Showing papers in "International Journal of Cancer in 2012"

Human papillomavirus types in 115,789 HPV‐positive women: A meta‐analysis from cervical infection to cancer

Abstract: Genotyping may improve risk stratification of high-risk (HR) human papillomavirus (HPV)-positive women in cervical screening programs; however, prospective data comparing the natural history and carcinogenic potential of individual HR types remain limited. A meta-analysis of cross-sectional HR HPV-type distribution in 115,789 HPV-positive women was performed, including 33,154 normal cytology, 6,810 atypical squamous cells of undetermined significance (ASCUS), 13,480 low-grade squamous intraepithelial lesions (LSIL) and 6,616 high-grade SIL (HSIL) diagnosed cytologically, 8,106 cervical intraepithelial neoplasia grade 1 (CIN1), 4,068 CIN2 and 10,753 CIN3 diagnosed histologically and 36,374 invasive cervical cancers (ICCs) from 423 PCR-based studies worldwide. No strong differences in HPV-type distribution were apparent between normal cytology, ASCUS, LSIL or CIN1. However, HPV16 positivity increased steeply from normal/ASCUS/LSIL/CIN1 (20-28%), through CIN2/HSIL (40/47%) to CIN3/ICC (58/63%). HPV16, 18 and 45 accounted for a greater or equal proportion of HPV infections in ICC compared to normal cytology (ICC:normal ratios = 3.07, 1.87 and 1.10, respectively) and to CIN3 (ICC:CIN3 ratios = 1.08, 2.11 and 1.47, respectively). Other HR types accounted for important proportions of HPV-positive CIN2 and CIN3, but their contribution dropped in ICC, with ICC:normal ratios ranging from 0.94 for HPV33 down to 0.16 for HPV51. ICC:normal ratios were particularly high for HPV45 in Africa (1.85) and South/Central America (1.79) and for HPV58 in Eastern Asia (1.36). ASCUS and LSIL appear proxies of HPV infection rather than cancer precursors, and even CIN3 is not entirely representative of the types causing ICC. HPV16 in particular, but also HPV18 and 45, warrant special attention in HPV-based screening programs.

Cellular senescence and tumor suppressor gene p16.

Abstract: Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16-mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1 and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16.

ROS implication in a new antitumor strategy based on non-thermal plasma.

Abstract: Non-thermal plasma (NTP) is generated by ionizing neutral gas molecules/atoms leading to a highly reactive gas at ambient temperature containing excited molecules, reactive species and generating transient electric fields. Given its potential to interact with tissue or cells without a significant temperature increase, NTP appears as a promising approach for the treatment of various diseases including cancer. The aim of our study was to evaluate the interest of NTP both in vitro and in vivo. To this end, we evaluated the antitumor activity of NTP in vitro on two human cancer cell lines (glioblastoma U87MG and colorectal carcinoma HCT-116). Our data showed that NTP generated a large amount of reactive oxygen species (ROS), leading to the formation of DNA damages. This resulted in a multiphase cell cycle arrest and a subsequent apoptosis induction. In addition, in vivo experiments on U87MG bearing mice showed that NTP induced a reduction of bioluminescence and tumor volume as compared to nontreated mice. An induction of apoptosis was also observed together with an accumulation of cells in S phase of the cell cycle suggesting an arrest of tumor proliferation. In conclusion, we demonstrated here that the potential of NTP to generate ROS renders this strategy particularly promising in the context of tumor treatment.

Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies

Abstract: Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8-143.2) for SqCC, 111.3 (95% CI: 69.8-177.5) for SCLC and 21.9 (95% CI: 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5-124.6), 108.6 (95% CI: 50.7-232.8) and 16.8 (95% CI: 9.2-30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

Lung Carcinogenesis by Tobacco Smoke

Abstract: Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.

Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies.

Abstract: In recent years, increasing evidence has suggested a strong association between diabetes mellitus (DM) and hepatocellular carcinoma (HCC). To provide a quantitative assessment of this association, we performed a systematic review and meta-analysis of cohort studies. We collected studies through a literature search of Medline from January 1, 1966 and EMBASE from January 1, 1974, through July 31, 2010. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 25 cohort studies that met our inclusion and exclusion criteria were included in our analysis. Among these, 18 studies showed that DM was associated with an increased incidence of HCC (SRRs = 2.01, 95% CI: 1.61–2.51), compared with individuals without DM. There was a statistically significant heterogeneity among these studies (Q = 136.68, p < 0.001, I2 = 87.6%). Analyses subgrouped by controlling confounders revealed that the increased incidence of HCC was independent of geographic location, alcohol consumption, history of cirrhosis, or infections with hepatitis B (HBV) or hepatitis C virus (HCV). In addition, DM was also positively associated with HCC mortality (SRR = 1.56; 95% CI: 1.30–1.87), with no significant evidence of heterogeneity among studies (Q = 1.16, p = 0.56, I2 =0%). There were no significant publication bias (p = 0.79 for Egger's regression asymmetry test). These findings strongly support a positive association between DM and increased risk of HCC in both males and females.

Tumor-platelet interaction in solid tumors.

Abstract: Elevated platelet counts in patients diagnosed with malignant tumors were first described more than 100 years ago. Today it is well known that in many types of solid tumors, thrombocytosis at the time of diagnosis is associated with shorter survival. From this well-documented clinical correlation between platelet count and prognosis of solid tumors, the following questions arise: (i) Are the increased platelet counts the reason for shortened survival as platelet-secreted cytokines might boost tumor growth and angiogenesis? (ii) Do platelets affect tumor metastasis thereby shortening survival time? or (iii) Are increased platelet counts simply an epiphenomenon of tumor growth with larger tumors resulting in higher platelet counts and shorter survival times? We address these three questions within our review of the current literature to provide a comprehensive overview of the current concepts in tumor-platelet interaction.

Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer.

Abstract: Circulating micro-RNA (miR) profiles have been proposed as promising diagnostic and prognostic biomarkers for cancer, including lung cancer. We have developed methods to accurately and reproducibly measure micro-RNA levels in serum and plasma. Here, we study paired serum and plasma samples from 220 patients with early stage nonsmall cell lung cancer (NSCLC) and 220 matched controls. We use qRT-PCR to measure the circulating levels of 30 different miRs that have previously been reported to be differently expressed in lung cancer tissue. Duplicate RNA extractions were performed for 10% of all samples, and micro-RNA measurements were highly correlated among those duplicates. This demonstrates high reproducibility of our assay. The expressions of miR-146b, miR-221, let-7a, miR-155, miR-17-5p, miR-27a and miR-106a were significantly reduced in the serum of NSCLC cases, while miR-29c was significantly increased. No significant differences were observed in plasma of patients compared with controls. Overall, expression levels in serum did not correlate well with levels in plasma. In secondary analyses, reduced plasma expression of let-7b was modestly associated with worse cancer-specific mortality in all patients, and reduced serum expression of miR-223 was modestly associated with cancer-specific mortality in stage IA/B patients. MiR profiles also showed considerable differences comparing African American and European Americans. In summary, we found significant differences in miR expression when comparing cases and controls and find evidence that expression of let-7b is associated with prognosis in NSCLC.

MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer.

Abstract: MicroRNAs (miRNAs) are small non-coding RNAs which regulate gene expression by base-pairing to the 3′-UTR of the target mRNA Recently, miRNAs have been shown to regulate cancer metastasis, however, central molecular mechanisms of this ability still need to be investigated Epithelial to mesenchymal transition (EMT), which is characterized especially by repression of E-cadherin expression and increased cell motility, is an essential component of cancer metastasis and progression In the present study, we found that Snai1, a known transcriptional repressor of E-cadherin and modulator of EMT, is post-transcriptionally targeted by miRNA-30a in non-small cell lung cancer (NSCLC) Consistent with this, microRNA-30a expression was found inversely proportional to the invasive potential of various NSCLC cell lines, correlating positively with E-cadherin (epithelial marker) and negatively with N-cadherin (mesenchymal marker) expression Forced re-introduction of miR-30a significantly altered cell morphology, in vitro invasion and migration of invasive cell lines, this being paralleled by a downregulation of Snai1 and upregulation of E-cadherin expression Using a chicken embryonic metastasis assay, we found that miR-30a suppresses in vivo distant metastasis to the lungs and liver Finally, we screened the expression of miR-30a in 64 consecutively resected NSCLC patients and found that, in 81% of the patients, expression of miR-30a was downregulated significantly (p < 00001) in tumors compared to corresponding normal tissues These results suggest that miR-30a targets Snai1, inhibits invasion and metastasis, and is downregulated in NSCLC

Colon cancer associated transcript-1: A novel RNA expressed in malignant and pre-malignant human tissues

Abstract: Early detection of colorectal cancer (CRC) is currently based on fecal occult blood testing (FOBT) and colonoscopy, both which can significantly reduce CRC-related mortality. However, FOBT has low-sensitivity and specificity, whereas colonoscopy is labor- and cost-intensive. Therefore, the discovery of novel biomarkers that can be used for improved CRC screening, diagnosis, staging and as targets for novel therapies is of utmost importance. To identify novel CRC biomarkers we utilized representational difference analysis (RDA) and characterized a colon cancer associated transcript (CCAT1), demonstrating consistently strong expression in adenocarcinoma of the colon, while being largely undetectable in normal human tissues (p < 000.1). CCAT1 levels in CRC are on average 235-fold higher than those found in normal mucosa. Importantly, CCAT1 is strongly expressed in tissues representing the early phase of tumorigenesis: in adenomatous polyps and in tumor-proximal colonic epithelium, as well as in later stages of the disease (liver metastasis, for example). In CRC-associated lymph nodes, CCAT1 overexpression is detectable in all H&E positive, and 40.0% of H&E and immunohistochemistry negative lymph nodes, suggesting very high sensitivity. CCAT1 is also overexpressed in 40.0% of peripheral blood samples of patients with CRC but not in healthy controls. CCAT1 is therefore a highly specific and readily detectable marker for CRC and tumor-associated tissues.

Identification of ten serum microRNAs from a genome‐wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis

Abstract: The detection of nonsmall cell lung cancer (NSCLC) at an early stage presents a daunting challenge due to the lack of a specific noninvasive marker. The discovery of microRNAs (miRNAs), particularly those found in serum, has opened a new avenue for tumor diagnosis. To determine whether the expression profile of serum miRNAs can serve as a NSCLC fingerprint, we performed Taqman probe-based quantitative RT-PCR assay to selected differentially expressed serum miRNAs from a sample set including 400 NSCLC cases and 220 controls, and risk score analysis to evaluate the diagnostic value of the serum miRNA profiling system. After a two-phase selection and validation process, 10 miRNAs were found to have significantly different expression levels in NSCLC serum samples compared with the control serum samples. Risk score analysis showed that this panel of miRNAs was able to distinguish NSCLC cases from controls with high sensitivity and specificity. Under ROC curves, the AUC for tumor identification in training set and validation set were 0.966 and 0.972, respectively. Furthermore, the expression profile of the 10-serum miRNAs was correlated with the stage of NSCLC patients, especially in younger patients and patients with current smoking habits. More importantly, the serum miRNA-based biomarker for early NSCLC detection was supported by a retrospective analysis in which the 10-serum miRNA profile could accurately classify serum samples collected up to 33 months ahead of the clinical NSCLC diagnosis. Taken together, we demonstrate that the profiling of 10-serum miRNAs provides a novel noninvasive biomarker for NSCLC diagnosis.

Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer

Abstract: This study was performed to identify plasma microRNAs (miRNAs) as diagnostic biomarkers for pancreatic cancer (PCa) and to assess their supplementary role with serum CA19-9 in early identification of tumors. Plasma RNAs were extracted from 140 PCa patients, 111 chronic pancreatitis (CP) patients and 68 normal controls, and the relative abundances of seven miRNAs (miR-16, 21, 155, 181a, 181b, 196a and 210) were measured using real-time PCR. Their diagnostic utility for PCa and correlation with clinical characteristics were analyzed. All seven miRNAs were significantly aberrantly upregulated in the PCa group compared with both the CP and normal groups, between which only four miRNAs (miR-155, 181a, 181b and 196a) were significantly different. Logistic modeling proved that only miR-16 and miR-196a possessed an independent role in discriminating PCa from normal and CP. Furthermore, after including serum CA19-9 in the logistic model, the combination of miR-16, miR-196a and CA19-9 was more effective for discriminating PCa from non-PCa (normal+CP) (AUC-ROC, 0.979; sensitivity, 92.0%; specificity, 95.6%), and for discriminating PCa from CP (AUC-ROC, 0.956; sensitivity, 88.4%; specificity, 96.3%) compared with the miRNA panel (miR-16+miR-196a) or CA19-9 alone. Most significantly, the combination was effective at identification of tumors in Stage 1 (85.2%). In conclusion, plasma miRNAs were effective for distinguishing PCa from non-PCa (normal+CP). The combination of miR-16, miR-196a and CA19-9 was more effective for PCa diagnosis, especially in early tumor screening.

Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents*

Abstract: Surgery is of paramount importance in the management of solid tumors as definitive resection can be totally curative. Nonetheless, metastatic recurrence after surgery remains a major cause of morbidity and mortality. Interest in the impact of the perioperative period on cancer recurrence is now growing rapidly, with recent research suggesting that some anesthetics or anesthetic techniques may influence the pathophysiology of postoperative metastatic spread. Our review examines the most widely postulated mechanisms for this, including the impact of anesthesia on neuroendocrine and immune function. We also consider evidence for a direct impact on tumor cell signaling pathways based on findings from organ protection research. These studies have demonstrated that certain volatile anaesthetics confer cytoprotective properties to exposed cells and lead to significant upregulation of Hypoxia Inducible Factor-1α (HIF-1α). This ubiquitous transcription factor exerts many effects in cancer: its activity has been linked with more aggressive phenotypes and poorer clinical prognosis. It is proposed that such an upregulation of HIFs in tumor cells by these anesthetics may contribute to a tumor's recurrence by stimulating cytoprotective or protumorigenic behavior in residual cells. Conversely, other anesthetic agents appear to downregulate HIFs or cause negligible effect and thus may prove more suitable for use in cancer surgery. As anesthetic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastases, there is an urgent need to determine the most appropriate anesthetic strategy for surgical oncology so that the optimal techniques are used to maximize long-term survival.

Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells.

Abstract: Identification of cancer stem cells is crucial for advancing cancer biology and therapy. Several markers including CD24, CD44, CD117, CD133, the G subfamily of ATP-binding cassette transporters (ABCG), epithelial specific antigen (ESA) and aldehyde dehydrogenase (ALDH) are used to identify and investigate human epithelial cancer stem cells in the literature. We have now systemically analyzed and compared the expression of these markers in fresh ovarian epithelial carcinomas. Although the expression levels of these markers were unexpectedly variable and partially overlapping in fresh ovarian cancer cells from different donors, we reliably detected important levels of CD133 and ALDH in the majority of fresh ovarian cancer. Furthermore, most of these stem cell markers including CD133 and ALDH were gradually lost following in vitro passage of primary tumor cells. However, the expression of ALDH and CD133, but not CD24, CD44 and CD117, could be partially rescued by the in vitro serum-free and sphere cultures and by the in vivo passage in the immune-deficient xenografts. ALDH+ and CD133+ cells formed three-dimensional spheres more efficiently than their negative counterparts. These sphere-forming cells expressed high levels of stem cell core gene transcripts and could be expanded and form additional spheres in long-term culture. ALDH+ , CD133+ and ALDH+ CD133+ cells from fresh tumors developed larger tumors more rapidly than their negative counterparts. This property was preserved in the xenografted tumors. Altogether, the data suggest that ALDH+ and CD133+ cells are enriched with ovarian cancer-initiating (stem) cells and that ALDH and CD133 may be widely used as reliable markers to investigate ovarian cancer stem cell biology.

Progress in colorectal cancer survival in Europe from the late 1980s to the early 21st century: The EUROCARE study

Abstract: Colorectal cancer (CRC) is the second most common cause of death due to cancer causing death in Europe, accounting for more than 200,000 deaths per year. Prognosis strongly depends on stage at diagnosis, and the disease can be cured in most cases if diagnosed at an early stage. We aimed to assess trends and recent developments in 5-year relative survival in European countries, with a special focus on age, stage at diagnosis and anatomical cancer subsite. Data from 25 population-based cancer registries from 16 European countries collected in the context of the EUROCARE-4 project were analyzed. Using period analysis, age-adjusted and age-specific 5-year relative survival was calculated by country, European region, stage and cancer subsite for time periods from 1988-1990 to 2000-2002. Survival substantially increased over time in all European regions. In general, increases were more pronounced in younger than in older patients, for earlier than for more advanced cancer stages and for rectum than for colon cancer. Substantial variation of CRC survival between European countries and between age groups persisted and even tentatively increased over time. There is a huge potential for reducing the burden of CRC in Europe by more widespread and equal delivery of existing options of effective early detection and curative treatment to the European population.

Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma.

Abstract: Multikinase inhibitor sorafenib inhibits proliferation and angiogenesis of tumors by suppressing the Raf/MEK/ERK signaling pathway and VEGF receptor tyrosine kinase. It significantly prolongs median survival of patients with advanced hepatocellular carcinoma (HCC) but the response is disease-stabilizing and cytostatic rather than one of tumor regression. To examine the mechanisms underlying the relative resistance in HCC, we investigated the role of autophagy, an evolutionarily conserved self-digestion pathway, in hepatoma cells in vitro and in vivo. Sorafenib treatment led to accumulation of autophagosomes as evidenced by conversion from LC3-I to LC3-II observed by immunoblot in Huh7, HLF and PLC/PRF/5 cells. This induction was due to activation of autophagic flux, as there was further increase in LC3-II expression upon treatment with lysosomal inhibitors, clear decline of the autophagy substrate p62, and an mRFP-GFP-LC3 fluorescence change in sorafenib-treated hepatoma cells. Sorafenib inhibited the mammalian target of rapamycin complex 1 and its inhibition led to accumulation of LC3-II. Pharmacological inhibition of autophagic flux by chloroquine increased apoptosis and decreased cell viability in hepatoma cells. siRNA-mediated knockdown of the ATG7 gene also sensitized hepatoma cells to sorafenib. Finally, sorafenib induced autophagy in Huh7 xenograft tumors in nude mice and coadministration with chloroquine significantly suppressed tumor growth compared with sorafenib alone. In conclusion, sorafenib administration induced autophagosome formation and enhanced autophagic activity, which conferred a survival advantage to hepatoma cells. Concomitant inhibition of autophagy may be an attractive strategy for unlocking the antitumor potential of sorafenib in HCC.

Predictive impact of MGMT promoter methylation in glioblastoma of the elderly

Abstract: O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation identifies a subpopulation of glioblastoma patients with more favorable prognosis and predicts a benefit from alkylating agent chemotherapy (CT). Little is known about its prevalence and clinical significance in older glioblastoma patients. We studied 233 glioblastoma patients aged 70 years or more (144 males, 89 females, median age: 74 years, range: 70.0-86.6 years), who were prospectively enrolled in the German Glioma Network, for MGMT promoter methylation by methylation-specific PCR (MSP) in all patients and DNA pyrosequencing in 166 patients. MGMT data were correlated with patient outcome. Median progression-free survival (PFS) was 4.8 months (95% CI: 4.3-5.3) and median overall survival (OS) was 7.7 months (95% CI: 6.3-9.0). MGMT promoter methylation was detected by MSP in 134 patients (57.5%). For the whole cohort, PFS was 5.2 versus 4.7 months (p = 0.207) and OS was 8.4 versus 6.4 months (p = 0.031) in patients with versus without MGMT promoter methylation. Patients with MGMT methylated tumors had longer PFS when treated with radiotherapy (RT) plus CT or CT alone compared to patients treated with RT alone. Patients with MGMT unmethylated tumors appeared to derive no survival benefit from CT, regardless of whether given at diagnosis together with RT or as a salvage treatment. Patients treated with RT plus CT or CT alone demonstrated longer OS when pyrosequencing revealed >25% MGMT methylated alleles. Taken together, MGMT promoter methylation may be a useful biomarker to stratify elderly glioblastoma patients for treatment with versus without alkylating agent CT.

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease

Abstract: The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ~600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer Select/Detect™ versus Veridex CellSearch™ system.

Abstract: The detection of CTCs prior to and during therapy is an independent and strong prognostic marker, and it is predictive of poor treatment outcome. A major challenge is that different technologies are available for isolation and characterization of CTCs in peripheral blood (PB). We compare the CellSearch system and AdnaTest BreastCancer Select/Detect, to evaluate the extent that these assays differ in their ability to detect CTCs in the PB of MBC patients. CTCs in 7.5 ml of PB were isolated and enumerated using the CellSearch, before new treatment. Two cutoff values of ≥2 and ≥5 CTCs/7.5 ml were used. AdnaTest requires 5 ml of PB to detect gene transcripts of tumor markers (GA733-2, MUC-1, and HER2) by RT-PCR. AdnaTest was scored positive if ≥1 of the transcript PCR products for the 3 markers were detected at a concentration ≥0.15 ng/μl. A total of 55 MBC patients were enrolled. 26 (47%) patients were positive for CTCs by the CellSearch (≥2 cutoff), while 20 (36%) were positive (≥5 cutoff). AdnaTest was positive in 29 (53%) with the individual markers being positive in 18% (GA733-2), 44% (MUC-1), and 35% (HER2). Overall positive agreement was 73% for CTC≥2 and 69% for CTC≥5. These preliminary data suggest that the AdnaTest has equivalent sensitivity to that of the CellSearch system in detecting 2 or more CTCs. While there is concordance between these 2 methods, the AdnaTest complements the CellSearch system by improving the overall CTC detection rate and permitting the assessment of genomic markers in CTCs.

Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation

Abstract: Lactic acidosis is common to most solid tumors and has been found to affect infiltrating immune cells Here we document effector phase inhibition of cytotoxic T cells (CTLs) involving complete blockage of cytokine production and partial impairment of lytic granule exocytosis Lactic acidosis impaired TCR-triggered phosphorylation of JNK, c-Jun and p38, while not affecting MEK1 and ERK The select targeting of signaling proteins involved in IFNγ production (JNK/c-Jun, p38) without affecting those jointly used in cytokine regulation and granule exocytosis (MEK1/ERK) explains the observed split effect of lactic acidosis on the CTL responses CTL inhibition by lactic acidosis showed fast dynamics with immediate onset and reversion Functional recovery by neutralizing the extracellular pH despite continuous presence of lactate holds promise that CTL activity can be improved in the milieu of solid tumors with appropriate anti-acidosis treatment, thereby increasing the efficacy of adoptive T cell therapy

Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening.

Abstract: High-risk human papillomavirus (hrHPV) testing has a higher sensitivity but lower specificity than cytology for detection of high-grade intraepithelial neoplasia (CIN). To avoid over-referral to colposcopy and overtreatment, hrHPV-positive women require triage testing and/or followup. A total of 25,658 women (30-60 years) enrolled in a population-based cohort study had an adequate baseline Pap smear and hrHPV test. The end-point was cumulative two-year risk of CIN grade 3 or worse (CIN3+). In a post-hoc analysis, fourteen triage/followup strategies for hrHPV-positive women (n = 1,303) were evaluated for colposcopy referral rate, positive (PPV) and negative predictive value (NPV). Five strategies involved triage testing without a repeat test and nine strategies involved triage testing followed by one repeat testing. The tests were cytology, hrHPV, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping. Results were adjusted for women in the cohort study who did not attend repeat testing. Of the strategies without repeat testing, combined cytology and HPV16/18/31/33/45 genotyping gave the highest NPV of 98.9% (95%CI 97.6-99.5%). The corresponding colposcopy referral rate was 58.1% (95%CI 55.4-60.8%). Eight of the nine strategies with retesting had an estimated NPV of at least 98%. Of those, cytology triage followed by cytology at 12 months had a markedly lower colposcopy referral rate of 33.4% (95%CI 30.2-36.7%) than the other strategies. The NPV of the latter strategy was 99.3% (95%CI 98.1-99.8%). Triage hrHPV-positive women with cytology, followed by repeat cytology testing yielded a high NPV and modest colposcopy referral rate and appear to be the most feasible management strategy.

Incidence and survival of malignant bone sarcomas in England 1979-2007

Abstract: Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between 1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p = 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p 40 years compared with 53% <40 years (p < 0.0001) and 16% non-extremity tumour compared to 48% extremity tumour (p < 0.0001). This population-based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.

An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells.

Abstract: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer that frequently harbours Merkel cell polyomavirus (MCV) DNA integrated in the genome of the tumor cells. In our study, we elaborate our recent finding that MCV-positive MCC cell lines require the expression of the viral T antigens (TA). Indeed, in a xeno-transplantation model, we prove that TA expression is essential also in an in vivo situation, as knock down of TA leads to tumor regression. Moreover, rescuing TA short hairpin RNA (shRNA)-treated MCV-positive MCC cells by ectopic expression of shRNA-insensitive TAs clearly demonstrates that the observed effect is caused by TA knockdown. Notably, introduction of a mutation in the LTA protein interfering with LTA binding to the retinoblastoma protein (RB) ablated this rescue. The importance of this interaction was further confirmed as LTA-specific knockdown leads to explicit cell growth inhibition. In summary, the presented data demonstrate that established MCV-positive MCC tumors critically depend on TA expression, in particular the LTA and RB interaction, for sustained tumor growth. Consequently, interference with LTA/RB interaction appears as promising strategy to treat MCC.

Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics.

Abstract: Activation of the sonic hedgehog (SHh) pathway is required for the growth of numerous tissues and organs and recent evidence indicates that this pathway is often recruited to stimulate growth of cancer stem cells (CSCs) and to orchestrate the reprogramming of cancer cells via epithelial mesenchymal transition (EMT). The objectives of this study were to examine the molecular mechanisms by which (-)-epigallocatechin-3-gallate (EGCG), an active compound in green tea, inhibits self-renewal capacity of pancreatic CSCs and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Our data demonstrated that EGCG inhibited the expression of pluripotency maintaining transcription factors (Nanog, c-Myc and Oct-4) and self-renewal capacity of pancreatic CSCs. Inhibition of Nanog by shRNA enhanced the inhibitory effects of EGCG on self-renewal capacity of CSCs. EGCG inhibited cell proliferation and induced apoptosis by inhibiting the expression of Bcl-2 and XIAP and activating caspase-3. Interestingly, EGCG also inhibited the components of SHh pathway (smoothened, patched, Gli1 and Gli2) and Gli transcriptional activity. Furthermore, EGCG inhibited EMT by inhibiting the expression of Snail, Slug and ZEB1, and TCF/LEF transcriptional activity, which correlated with significantly reduced CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Furthermore, combination of quercetin with EGCG had synergistic inhibitory effects on self-renewal capacity of CSCs through attenuation of TCF/LEF and Gli activities. Since aberrant SHh signaling occurs in pancreatic tumorigenesis, therapeutics that target SHh pathway may improve the outcomes of patients with pancreatic cancer by targeting CSCs.

A million africans a year dying from cancer by 2030: what can cancer research and control offer to the continent?

Abstract: In Africa, there were an estimated 681,000 new cancer cases and 512,000 deaths in 2008. Projections to 2030 show a startling rise, with corresponding figures of 1.27 million cases and 0.97 million deaths resulting from population growth and aging alone. The figures make no assumptions about incidence rates which may increase due to the further introduction of tobacco and a more westernized lifestyle. The current situation in many parts of Africa with respect to health care systems suggests that improved cancer treatment would be an insufficient response to this increasing burden. Much could be achieved through cancer prevention by applying current knowledge about major risk factors and the natural history of the disease. For example, vaccination against hepatitis B virus and human papilloma viruses would prevent the occurrence of two of the most common cancers in Africa, liver and cervix, respectively, in the long-term. Strong measures to prevent the widespread introduction of tobacco must be a priority. Early detection and treatment of cervical and breast cancers using approaches applicable now in Africa would provide immediate value, as would the management of human immunodeficiency virus (HIV) infection in respect to HIV-associated malignancies. In parallel, further research is needed into the causes of cancer and the barriers to implementation of promising prevention strategies. Underpinning all is the need for African governments to look forward and prioritize cancer through national cancer control plans, to invest in public health infrastructure and to ensure the adequate training and support for people in cancer prevention and control. Given this core commitment from within Africa, international partners can provide complementary support in a cooperation that permits action now to mitigate the impending tragedy of cancer in the continent of Africa.

The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus

Abstract: Metformin use has been associated with decreased cancer risk and mortality. However, the effects of metformin on clinical outcomes of colorectal cancer (CRC) are not defined. This study aimed to evaluate the association between metformin use and mortality of CRC in diabetic patients. We identified 595 patients who were diagnosed both CRC and diabetes mellitus. Patients were compared by two groups; 258 diabetic patients taking metformin and 337 diabetic patients not taking metformin. Patient's demographics, clinical characteristics, overall mortality and CRC-specific mortality were analyzed. After a median follow-up of 41 months, there were 71 total deaths (27.5%) and 55 CRC-specific deaths (21.3%) among 258 patients who used metformin, compared with 136 total deaths (40.4%) and 104 CRC-specific deaths (30.9%) among 337 patients who did not use metformin. Metformin use was associated with decreased overall mortality (p = 0.018) and CRC-specific mortality (p = 0.042) by univariate analysis. After adjustment for clinically relevant factors, metformin use showed lower risk of overall mortality (HR, 0.66; 95% CI 0.476-0.923; p = 0.015) and CRC-specific mortality (HR, 0.66; 95% CI 0.45-0.975; p = 0.037) in CRC patients with diabetes. Metformin use in CRC patients with diabetes is associated with lower risk of CRC-specific and overall mortality.

MED12 mutations in uterine fibroids—their relationship to cytogenetic subgroups

Abstract: Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates b-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a ‘‘fibroid-type mutation’’ in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.

Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease.

Abstract: Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.

Clinicopathologic factors associated with HER2-positive gastric cancer and its impact on survival outcomes—A systematic review

Abstract: With the availability of a therapeutic target and an effective agent in trastuzumab, a systematic examination of the literature to investigate the role of human epidermal growth factor 2 (HER2) as a prognostic factor for survival and its association with clinicopathologic markers may improve treatment. An electronic search of the MEDLINE and PubMed databases (January 1990 to January 2011) was undertaken to identify translational studies that correlated HER2 with clinicopathologic markers and/or survival outcome. This review included 49 studies totaling 11,337 patients. Forty-four percent of patients had Stage I/II, and 56% had Stage III/IV disease. Immunohistochemistry was most commonly used to assess HER2 expression, identifying a median rate of 18% (range, 4–53%) of gastric cancer demonstrating HER2 overexpression. In patients with and without HER2 overexpression, the median 3-year disease-free survival rate was 58% (range, 50–88%) and 86% (range, 62–97%), respectively. Of the 35 studies reporting the impact of HER2 overexpression on survival, 20 studies (57%) reported no difference in overall survival, two studies (6%) reported significantly longer overall survival in patients with HER2 overexpression and 13 studies (37%) reported significantly poorer overall survival in patients with HER2 overexpression. The median overall survival and 5-year survival rate was 21 (range, 10–57) months and 42%, and 33 (range, 13–80) months and 52% in patients with and without HER2 overexpression, respectively. HER2 overexpression appears to be associated with poorer survival and with intestinal-type gastric cancer in this group of patients for whom majority undergone curative gastrectomy.

Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer

Abstract: Both cancer-related inflammation and tumor-induced immune suppression are associated with expansion of myeloid cell subsets including myeloid-derived suppressor cells. However, little known regarding characteristics of myeloid cells in patients with bladder cancer. In this study, we analyzed myeloid cells from peripheral blood (PBMC) and tumor tissue that were collected from patients with superficial noninvasive and invasive urothelial carcinomas. Our results demonstrate that PBMC from bladder cancer patients contain two major CD11b myeloid cell subsets: granulocyte-type CD15 high CD33 low cells and monocyte-type CD15 low CD33 high cells. The number of circulating granulocytic but not monocytic myeloid cells in cancer patients was markedly increased when compared to healthy individuals. Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, GCSF, IL-8 and IL-6. Granulocytic myeloid cells were able to inhibit in vitro T cell proliferation through induction of CD4 1 Foxp3 1 T regulatory cells. Analysis of bladder cancer tissues revealed that tumors were infiltrated with monocyte–macrophage CD11b 1 HLA-DR 1 and granulocytic CD11b 1 CD15 1 HLA-DR - myeloid cells. Collectively, this study identifies myeloid cell subsets in patients with bladder cancer. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.