choices about outcomes considered most relevant through searching the references considered most relevant and evaluating their value. The scientific evidence of papers collected from the literature was evaluated and graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and recommendations were given accordingly. The recommendations will provide a framework and assurance for the strategy of diagnostic and therapeutic measures to reduce complications from unnecessary treatment and cost. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China.

Osteosarcoma (OS) is the most frequent paediatric bone cancer, responsible for 9% of all cancer-related deaths in children. In this paper, a new strategy based on delivering edelfosine (ET) in lipid nanoparticles (LN) was explored in order to target the primary tumour and eliminate metastases. The in vitro and in vivo efficacy of the free drug, drug loaded into lipid nanoparticles (ET-LN) and doxorubicin (DOX) against osteosarcoma (OS) cells was analysed. ET and ET-LN decreased the growth of OS cells in vitro in a time- and dose-dependent manner. Interestingly, the uptake of ET and ET-LN was lower when OS cells were pre-treated with DOX. In vivo studies revealed that ET and ET-LN slowed down the primary tumour growth in two OS models. However, the combination of both drugs showed no additional anti-tumour effect. Importantly, ET-LN successfully prevented the metastatic spread of OS cells from the primary tumour to the lungs. On the whole, ET-LN are a promising candidate for OS chemotherapy.

The recent demonstration of a role of Escherichia coli in the development of invasive carcinoma in mice ushers a new era of bacterial involvement in cancer etiology. It has been shown previously that the colonic mucosa of colorectal carcinoma (CRC) is exclusively colonized by intracellular E. coli instead of extracellular form found in normal colonic mucosa. Surprisingly, the DNA repair gene MUTYH, which is a homologue of the E. coli gene mutY, is responsible for CRC. The current paper discusses the potential role of mutY in CRC etiology and concludes that research in this area can bring together the diverse threads of the CRC etiology puzzle.

Metabolites of tobacco smoke constituents can be quantified in urine and other body fluids providing a realistic measure of carcinogen and toxicant dose in a smoker. Many previous studies have demonstrated that these metabolites – referred to as biomarkers in this paper – are related to tobacco smoke exposure. The studies reviewed here were designed to answer another question: are these substances also biomarkers of cancer risk? Using a prospective study design comparing biomarker levels in cancer cases and controls, all of whom were smokers, the results demonstrate that several of these biomarkers – total cotinine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), and total N’-nitrosonornicotine (NNN) - are biomarkers of cancer risk. Therefore, these biomarkers have the potential to become part of a cancer risk prediction algorithm for smokers.

Base excision repair is the system used from bacteria to man to remove the tens of thousands of endogenous DNA damages produced daily in each human cell. Base excision repair is required for normal mammalian development and defects have been associated with neurological disorders and cancer. In this paper we provide an overview of short patch base excision repair in humans and summarize current knowledge of defects in base excision repair in mouse models and functional studies on short patch base excision repair germ line polymorphisms and their relationship to cancer. The biallelic germ line mutations that result in MUTYH-associated colon cancer are also discussed.

Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet.

In this paper we studied the in vivo neoadjuvant Androgen Deprivation Therapy (ADT) effect on the expression of TGF-β1 and its receptor Tβ-RII. Mechanisms of androgen dependence are critical to understanding prostate cancer progression to androgen independence associated with disease mortality, and TGF-β is thought to support prostatic apoptosis as its expression coincides with androgen ablation in benign and cancer tissues. Increase of both mRNA and protein level were shown for the first time only in the patients who underwent neoadjuvant ADT for 1-month. This transient increase of TGF-β expression after androgen ablation suggested cooperation of the pathways in prostate regression. Since no alteration was observed in the gene transcriptional activity, the molecular mechanism of this cooperation, probably act at the post-transcriptional level. TGF-β1 and Tβ-RII specific signals were co-localized within the neoplastic prostate epithelium. Our results suggests that the androgens deprivation by means of ADT for 1-month, involves a shift of the TGF-β1 mechanism in prostate cancer, suggesting that the TGF-β1 promotes prostate epithelial cell proliferation and inhibits apoptosis in a autocrine way.

This paper reviews published studies of a possible relationship of consumption of methylxanthine-containing beverages, primarily coffee, to risk of pancreatic cancer (PC). Certain ecologic studies suggested a possible relation of pancreatic cancer mortality and coffee consumption by country. The findings from case-control studies are not entirely consistent; in general, no significant increased risk with a clear dose-response relationship is reported, but some of the studies suggest the possibility of some increase in risk. The prospective studies reported gererally agree that there is no significant association of coffee consumption with increased risk of PC. The few data available on tea consumption do not suggest an increased risk of PC. It seems reasonable to conclude that current epidemiologic evidence does not suggest any significant increased risk of PC with coffee consumption. Further research might clarify whether the divergent results reported for coffee consumption might be a result of confounding or other methodologic problems or might reflect some small but real increase in risk of PC associated with coffee consumption.

Since first described in a rodent model in 1987, aberrant crypt foci (ACF) in the colon have been shown to exhibit many of the molecular features of the more advanced colonic neoplasms including cancer. Therefore, they may be early lesions with potential for progression, and be valuable biomarkers for reduction of risk of colorectal cancer (CRC). For this review, we searched PubMed, and reference lists of recent publications, for studies which reported on associations of features of ACF in humans, such as number or size, with subject characteristics, such as age or family history of CRC. Over 150 papers have reported on ACF in humans. However, the vast majority of these publications are concerned with molecular and morphological features of biopsied lesions, and not their epidemiology. None of the epidemiological studies were of optimum design, primarily due to their absence of a well-defined subject sampling frame or method. Given their ‘first-generation’ nature, consistent findings were of increased ACF number with age and with synchronous advanced colonic neoplasia. One study reported a higher mean number of ACF in subjects with a family history of CRC than in those without. The strongest evidence on the ability of ACF to predict a diagnosis of CRC will be from prospective studies with baseline ACF assessment in a large sample of disease-free persons (many thousands) who are followed carefully for many years. In the interim, because ACF are asymptomatic, well-designed cross-sectional studies are feasible and will yield valuable information on the relation of ACF to the known risk factors for CRC. This information can then be used to improve the design of prospective studies, and of clinical intervention trials that use ACF as an intermediate endpoint.

Treatment of estrogen-sensitive breast cancer with selective estrogen selective modulators (SERMs) and, more recently, aromatase inhibitors has met with wide success. However, antagonism of estrogen receptor (ER) activity in breast carcinomas by SERMs such as tamoxifen has been associated with increased risk of cancer in other tissue such as the endometrium. Furthermore, current therapies using aromatase inhibitors have side effects on bone resulting in development of osteoporosis in some patients. We present in this paper the results of a study using 4-chlorophenylacetate (4-CPA), a compound which belongs to a family of small aromatic fatty acids that has been shown to possess anticancer properties, to treat DMBA exposed MMTV-aromatase mice. These animals exhibit elevated levels of estrogen in their mammary glands and develop estrogen-responsive tumors. Consistent with our earlier findings showing that 4-CPA inhibited the growth of ER positive breast cancer cells in vitro, we now demonstrate that this compound inhibits tumor formation in MMTV-aromatase mice. This effect was not associated with reduction of ER expression in their mammary tissue, or to alteration of aromatase levels or activity. The data suggest that 4-CPA is a novel therapeutic agent that could be used in the prevention or treatment of estrogen-sensitive breast cancer.

Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate into mature hepatocytes or biliary epithelial cells (BECs). They are thought to be involved in repair of liver injury and the incidence of hepatic carcinoma. Their physiology is closely associated with the microenvironment where they reside. Lipopolysaccharide (LPS), an important component of the hepatic pathological microenvironment, is stored in the liver and affects many types of cells in various hepatosis. HPCs may also be influenced by LPS. In this paper, mouse ED13.5 E-cadherin+ foetal liver cells were isolated as mouse hepatic progenitor cells (mHPCs). Proliferation of mHPCs was promoted under LPS conditions both in vivo and in vitro. Moreover, LPS enhanced colony formation ability of mHPCs, and blocked them differentiation into mature hepatocytes and formation of a bile duct-liked structure. More importantly, long-term treatment with LPS promoted tumorigenesis of mHPCs in nude mice. Thus, we conclude that LPS may promote aberrant proliferation of mHPCs and restrict their normal differentiation. Long-term exposure of mHPCs to LPS increased the risk of tumour formation. These data provide insight into the links between LPS, HPCs fate, and tumorigenesis, and present novel insight into the relationship between HPCs and their microenvironment.