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Showing papers in "International Journal of Cancer in 2015"


Journal ArticleDOI
TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).

24,414 citations


Journal ArticleDOI
TL;DR: The declines in thyroid cancer mortality reflect both variations in risk factor exposure and changes in the diagnosis and treatment of the disease, while the increases in the incidence are likely due to the increase in the detection of this neoplasm over the last few decades.
Abstract: In most areas of the world, thyroid cancer incidence has been appreciably increasing over the last few decades, whereas mortality has steadily declined. We updated global trends in thyroid cancer mortality and incidence using official mortality data from the World Health Organization (1970-2012) and incidence data from the Cancer Incidence in Five Continents (1960-2007). Male mortality declined in all the major countries considered, with annual percent changes around -2/-3% over the last decades. Only in the United States mortality declined up to the mid 1980s and increased thereafter. Similarly, in women mortality declined in most countries considered, with APCs around -2/-5% over the last decades, with the exception of the UK, the United States and Australia, where mortality has been declining up to the late 1980s/late 1990s to level off (or increase) thereafter. In 2008-2012, most countries had mortality rates (age-standardized, world population) between 0.20 and 0.40/100,000 men and 0.20 and 0.60/100,000 women, the highest rates being in Latvia, Hungary, the Republic of Moldova and Israel (over 0.40/100,000) for men and in Ecuador, Colombia and Israel (over 0.60/100,000) for women. In most countries, a steady increase in the incidence of thyroid cancer (mainly papillary carcinomas) was observed in both sexes. The declines in thyroid cancer mortality reflect both variations in risk factor exposure and changes in the diagnosis and treatment of the disease, while the increases in the incidence are likely due to the increase in the detection of this neoplasm over the last few decades.

755 citations


Journal ArticleDOI
TL;DR: The purpose of this short report is to update the attributable fraction (AF) estimate for H. pylori in NCGC, and to reassess the global burden of cancer attributable to H. Pylori as a major cause of cancer.
Abstract: We previously estimated that 660,000 cases of cancer in the year 2008 were attributable to the bacterium Helicobacter pylori (H. pylori), corresponding to 5.2% of the 12.7 million total cancer cases that occurred worldwide. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti-H. pylori antibodies than ELISA, the detection method used in our previous analysis. The purpose of this short report is to update the attributable fraction (AF) estimate for H. pylori after briefly reviewing new evidence, and to reassess the global burden of cancer attributable to H. pylori. We therefore reviewed the literature for studies comparing the risk of developing non-cardia gastric cancer (NCGC) in cases and controls, using both ELISA and multiple antigen immunoblot for detection of H. pylori. The results from prospective studies were combined, and the new pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection-related cancers worldwide. Using the immunoblot-based data, the worldwide AF for H. pylori in NCGC increased from 74.7% to 89.0%. This implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2% instead of 5.2% of all cancers). These updated estimates reinforce the role of H. pylori as a major cause of cancer.

673 citations


Journal ArticleDOI
TL;DR: The poor population survival rates in China emphasize the urgent need for government policy changes and investment to improve health services and increasing access of health service in rural areas and providing basic health‐care to the disadvantaged populations will be essential for reducing this disparity in the future.
Abstract: Limited population-based cancer registry data available in China until now has hampered efforts to inform cancer control policy. Following extensive efforts to improve the systematic cancer surveillance in this country, we report on the largest pooled analysis of cancer survival data in China to date. Of 21 population-based cancer registries, data from 17 registries (n = 138,852 cancer records) were included in the final analysis. Cases were diagnosed in 2003-2005 and followed until the end of 2010. Age-standardized relative survival was calculated using region-specific life tables for all cancers combined and 26 individual cancers. Estimates were further stratified by sex and geographical area. The age-standardized 5-year relative survival for all cancers was 30.9% (95% confidence intervals: 30.6%-31.2%). Female breast cancer had high survival (73.0%) followed by cancers of the colorectum (47.2%), stomach (27.4%), esophagus (20.9%), with lung and liver cancer having poor survival (16.1% and 10.1%), respectively. Survival for women was generally higher than for men. Survival for rural patients was about half that of their urban counterparts for all cancers combined (21.8% vs. 39.5%); the pattern was similar for individual major cancers except esophageal cancer. The poor population survival rates in China emphasize the urgent need for government policy changes and investment to improve health services. While the causes for the striking urban-rural disparities observed are not fully understood, increasing access of health service in rural areas and providing basic health-care to the disadvantaged populations will be essential for reducing this disparity in the future.

508 citations


Journal ArticleDOI
TL;DR: The concomitant evaluation of PaCIC and PaCa‐related miRNA marker panels awaits retrospective analyses of larger cohorts, as it should allow for a highly sensitive, minimally‐invasive PaCa diagnostics.
Abstract: Late diagnosis contributes to pancreatic cancer (PaCa) dismal prognosis, urging for reliable, early detection. Serum-exosome protein and/or miRNA markers might be suitable candidates, which we controlled for patients with PaCa. Protein markers were selected according to expression in exosomes of PaCa cell line culture supernatants, but not healthy donors' serum-exosomes. miRNA was selected according to abundant recovery in microarrays of patients with PaCa, but not healthy donors' serum-exosomes and exosome-depleted serum. According to these preselections, serum-exosomes were tested by flow cytometry for the PaCa-initiating cell (PaCIC) markers CD44v6, Tspan8, EpCAM, MET and CD104. Serum-exosomes and exosome-depleted serum was tested for miR-1246, miR-4644, miR-3976 and miR-4306 recovery by qRT-PCR. The majority (95%) of patients with PaCa (131) and patients with nonPa-malignancies reacted with a panel of anti-CD44v6, -Tspan8, -EpCAM and -CD104. Serum-exosomes of healthy donors' and patients with nonmalignant diseases were not reactive. Recovery was tumor grading and staging independent including early stages. The selected miR-1246, miR-4644, miR-3976 and miR-4306 were significantly upregulated in 83% of PaCa serum-exosomes, but rarely in control groups. These miRNA were also elevated in exosome-depleted serum of patients with PaCa, but at a low level. Concomitant evaluation of PaCIC and miRNA serum-exosome marker panels significantly improved sensitivity (1.00, CI: 0.95-1) with a specificity of 0.80 (CI: 0.67-0.90) for PaCa versus all others groups and of 0.93 (CI: 0.81-0.98) excluding nonPa-malignancies. Thus, the concomitant evaluation of PaCIC and PaCa-related miRNA marker panels awaits retrospective analyses of larger cohorts, as it should allow for a highly sensitive, minimally-invasive PaCa diagnostics.

399 citations


Journal ArticleDOI
TL;DR: The status of population‐based cancer registries worldwide are assessed, the techniques used in CI5 to evaluate their quality are described and the notable variation in the incidence rates of selected cancers contained within Volume X of CI5 is highlighted.
Abstract: Cancer Incidence in Five Continents (CI5), a longstanding collaboration between the International Agency for Research on Cancer and the International Association of Cancer Registries, serves as a unique source of cancer incidence data from high-quality population-based cancer registries around the world. The recent publication of Volume X comprises cancer incidence data from 290 registries covering 424 populations in 68 countries for the registration period 2003-2007. In this article, we assess the status of population-based cancer registries worldwide, describe the techniques used in CI5 to evaluate their quality and highlight the notable variation in the incidence rates of selected cancers contained within Volume X of CI5. We also discuss the Global Initiative for Cancer Registry Development as an international partnership that aims to reduce the disparities in availability of cancer incidence data for cancer control action, particularly in economically transitioning countries, already experiencing a rapid rise in the number of cancer patients annually.

350 citations


Journal ArticleDOI
TL;DR: There is a substantial reservoir of incidental prostate cancer which increases with age, and the high risk of overdiagnosis limits the usefulness of prostate cancer screening.
Abstract: Prostate cancer screening may detect nonprogressive cancers, leading to overdiagnosis and overtreatment. The potential for overdiagnosis can be assessed from the reservoir of prostate cancer in autopsy studies that report incidental prostate cancer rates in men who died of other causes. We aimed to estimate the age-specific incidental cancer prevalence from all published autopsy studies. We identified eligible studies by searches of Medline and Embase, forward and backward citation searches and contacting authors. We screened the titles and abstracts of all articles; checked the full-text articles for eligibility and extracted clinical and pathology data using standardized forms. We extracted mean cancer prevalence, age-specific cancer prevalence and validity measures and then pooled data from all studies using logistic regression models with random effects. The 29 studies included in the review dated from 1948 to 2013. Incidental cancer was detected in all populations, with no obvious time trends in prevalence. Prostate cancer prevalence increased with each decade of age, OR 51.7 (1.6–1.8), and was higher in studies that used the Gleason score, OR 52.0 (1.1–3.7). No other factors were significantly predictive. The estimated mean cancer prevalence increased in a nonlinear fashion from 5% (95% CI: 3–8%) at age 79 years. There was substantial variation between populations in estimated cancer prevalence. There is a substantial reservoir of incidental prostate cancer which increases with age. The high risk of overdiagnosis limits the usefulness of prostate cancer screening.

291 citations


Journal ArticleDOI
TL;DR: The efficacy of various targeted therapies in such disparate tumours suggests that the authors are entering an era in which treatment decisions will be based on tumour molecular abnormality profile or “signature,” rather than tumour tissue type or anatomical site of origin, improving patient prognosis and quality of life.
Abstract: The evolving field of personalised medicine is playing an increasingly important role in cancer prevention, diagnosis, prognosis and therapeutics. Its importance in clinical management is demonstrated by the recent introduction into routine clinical practice of various individualised, molecularly targeted therapies with increased efficacy and/or reduced toxicity. The identification of cancer predisposition genes, such as the BRCA genes in breast cancer, permits screening programmes to identify patients “at-risk” of developing cancer and helps them make decisions on individual risk-modification behaviours. Personalised medicine also plays an increasingly important role in cancer treatment. It is increasingly clear that there are molecularly distinct subtypes of various common cancers, with different therapeutic approaches required for each subtype, for example, the use of the monoclonal antibodies (trastuzumab and cetuximab) in HER2-positive breast cancer and wild-type KRAS colorectal cancer; tyrosine kinase inhibitors (imatinib, gefitinib, erlotinib and crizotinib) in chronic myeloid leukaemia, gastrointestinal stromal tumours and non-small-cell lung cancer and intracellular agents (vemurafenib and olaparib) in metastatic malignant melanoma and ovarian, breast and prostate cancer. The efficacy of various targeted therapies in such disparate tumours suggests that we are entering an era in which treatment decisions will be based on tumour molecular abnormality profile or “signature,” rather than tumour tissue type or anatomical site of origin, improving patient prognosis and quality of life. This mini review focuses on the role of personalised medicine in cancer prevention and treatment as well as its future direction in oncology.

274 citations


Journal ArticleDOI
TL;DR: In view of the results of HPV DNA and high proportion of p16INK4a overexpression, infection by HPV is most likely to be a necessary cause for anal cancers in both men and women.
Abstract: Knowledge about human papillomaviruses (HPV) types involved in anal cancers in some world regions is scanty. Here, we describe the HPV DNA prevalence and type distribution in a series of invasive anal cancers and anal intraepithelial neoplasias (AIN) grades 2/3 from 24 countries. We analyzed 43 AIN 2/3 cases and 496 anal cancers diagnosed from 1986 to 2011. After histopathological evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping was performed using SPF-10/DEIA/LiPA25 system (version 1). A subset of 116 cancers was further tested for p16(INK4a) expression, a cellular surrogate marker for HPV-associated transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance in the anal cancer data set. HPV DNA was detected in 88.3% of anal cancers (95% confidence interval [CI]: 85.1-91.0%) and in 95.3% of AIN 2/3 (95% CI: 84.2-99.4%). Among cancers, the highest prevalence was observed in warty-basaloid subtype of squamous cell carcinomas, in younger patients and in North American geographical region. There were no statistically significant differences in prevalence by gender. HPV16 was the most frequent HPV type detected in both cancers (80.7%) and AIN 2/3 lesions (75.4%). HPV18 was the second most common type in invasive cancers (3.6%). p16(INK4a) overexpression was found in 95% of HPV DNA-positive anal cancers. In view of the results of HPV DNA and high proportion of p16(INK4a) overexpression, infection by HPV is most likely to be a necessary cause for anal cancers in both men and women. The large contribution of HPV16 reinforces the potential impact of HPV vaccines in the prevention of these lesions.

267 citations


Journal ArticleDOI
TL;DR: The presence of F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP‐high lesions, and its positivity increased according to histological grade, suggesting that it may contribute to the progression of coloreCTal neoplasia.
Abstract: Human gut microbiota is being increasingly recognized as a player in colorectal cancers (CRCs). Evidence suggests that Fusobacterium nucleatum (F. nucleatum) may contribute to disease progression and is associated with CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in CRCs; however, to date, there are no reports about the relationship between F. nucleatum and molecular features in the early stage of colorectal tumorigenesis. Therefore, we investigated the presence of F. nucleatum in premalignant colorectal lesions. In total, 465 premalignant lesions (343 serrated lesions and 122 non-serrated adenomas) and 511 CRCs were studied. We determined the presence of F. nucleatum and analyzed its association with molecular features including CIMP, MSI and microRNA-31 status. F. nucleatum was detected in 24% of hyperplastic polyps, 35% of sessile serrated adenomas (SSAs), 30% of traditional serrated adenomas (TSAs) and 33% of non-serrated adenomas. F. nucleatum was more frequently detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions (p = 0.0023). In SSAs, F. nucleatum positivity increased gradually from sigmoid colon to cecum (p = 0.042). F. nucleatum positivity was significantly higher in CRCs (56%) than in premalignant lesions of any histological type (p < 0.0001). In conclusion, F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP-high lesions. Moreover, F. nucleatum positivity increased according to histological grade, suggesting that it may contribute to the progression of colorectal neoplasia. Our data also indicate that F. nucleatum positivity in SSAs may support the "colorectal continuum" concept.

223 citations


Journal ArticleDOI
TL;DR: In this paper, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed, with nearly 100% of cervical, 88% of anal, and <50% of lower genital tract and oropharyngeal cancers attributable to HPV.
Abstract: Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and <50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often, mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet, HPV-related cancer incidence at this site is several-fold higher than at either the anal canal or the penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age-specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts.

Journal ArticleDOI
TL;DR: These main approaches to de‐escalate treatment in HPV‐positive OPSCC are reviewed, the rationale behind them are discussed, and the issues raised by treatment de-escalation are discussed.
Abstract: Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.

Journal ArticleDOI
TL;DR: The prevalence of unsuspected prostate cancer discovered at autopsy among 6,024 men was reviewed, and among men aged 70–79, tumor was found in 36% of Caucasians and 51% of African‐Americans.
Abstract: Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.

Journal ArticleDOI
TL;DR: In this article, the authors investigated whether resistance exercise during chemotherapy provides benefits on fatigue and quality of life (QoL) beyond potential psychosocial effects of group-based interventions, and they found that resistance exercise appeared to mitigate physical fatigue and maintain QoL during chemotherapy beyond psychossocial effects inherent to supervised, groupbased settings.
Abstract: Multiple exercise interventions have shown beneficial effects on fatigue and quality of life (QoL) in cancer patients, but various psychosocial interventions as well. It is unclear to what extent the observed effects of exercise interventions are based on physical adaptations or rather on psychosocial factors associated with supervised, group-based programs. It needs to be determined which aspects of exercise programs are truly effective. Therefore, we aimed to investigate whether resistance exercise during chemotherapy provides benefits on fatigue and QoL beyond potential psychosocial effects of group-based interventions. One-hundred-one breast cancer patients starting chemotherapy were randomly assigned to resistance exercise (EX) or a relaxation control (RC) group. Both interventions were supervised, group-based, 2/week over 12 weeks. The primary endpoint fatigue was assessed with a 20-item multidimensional questionnaire, QoL with the EORTC QLQ-C30/BR23. Analyses of covariance for individual changes from baseline to Week 13 were calculated. In RC, total and physical fatigue worsened during chemotherapy, whereas EX showed no such impairments (between-group p = 0.098 and 0.052 overall, and p = 0.038 and 0.034 among patients without severe baseline depression). Differences regarding affective or cognitive fatigue were not significant. Benefits of EX were also seen to affect role and social function. Effect sizes were between 0.43 and 0.48. Explorative analyses indicated significant effect modification by thyroxin use (p-interaction = 0.044). In conclusion, resistance exercise appeared to mitigate physical fatigue and maintain QoL during chemotherapy beyond psychosocial effects inherent to supervised group-based settings. Thus, resistance exercise could be an integral part of supportive care for breast cancer patients undergoing chemotherapy.

Journal ArticleDOI
TL;DR: A meta‐analysis revealed that four miRNAs could be used as preclinical biomarkers for HCC screening and the expression profile of the eight‐miRNA panel can be used to discriminate HCC patients from cancer‐free controls, and the four‐mi RNA panel (alone or combined with AFP) could be a blood‐based early detection biomarker for H CC screening.
Abstract: The early detection of hepatocellular carcinoma (HCC) presents a challenge because of the lack of specific biomarkers. Serum/ plasma microRNAs (miRNAs) can discriminate HCC patients from controls. We aimed to identify and evaluate HCC-associated plasma miRNAs originating from the liver as early biomarkers for detecting HCC. In this multicenter three-phase study, we first performed screening using both plasma (HCC before and after liver transplantation or liver hepatectomy) and tissue samples (HCC, para-carcinoma and cirrhotic tissues). Then, we evaluated the diagnostic potential of the miRNAs in two case–control studies (training and validation sets). Finally, we used two prospective cohorts to test the potential of the identified miRNAs for the early detection of HCC. During the screening phase, we identified ten miRNAs, eight of which (miR-20a-5p, miR-25-3p,

Journal ArticleDOI
TL;DR: The present review aims to provide a current overview of VCAM‐1 relevance for tumor growth, metastasis, angiogenesis, and related processes to illustrate the intriguing role of VC AM‐1 in cancer disease.
Abstract: Vascular cell adhesion molecule-1 (VCAM-1) first attracted attention more than two decades ago as endothelial adhesion receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM-1 binding to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the only link of VCAM-1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understanding of tumorigenicity and metastasis, an impressive variety of VCAM-1 functionalities in cancer have been elucidated. The present review aims to provide a current overview of VCAM-1 relevance for tumor growth, metastasis, angiogenesis, and related processes. By illustrating the intriguing role of VCAM-1 in cancer disease, VCAM-1 is suggested as a new and up to now underestimated target in cancer treatment and in clinical diagnosis of malignancies.

Journal ArticleDOI
TL;DR: The therapeutic activity of NDV against GL261 tumors, evidenced in an orthotopic mouse model, is described for the first time, and the importance of a functional adaptive immune system in this paradigm was demonstrated in immunodeficient Rag2−/− mice and in CD8+ T cell depleted animals, where NDV slightly prolonged survival, but failed to induce long‐term cure.
Abstract: The oncolytic features of several naturally oncolytic viruses have been shown on Glioblastoma Multiforme cell lines and in xenotransplant models. However, orthotopic glioma studies in immunocompetent animals are lacking. Here we investigated Newcastle disease virus (NDV) in the orthotopic, syngeneic murine GL261 model. Seven days after tumor induction, mice received NDV intratumorally. Treatment significantly prolonged median survival and 50% of animals showed long-term survival. We demonstrated immunogenic cell death (ICD) induction in GL261 cells after NDV infection, comprising calreticulin surface exposure, release of HMGB1 and increased PMEL17 cancer antigen expression. Uniquely, we found absence of secreted ATP. NDV-induced ICD occurred independently of caspase signaling and was blocked by Necrostatin-1, suggesting the contribution of necroptosis. Autophagy induction following NDV infection of GL261 cells was demonstrated as well. In vivo, elevated infiltration of IFN-γ(+) T cells was observed in NDV-treated tumors, along with reduced accumulation of myeloid derived suppressor cells. The importance of a functional adaptive immune system in this paradigm was demonstrated in immunodeficient Rag2(-/-) mice and in CD8(+) T cell depleted animals, where NDV slightly prolonged survival, but failed to induce long-term cure. Secondary tumor induction with GL261 cells or LLC cells in mice surviving long-term after NDV treatment, demonstrated the induction of a long-term, tumor-specific immunological memory response by ND virotherapy. For the first time, we describe the therapeutic activity of NDV against GL261 tumors, evidenced in an orthotopic mouse model. The therapeutic effect relies on the induction of ICD in the tumor cells, which primes adaptive antitumor immunity.

Journal ArticleDOI
TL;DR: It is found that tumors with transcriptionally inactive HPV16 (DNA+ RNA‐) are similar to HPV‐negative (DNA‐) tumors regarding gene expression and frequency of TP53 mutations and that an immune response‐related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status.
Abstract: Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Journal ArticleDOI
TL;DR: The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women.
Abstract: Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring seru ...

Journal ArticleDOI
TL;DR: It is demonstrated that IL‐34 is expressed by osteosarcoma cells, is regulated by TNF‐α, IL‐1β, and contributes to osteosARcoma growth by increasing the neo‐angiogenesis and the recruitment of M2 macrophages.
Abstract: Interleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases.

Journal ArticleDOI
TL;DR: GBM‐derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor‐supportive phenotypes observed in patients.
Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor and is without exception lethal. GBMs modify the immune system, which contributes to the aggressive nature of the disease. Particularly, cells of the monocytic lineage, including monocytes, macrophages and microglia, are affected. We investigated the influence of GBM-derived extracellular vesicles (EVs) on the phenotype of monocytic cells. Proteomic profiling showed GBM EVs to be enriched with proteins functioning in extracellular matrix interaction and leukocyte migration. GBM EVs appeared to skew the differentiation of peripheral blood-derived monocytes to alternatively activated/M2-type macrophages. This was observed for EVs from an established cell line, as well as for EVs from primary cultures of GBM stem-like cells (GSCs). Unlike EVs of non-GBM origin, GBM EVs induced modified expression of cell surface proteins, modified cytokine secretion (e.g., an increase in vascular endothelial growth factor and IL-6) and increased phagocytic capacity of the macrophages. Most pronounced effects were observed upon incubation with EVs from mesenchymal GSCs. GSC EVs also affected primary human microglia, resulting in increased expression of Membrane type 1-matrix metalloproteinase, a marker for GBM microglia and functioning as tumor-supportive factor. In conclusion, GBM-derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor-supportive phenotypes observed in patients.

Journal ArticleDOI
TL;DR: A plasma microRNA panel that has potential clinical value in early CRC detection and would play a critical role on preliminarily screening CRC in general population is revealed.
Abstract: Colonoscopy remains the standard screening method for detecting colorectal cancer (CRC) at an early stage. However, many people avoid having a colonoscopy because of the fear for its potential complications. Our study aimed to identify plasma microRNAs for preliminarily screening CRC in general population, so that some unnecessary colonoscopies can be avoided. We investigated plasma microRNA expression in three independent cohorts including the discovery (n = 80), training (n = 112), and validation (n = 49) phases recruited at two medical centers. Microarrays were used for screening 723 microRNAs in 80 plasma samples to identify candidate microRNAs. Quantitative reverse-transcriptase PCR was performed on the 161 training and validation plasma samples to evaluate the candidate microRNAs discovered from microarrays. A logistic regression model was constructed based on the training cohort and then verified by using the validation dataset. Area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified a panel of miR-409-3p, miR-7, and miR-93 that yielded high diagnostic accuracy in discriminating CRC from healthy group (AUC: 0.866 and 0.897 for training and validation dataset, respectively). Moreover, the diagnostic performance of the microRNA panel persisted in nonmetastasis CRC stages (Dukes' A-B, AUC: 0.809 and 0.892 for training and validation dataset, respectively) and in metastasis CRC stages (Dukes' C-D, AUC: 0.917 and 0.865 for training and validation dataset, respectively). In conclusion, our study reveals a plasma microRNA panel that has potential clinical value in early CRC detection and would play a critical role on preliminarily screening CRC in general population.

Journal ArticleDOI
TL;DR: Three‐lncRNA signature in serum was identified as diagnostic marker for GC and may facilitate the detection of GC and serve as the basis for further studies of the clinical value of serum lncRNAs in maintaining surveillance and forecasting prognosis.
Abstract: The examination of circulating nucleic acids (CNAs) is an emerging noninvasive diagnostic technique. However, it is unclear if serum long noncoding RNAs (lncRNAs) represent a novel marker to detect gastric cancer (GC). In this study, we measured 39 candidate cancer-associated lncRNAs by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in sera from 110 patients with GC, 106 age- and sex-matched healthy subjects and 15 patients with gastric peptic ulcer, markers were validated and assessed by RT-qPCR. The correlation of the expression levels of the candidate serum lncRNAs with clinical parameters of GC patients was performed. A three-lncRNA signature, including CUDR, LSINCT-5 and PTENP1, was identified that may be potential diagnostic marker for GC. The areas under the receiver operating characteristic (ROC) curve for this serum three-lncRNA signature were 0.920 and 0.829 for the two sets of serum samples. Moreover, a risk model for the serum three-lncRNA signature demonstrated that healthy samples can be distinguished from early GC samples. Three-lncRNA signature in serum was identified as diagnostic marker for GC. This work may facilitate the detection of GC and serve as the basis for further studies of the clinical value of serum lncRNAs in maintaining surveillance and forecasting prognosis.

Journal ArticleDOI
TL;DR: A self‐enforcing feedback loop that employs CD44s to activate Z EB1 expression renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promotingCD44s isoform synthesis.
Abstract: Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial-mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor-initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT-induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self-sustaining ZEB1 and CD44s expression. Activation of this novel CD44s-ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor-sphere initiation capacity, drug-resistance and tumor recurrence. In summary, we identified a self-enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.

Journal ArticleDOI
Annett Müller1, Susan Brandenburg1, Kati Turkowski1, Susanne Müller1, Peter Vajkoczy1 
TL;DR: It is demonstrated that the HPI model impeded a massive unspecific influx of donor‐derived myeloid cells into naive as well as tumor‐bearing brains and evidenced for the first time that microglia are able to up‐regulate CD45 and represent an inherent part of the CD45high population in the tumor context.
Abstract: Gliomas consist of multiple cell types, including an abundant number of microglia and macrophages, whereby their impact on tumor progression is controversially discussed. To understand their unique functions and consequently manipulate either microglia or macrophages in therapeutic approaches, it is essential to discriminate between both cell populations. Because of the lack of specific markers, generally total body irradiated chimeras with labeled bone marrow cells were used to identify infiltrated cells within the brain. However, total body irradiation (TBI) affects the blood-brain barrier integrity, which in turn potentially facilitates immune cell infiltration. In this study, changes on the blood-brain barrier were avoided using head-protected irradiation (HPI). Head protection and total body irradiated chimeras exhibited similar reconstitution levels of the myeloid cell lineage in the blood, enabling the comparable analyses of brain infiltrates. We demonstrate that the HPI model impeded a massive unspecific influx of donor-derived myeloid cells into naive as well as tumor-bearing brains. Moreover, experimental artifacts such as an enlarged distribution of infiltrated cells and fourfold increased tumor volumes are prevented in head-protected chimeras. In addition, our data evidenced for the first time that microglia are able to up-regulate CD45 and represent an inherent part of the CD45(high) population in the tumor context. All in all, HPI allowed for the unequivocal distinction between microglia and macrophages without alterations of tumor biology and consequently permits a detailed and realistic description of the myeloid cell composition in gliomas.

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TL;DR: The data highlight a complex association between circulating inflammatory mediators, Mo‐MDSCs and the clinical outcome as well as suggest that their levels in patients with advanced melanoma are of important prognostic value allowing the identification of those with high risk of disease progression.
Abstract: Chronic inflammation is considered to be one of the hallmarks for tumor initiation and progression. Moreover, a long-term production and accumulation of inflammatory factors lead to a local and systemic immunosuppression associated with cancer progression. However, the correlation between inflammatory mediators, immunosuppressive cells and the clinical outcome of malignant melanoma patients was poorly investigated. In this study, we performed a complex analysis of various inflammatory factors, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the peripheral blood of patients suffering from malignant melanoma of different stages. We demonstrated that levels of serum IL-1β, IFN-γ and CXCL10 were significantly increased in advanced melanoma patients. In addition, these factors were found to be associated with an increased frequency of MDSCs and Tregs as compared to age- and gender-matched healthy donors. Importantly, advanced melanoma patients with signs of progression displayed markedly elevated concentrations of IL-1β and CXCL10 as compared to patients with stable disease. Moreover, an enrichment of circulating monocytic (Mo)-MDSCs significantly correlated with a decreased progression free survival of these patients. Our data highlight a complex association between circulating inflammatory mediators, Mo-MDSCs and the clinical outcome as well as suggest that their levels in patients with advanced melanoma are of important prognostic value allowing the identification of those with high risk of disease progression.

Journal ArticleDOI
TL;DR: Using both shotgun and 2D‐imaging lipidomics analysis, a hitherto unrecognized alteration in phospholipid profiles in NSCLC is uncovered, which may have important biological implications and may have significant potential for biomarker development.
Abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.

Journal ArticleDOI
TL;DR: Results from the pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long‐term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.
Abstract: To investigate the association between cannabis smoking and lung cancer risk, data on 2,159 lung cancer cases and 2,985 controls were pooled from 6 case-control studies in the US, Canada, UK, and New Zealand within the International Lung Cancer Consortium. Study-specific associations between cannabis smoking and lung cancer were estimated using unconditional logistic regression adjusting for sociodemographic factors, tobacco smoking status and pack-years; odds-ratio estimates were pooled using random effects models. Subgroup analyses were done for sex, histology and tobacco smoking status. The shapes of dose-response associations were examined using restricted cubic spline regression. The overall pooled OR for habitual versus nonhabitual or never users was 0.96 (95% CI: 0.66-1.38). Compared to nonhabitual or never users, the summary OR was 0.88 (95%CI: 0.63-1.24) for individuals who smoked 1 or more joint-equivalents of cannabis per day and 0.94 (95%CI: 0.67-1.32) for those consumed at least 10 joint-years. For adenocarcinoma cases the ORs were 1.73 (95%CI: 0.75-4.00) and 1.74 (95%CI: 0.85-3.55), respectively. However, no association was found for the squamous cell carcinoma based on small numbers. Weak associations between cannabis smoking and lung cancer were observed in never tobacco smokers. Spline modeling indicated a weak positive monotonic association between cumulative cannabis use and lung cancer, but precision was low at high exposure levels. Results from our pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.

Journal ArticleDOI
TL;DR: TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEX‐presentation that was supported by prolonged persistence, preferential processing in the MHCII‐loading compartment and pronounced trogocytosis by T helper cells.
Abstract: Leukemia immunotherapy frequently does not meet expectation, one of the handicaps being tumor exosome (TEX)-promoted immunosuppression. We here asked, using the mouse myeloid leukemia WEHI3B and the renal cell carcinoma line RENCA, whether dendritic cell (DC) vaccination suffices to counterregulate TEX-induced immunosuppression and whether TEX could serve as tumor antigen for DC-loading. DC-vaccination significantly prolonged the survival time of WEHI3B-bearing mice, TEX-loaded DC (DC-TEX) being superior to lysate-loaded DC (DC-lys), even an excess of TEX not interfering with immune response induction. The superior response to DC-TEX was accompanied by an increase in WEHI3B-specific CD4+ T cells, evaluated by trogocytosis and proliferation. Similar findings accounted for DC loaded with RENCA TEX. TEX was efficiently taken-up by DC and TEX uptake supported CD11c, MHCII and IL12 upregulation in DC. Importantly, TEX was partly recruited into the MHCII-loading compartment such that "TEX" presentation time and recovery in T cells significantly exceeded that of tumor-lysate. Thus, TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEX-presentation that is supported by prolonged persistence, preferential processing in the MHCII-loading compartment and pronounced trogocytosis by T helper cells. TEX is present in tumor patients' sera. TEX, recovered and enriched from patients' sera, might well provide an optimized, individual-specific antigen source for DC-loading and vaccination.

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TL;DR: Overall risk was higher among subjects with an evening chronotype, but also increased in morning chronotypes after long‐term night work, particularly for tumors with worse prognosis.
Abstract: Night shift work has been classified as a probable human carcinogen based on experimental studies and limited human evidence on breast cancer. Evidence on other common cancers, such as prostate cancer, is scarce. Chronotype is an individual characteristic that may relate to night work adaptation. We evaluated night shift work with relation to prostate cancer, taking into account chronotype and disease severity in a population based case-control study in Spain. We included 1,095 prostate cancer cases and 1,388 randomly selected population controls. We collected detailed information on shift schedules (permanent vs. rotating, time schedules, duration, frequency), using lifetime occupational history. Sociodemographic and lifestyle factors were assessed by face-to-face interviews and chronotype through a validated questionnaire. We used unconditional logistic regression analysis adjusting for potential confounders. Subjects who had worked at least for one year in night shift work had a slightly higher prostate cancer risk [Odds Ratio (OR) 1.14; 95%CI 0.94, 1.37] compared with never night workers; this risk increased with longer duration of exposure (≥28 years: OR 1.37; 95%CI 1.05, 1.81; p-trend = 0.047). Risks were more pronounced for high risk tumors [D'Amico classification, Relative Risk Ratio (RRR) 1.40; 95%CI 1.05, 1.86], particularly among subjects with longer duration of exposure (≥28 years: RRR 1.63; 95%CI 1.08, 2.45; p-trend = 0.027). Overall risk was higher among subjects with an evening chronotype, but also increased in morning chronotypes after long-term night work. In this large population based study, we found an association between night shift work and prostate cancer particularly for tumors with worse prognosis.