Showing papers in "International Journal of Cancer in 2020"

In search of definitions: Cancer-associated fibroblasts and their markers.

Abstract: The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor-modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various "CAF markers", such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross-applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.

Efficacy and Safety of Pembrolizumab for the Treatment of Advanced Biliary Cancer: Results From the KEYNOTE-158 and KEYNOTE-028 Studies

Abstract: We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.

International trends in hepatocellular carcinoma incidence, 1978-2012.

Abstract: Primary liver cancer, the major histology of which is hepatocellular carcinoma (HCC), is the second leading cause of cancer death worldwide. We comprehensively examined recent international trends of primary liver cancer and HCC incidence using population-based cancer registry data. Incidence for all primary liver cancer and for HCC by calendar time and birth cohort was examined for selected countries between 1978 and 2012. For each successive 5-year period, age-standardized incidence rates were calculated from Volumes V to XI of the Cancer Incidence in Five Continents (CI5) series using the online electronic databases, CI5plus. Large variations persist in liver cancer incidence globally. Rates of liver cancer remain highest in Asian countries, specifically in the East and South-East, and Italy. However, rates in these high-risk countries have been decreasing in recent years. Rates in India and in most countries of Europe, the Americas and Oceania are rising. As the population seroprevalence of hepatitis B virus (HBV) continues to decline, we anticipate rates of HCC in many high-risk countries will continue to decrease. Treatment of hepatitis C virus (HCV) is likely to bring down rates further in some high-rate, as well as low-rate, countries with access to effective therapies. However, such gains in the control of liver cancer are at risk of being reversed by the growing obesity and diabetes epidemics, suggesting diabetes treatment and primary prevention of obesity will be key in reducing liver cancer in the longer-term.

Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial.

Abstract: In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.

Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review.

Abstract: Cervical cancer (CC) is the fourth most common cause of cancer death in women. The most important risk factor for the development of CC is cervical infection with human papilloma virus (HPV). Inflammation is a protective strategy that is triggered by the host against pathogens such as viral infections that acts rapidly to activate the innate immune response. Inflammation is beneficial if it is brief and well-controlled, however, if the inflammation is excessive or it becomes of chronic duration, it can produce detrimental effects. HPV proteins are involved, both directly and indirectly, in the development of chronic inflammation, which is a causal factor in the development of CC. However, other factors may also have a potential role in stimulating chronic inflammation. MicroRNAs (miRNAs) (a class of non-coding RNAs) are strong regulators of gene expression. They have emerged as key players in several biological processes, including inflammatory pathways. Abnormal expression of miRNAs may be linked to the induction of inflammation that occurs in CC. Exosomes are a subset of extracellular vesicles shed by almost all types of cells, which can function as cargo transfer vehicles. Exosomes contain proteins and genetic material (including miRNAs) derived from their parent cells and can potentially affect recipient cells. Exosomes have recently been recognized to be involved in inflammatory processes and can also affect the immune response. In this review, we discuss the role of HPV proteins, miRNAs and exosomes in the inflammation associated with CC.

Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells

Abstract: Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long-standing recognition of the crosstalk between carcinoma-associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer-associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA-ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β-catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β-catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.

Circulating lncRNA SNHG11 as a novel biomarker for early diagnosis and prognosis of colorectal cancer

Abstract: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer mortality worldwide. Emerging evidence indicates that tumour cells release substantial amounts of RNA into the bloodstream, in which RNA strongly resists RNases and is present at sufficient levels for quantitative analyses. Our study aimed to discover blood-based markers for the early detection of CRC and to ascertain their efficiency in discriminating healthy controls, patients with polyps and adenomas and cancer patients. We first analysed and screened ZFAS1, SNHG11, LINC00909 and LINC00654 in a bioinformatics database and then collected clinical plasma samples for preliminary small-scale analysis and further large-scale verification. We then explored the mechanism of dominant lncRNA SNHG11 expression in CRC by in vitro and in vivo assays. The combination of ZFAS1, SNHG11, LINC00909 and LINC00654 showed high diagnostic performance for CRC (AUC: 0.937), especially early-stage disease (AUC: 0.935). Plasma levels of the four candidate lncRNAs were significantly reduced in postoperative samples compared to preoperative samples. A panel including these four lncRNAs performed well in distinguishing patient groups with different stages of colon disease, and SNHG11 exhibited the greatest diagnostic ability to identify precancerous lesions and early-stage tumour formation. Mechanistically, high SNHG11 expression promotes proliferation and metastasis by targeting the Hippo pathway. Taken together, the data indicate that SNHG11 may be a novel therapeutic target for the treatment of CRC and a potential biomarker for the early detection of CRC.

Oxidative phosphorylation as a potential therapeutic target for cancer therapy.

Abstract: In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate-or at least are compatible with-anticancer immune responses for long-term tumor control.

Cervical cancer survival in sub-Saharan Africa by age, stage at diagnosis and Human Development Index: A population-based registry study.

Abstract: Breast cancer is the leading cancer diagnosis and second most common cause of cancer deaths in sub-Saharan Africa (SSA). Yet, there are few population-level survival data from Africa and none on the survival differences by stage at diagnosis. Here, we estimate breast cancer survival within SSA by area, stage and country-level human development index (HDI). We obtained data on a random sample of 2,588 breast cancer incident cases, diagnosed in 2008-2015 from 14 population-based cancer registries in 12 countries (Benin, Cote d'Ivoire, Ethiopia, Kenya, Mali, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Uganda and Zimbabwe) through the African Cancer Registry Network. Of these, 2,311 were included for survival analyses. The 1-, 3- and 5-year observed and relative survival (RS) were estimated by registry, stage and country-level HDI. We equally estimated the excess hazards adjusting for potential confounders. Among patients with known stage, 64.9% were diagnosed in late stages, with 18.4% being metastatic at diagnosis. The RS varied by registry, ranging from 21.6%(8.2-39.8) at Year 3 in Bulawayo to 84.5% (70.6-93.5) in Namibia. Patients diagnosed at early stages had a 3-year RS of 78% (71.6-83.3) in contrast to 40.3% (34.9-45.7) at advanced stages (III and IV). The overall RS at Year 1 was 86.1% (84.4-87.6), 65.8% (63.5-68.1) at Year 3 and 59.0% (56.3-61.6) at Year 5. Age at diagnosis was not independently associated with increased mortality risk after adjusting for the effect of stage and country-level HDI. In conclusion, downstaging breast cancer at diagnosis and improving access to quality care could be pivotal in improving breast cancer survival outcomes in Africa.

Assessment of the expression of the immune checkpoint molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 across different cancers in relation to treatment response, tumor‐infiltrating immune cells and survival

Abstract: Immune checkpoint molecules have been identified as crucial regulators of the immune response, which motivated the emergence of immune checkpoint-targeting therapeutic strategies. However, the prognostic significance of the immune checkpoint molecules PD-1, CTLA4, TIM-3 and LAG-3 remains controversial. The aim of our study was to conduct a systematic assessment of the expression of these immune checkpoint molecules across different cancers in relation to treatment response, tumor-infiltrating immune cells and survival. Oncomine and PrognoScan database analyses were used to investigate the expression levels and prognostic values of these immune checkpoint molecule genes across various cancers. Then, we used Kaplan-Meier plotter to validate the associations between the checkpoint molecules and cancer survival identified in the PrognoScan analysis. TIMER analysis was used to evaluate immune cell infiltration data from The Cancer Genome Atlas. Finally, we used Gene Expression Profiling Interactive Analysis to investigate the prognostic value of these four checkpoint molecules and assess the correlations between these four checkpoint molecules and genetic markers. These immune checkpoint molecules may potentially serve as prognostic factors and therapeutic targets in breast cancer, ovarian cancer and lung cancer. The prognostic roles of these checkpoint molecules varied greatly across cancers, which implied a noteworthy amount of heterogeneity among tumors, even within the same molecular subtype. In addition, the expression patterns of these checkpoint molecules were closely associated with treatment response and provided some useful direction when choosing chemotherapeutic drugs. These findings enhance our understanding of these checkpoints in cancer treatment and identify strategies to promote synergistic activities in the context of other immunotherapies.

Sex-specificity in lung cancer risk

Abstract: Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme polymorphisms have been identified to increase the risk for smokers, recent epidemiological data suggest even sex-specificity as a new and additional factor. Obviously, women have a higher risk to develop lung cancer upon smoking than men. Overall, the odds ratio to develop lung cancer was almost three times greater for women than for men, DNA adduct levels were higher among females than in males and mutations in the tumor suppressor gene p53 and the proto-oncogene K-RAS were more frequently found in women than in men. A growing number of studies suggest that the interaction between tobacco carcinogens and endogenous and exogenous sex steroids may be important. Women taking hormone replacement therapy (HRT) or oral contraceptives experienced to have an increased lung cancer incidence. Epidemiologic data on HRT show a significant association between both a younger median age at lung cancer diagnosis and a shorter median survival time. Another clue is the significantly higher number of lung cancer diagnosed women who are largely premenopausal in comparison to diagnosed men in the same age or women with shorter menstrual cycles. Finally, the Coronary Drug Project (men who received estrogen preparations to reduce future cardiac events) was stopped when increased lung cancer mortality was observed in the estrogen therapy group. The present review provides a short overview and discussion on lung cancer risk and the impact thereon of sex.

The cancer exosomes: Clinical implications, applications and challenges.

Abstract: The exosome is a small functional vesicle enriched in selected proteins, lipids and nucleic acids, displaying distinct molecular heterogeneity. Exosomes released can transform the extracellular matrix microenvironments, transmit signals and molecules to recipient cells and trigger changes in their pathophysiological functions. Tumor-derived exosomes mediate the interactions of tumor cells and microenvironment significantly, and they stimulate tumor growth and development through specific signaling pathways related to metastasis, therapeutic resistance and immunosuppression. Exosome biogenesis from tumors often represents abundant biological information, and novel and efficient isolation and detection methods of exosomes provide a promising approach for tumor diagnosis and prognosis estimation. Moreover, exosome can even be developed as therapeutic agents for multiple disease models based on effective material transport characteristics and biofilm specificity. This review reports the clinical implications and challenges of exosomes in cancer progression, therapy resistance, metastasis and immune escape, and underlying cancerogenic pathological phenotypes including fibrosis and viral infection.

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors.

Abstract: Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.

Plasma circular RNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma: A large-scale, multicenter study.

Abstract: To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819-0.907] vs. 0.790 [0.738-0.842], p = 0.036 in training set; 0.843 [0.796-0.890] vs. 0.747 [0.691-0.804], p = 0.011 in validation set 1 and 0.864 [0.830-0.898] vs. 0.769 [0.728-0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.

Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.

Abstract: Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

The role of CDK6 in cancer.

Abstract: The regulation and function of cyclin-dependent kinase 6 (CDK6)- and cyclin-dependent kinase 4 (CDK4)-cyclin complexes are commonly altered with enhanced kinase activity found in hematopoietic malignancies, breast cancer and melanoma making CDK4 and CDK6 attractive targets for therapeutic interference. Although dual CDK4/6 inhibitors have revolutionized treatment of breast cancer patients and reveal promising results in several solid tumors and hematological malignancies, there is a need for novel compounds targeting the versatile kinase-independent functions of CDK6 to improve cancer treatment. The following review summarizes the latest findings on CDK6 in cancer development and discusses novel therapeutic approaches to selectively inhibit CDK6s function as a transcriptional regulator.

The systemic immune-inflammation index is associated with an increased risk of incident cancer-A population-based cohort study.

Abstract: Several studies found that the systemic immune-inflammation index (SII) is a prognostic factor for mortality in patients with solid tumors. It is unknown whether an increased SII in generally healthy individuals reflects a risk for developing cancer. Our objective was to investigate the association between the SII and incident cancers in a prospective cohort study. Data were obtained from the Rotterdam Study; a population-based study of individuals aged ≥45 years, between 2002 and 2013. The SII at baseline was calculated from absolute blood counts. The association between the SII and the risk of any solid incident cancer during follow-up was assessed using Cox proportional hazard models. Individuals with a prior cancer diagnosis were excluded. Data of 8,024 individuals were included in the analyses. The mean age at baseline was 65.6 years (SD 10.5 years) and the majority were women. During a maximum follow-up period of 10.7 years, 733 individuals were diagnosed with cancer. A higher SII at baseline was associated with a 30% higher risk of developing a solid cancer (HR of 1.30 [95% CI; 1.11–1.53]), after adjustment for age, sex, socioeconomic status, smoking, BMI and type 2 diabetes. The absolute cumulative 10-year cancer risk increased from 9.7% in the lowest quartile of SII to 14.7% in the highest quartile (p-value = 0.009). The risk of developing cancer was persistent over time and increased for individuals with the longest follow-up. In conclusion, a high SII is a strong and independent risk indicator for developing a solid cancer.

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

Abstract: The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.

Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

Abstract: Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation-44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T-TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration-approved drug preventing Y/T-TEAD interaction, on gastric CSC tumorigenic properties. Y/T-TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient-derived GC and cell lines. Verteporfin effects on Y/T-TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient-derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T-TEAD molecular signature was enriched in CD44+ patient-derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T-TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere-forming CD44+ /aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T-TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ-TEAD activity could be a promising CSC-based strategy for the treatment of GC.

Regulatory roles of long noncoding RNAs implicated in cancer hallmarks

Abstract: Cancer cells acquire numerous biological properties (designated "cancer hallmarks"), such as cell survival and energy metabolism, that facilitate tumor growth and metastatic dissemination during development. To date, eight hallmarks of cancer have been identified that provide a logical framework for understanding the remarkable diversity of neoplastic diseases, as proposed by Douglas Hanahan and Robert A. Weinberg. Long noncoding RNAs (lncRNAs), a category of transcripts widely demonstrated to exert significant regulatory effects on biological processes, have attracted considerable research attention due to their association with the occurrence and development of cancer. The mechanisms by which lncRNAs exert their functions require elucidation to optimize their potential utility as alternative biomarkers and therapeutic targets during tumor occurrence and progression. In this review, we have discussed recent research progress on lncRNAs involved in various cancer hallmarks and their related mechanisms of action, with a view to providing an updated picture of their immense therapeutic potential in the fight against cancer.

A novel lncRNA-LINC01116 regulates tumorigenesis of glioma by targeting VEGFA.

Abstract: Brain glioma is the most common malignant tumor of the central nervous system, and one of the leading causes of death in patients with intracranial tumors. The clinical outcome of glioma is usually poor due to abundant vascularity, fast growth and susceptibility of invasion to normal brain tissues. Our microarray study showed that lncRNA-LINC01116 was significantly upregulated in glioma tissues and played an important role in cell proliferation, cycle, migration, invasion and angiogenesis. In addition, vascular endothelial growth factor (VEGFA) may be the major target genes in the downstream of lncRNA-LINC01116. Dual luciferase assay showed that LINC01116 and VEGFA both contained a miR-31-5p binding site, and LINC01116 could regulate the expression of VEGFA through competitive absorption of miR-31-5p. RNA immunoprecipitation indicated that LINC01116 and VEGFA were present in the miR-31-5p-RISC complex, and biotinylated miR-31-5p pull-down assay suggested that there was a competitive relationship between LINC01116 and VEGFA to bind with miR-31-5p. Collectively, our study has identified a novel lncRNA-LINC01116 and clarified the role and mechanism of LINC01116 in the tumorigenesis of glioma. LINC01116 may prove to be a potential target for the clinical diagnosis and treatment of glioma.

Lung cancer incidence in young women vs. young men: A systematic analysis in 40 countries.

Abstract: Previous studies have reported converging lung cancer rates between sexes. We examine lung cancer incidence rates in young women vs. young men in 40 countries across five continents. Lung and bronchial cancer cases by 5-year age group (ages 30-64) and 5-year calendar period (1993-2012) were extracted from Cancer Incidence in Five Continents. Female-to-male incidence rate ratios (IRRs) and 95% confidence intervals (95%CIs) were calculated by age group and birth cohort. Among men, age-specific lung cancer incidence rates generally decreased in all countries, while in women the rates varied across countries with the trends in most countries stable or declining, albeit at a slower pace compared to those in men. As a result, the female-to-male IRRs increased among recent birth cohorts, with IRRs significantly greater than unity in Canada, Denmark, Germany, New Zealand, the Netherlands and the United States. For example, the IRRs in ages 45-49 year in the Netherlands increased from 0.7 (95% CI: 0.6-0.8) to 1.5 (95% CI: 1.4-1.7) in those born circa 1948 and 1963, respectively. Similar patterns, though nonsignificant, were found in 23 additional countries. These crossovers were largely driven by increasing adenocarcinoma incidence rates in women. For those countries with historical smoking data, smoking prevalence in women approached, but rarely exceeded, those of men. In conclusion, the emerging higher lung cancer incidence rates in young women compared to young men is widespread and not fully explained by sex differences in smoking patterns. Future studies are needed to identify reasons for the elevated incidence of lung cancer among young women.

The exosome encapsulated microRNAs as circulating diagnostic marker for hepatocellular carcinoma with low alpha‐fetoprotein

Abstract: Diagnosis of hepatocellular carcinoma (HCC) remains challenging to clinicians, particularly in a patient with low alpha-fetoprotein. Here, in silico, ex vivo and in vitro data were combined to identify liver-specific exosomal miRNAs as an early diagnostic marker for HCC. Transcriptome profiling for mRNA and small RNA in same HCV-HCC and normal liver tissues followed by cross-validation of 41 deregulated miRNAs (log2 FoldChange > 1.5, Padj < .1) with GEO/TCGA datasets of HCV/HBV related HCC vs normal/adjacent tissue revealed three miRNAs were commonly deregulated (miR-10b/miR-21/miR-182) among all HCC irrespective of viral etiology. Targets of top deregulated miRNAs were identified by TargetScan/miRwalk and validated in mRNA transcriptome data followed by Panther/Gene Ontology enrichment/Cytoscape analysis suggested that targets were mostly from carcinogenesis pathways. Hence, those miRNAs were validated in normal and HCV-HCC tissues by qRT-PCR and subsequently in plasma-derived-exosomes of both HBV/HCV infected non-HCC (chronic hepatitis [CH]/liver cirrhosis [LC]) and HCC samples, and in liver-specific Anti-Asgr2 immuno-enriched exosomes. Exosomes were verified using Nanosight/TEM/immune-blotting with anti-Alix/anti-GRP78/anti-Asgr2. Along with miR-21-5p, miR-10b-5p/miR-221-3p/miR-223-3p was found significantly upregulated in the exosome of HCC patients than CH/non-HCC. The comparable expression pattern was seen in anti-Asgr2 immuno-precipitated exosomes. Interestingly, the AFP level was found below 250 ng/mL in about 94% of HCV-HCC and 62% of HBV-HCC patients. ROC analysis showed that miR-10b-5p + miR-221-3p + miR-223-3p + miR-21-5p could differentiate CH/non-HCC(CH + LC) from HCC with AUROC: 0.86 (97.5% CI: 0.77-0.94)/0.80 (97.5% CI: 0.70-0.89), sensitivity: 74%/58% and specificity: 86%/95% while miR-10b-5p + miR-221-3p + miR-223-3p showed AUROC: 0.84 (97.5% CI: 0.74-0.94)/0.74 (97.5% CI: 0.63-0.84), sensitivity: 86%/86% and specificity:66%/53% for low AFP-HCC vs CH/non-HCC, respectively, having better sensitivity than the combination of four miRNAs. Multivariate analysis further revealed low Albumin and high miR-21-5p as probable independent risk factor for HCC.

Global trends in oral and pharyngeal cancer incidence and mortality

Abstract: To provide an up-to-date overview of recent trends in mortality from oral and pharyngeal cancer, we analyzed death certification data for 61 countries worldwide provided by the World Health Organization in 2010-2015, and, for selected most populous countries, over the period 1970-2016. For 12 largest countries, we analyzed incidence derived from Cancer Incidence in Five Continents in 1960-2012 for all oral and pharyngeal cancers and by subsites. In 2015, male age-standardized (world population) death rates per 100,000 were 5.03 in the European Union (EU), 8.33 in the Russian Federation, 2.53 in the United States (USA), and 3.04 in Japan; corresponding rates in women were 1.23, 1.23, 0.82, and 0.76. Male mortality decreased over the last decades in several European countries, with earlier and sharper declines in southern Europe; conversely, mortality was still increasing in a few eastern European countries and the United Kingdom. Mortality in men also decreased in Argentina, Australia, and Hong Kong, while it leveled off over more recent calendar years in Brazil, Japan, Mexico, the Republic of Korea, as well as in Australia and the USA. Female mortality slightly rose in various European countries. Overall incidence trends in the largest countries were broadly consistent with mortality ones, but oropharyngeal cancer incidence rose in many countries. Changes in tobacco and alcohol exposure in men over the last decades likely explain the favorable trends in oral and pharyngeal cancer mortality and incidence observed in selected countries worldwide, while increased human papillomavirus infection is likely responsible for the rise in oropharyngeal cancer incidence.

Profiling global cancer incidence and mortality by socioeconomic development.

Abstract: Economic and living conditions have improved over time in most countries, although often in association with detrimental lifestyle and environmental changes that are major determinants of cancer. In this ecological study, we assess the association between national socioeconomic levels and incidence and mortality rates for all cancers combined and 27 cancer types, in 175 countries. We obtained national level cancer incidence and mortality estimates for 2018 from GLOBOCAN and computed an index of socioeconomic development based on national education and income levels extracted from the United Nations Development Programme. Cancer incidence rates are strongly positively associated with the national socioeconomic level for all cancers combined and for a large number of cancer types, in both sexes. Conversely, the association between socioeconomic development and cancer mortality rates is less clear. The most common pattern for type-specific cancers is an increasing incidence rate with a relatively stable mortality rate as socioeconomic development increases. Despite the high incidence rates for many cancer types, mortality rates are relatively low in high-income countries, partly due to the availability of early detection and effective treatments. As socioeconomic development continues to rise, countries with currently low- and medium-development levels may experience large increases in the incidence of several cancers. Given the limited resources and lack of infrastructure, increases in incidence rates in low-income countries will likely be paralleled by increases in mortality rates. Efforts to plan, implement and evaluate prevention programs must therefore be considered as greater priorities in Low- and Middle-income countries.

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Abstract: Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross-check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.

Association between ambient air pollution and breast cancer risk: The multiethnic cohort study.

Abstract: Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ) and California Line Source Dispersion model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 μg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [95% CI]: 1.02-1.79), NO2 (HR = 1.44, 95% CI: 1.04-1.99), PM10 (HR = 1.29, 95% CI: 1.07-1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01-1.45) and NO2 (HR = 1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near-roadway exposures, on the risk of breast cancer is warranted.

The evolving epidemic of breast cancer in sub-Saharan Africa: Results from the African Cancer Registry Network.

Abstract: Breast cancer (BC) is the leading cause of cancer in sub-Saharan Africa (SSA) with rapidly increasing incidence rates reported in Uganda and Zimbabwe. However, the magnitude of these rising trends in premenopausal and postmenopausal women is unknown in most African countries. We used data from the African Cancer Registry Network on incident breast cancers in women from 11 population-based cancer registries in 10 countries representing each of the four SSA regions. We explored incidence changes among women before and after age 50 by calendar period and, where possible, generational effects in this unique sub-Saharan African cohort. Temporal trends revealed increasing incidence rates in all registries during the study period, except in Nairobi where rates stabilised during 2010 to 2014 after rapidly increasing from 2003 to 2010 (APC = 8.5 95%, CI: 3.0-14.2). The cumulative risk varied between and within regions, with the highest risks observed in Nairobi-Kenya, Mauritius and the Seychelles. There were similar or more rapidly increasing incidence rates in women aged 50+ compared to women <50 years in all registries except The Gambia. Birth cohort analyses revealed increases in the incidence rates in successive generations of women aged 45 and over in Harare-Zimbabwe and Kampala-Uganda. In conclusion, the incidence of BC is increasing rapidly in many parts of Africa; however, the magnitude of these changes differs. These results highlight the need for urgent actions across the cancer continuum from in-depth risk factor studies to provision of adequate therapy as well as the necessity of supporting the maintenance of good quality population-based cancer registration in Africa.

Incidence of childhood renal tumours: An international population‐based study

Abstract: Malignant renal tumours represent 5% of childhood cancers and include types with likely different aetiology: Wilms tumour (WT), rhabdoid renal tumour, kidney sarcomas and renal carcinomas WT is the most common renal tumour in children, previously shown to vary internationally and with ethnicity Using the comprehensive database of the International Incidence of Childhood Cancer study (IICC), we analysed global variations and time trends in incidence of renal tumour types in children (age 0-14 years) and adolescents (age 15-19 years) The results were presented by 14 world regions, and five ethnic groups in the US We included 15 320 renal tumours in children and 800 in adolescents reported to the 163 contributing registries during 2001-2010 In children, age-standardised incidence rate (ASR) of renal tumours was 83 per million (95% confidence interval, CI = 81, 84); it was the highest in North America and Europe (9-10 per million) and the lowest in most Asian regions (4-5 per million) In the US, Blacks had the highest ASR (109 per million, 95% CI = 102, 116) and Asian and Pacific Islanders the lowest (44 per million, 95% CI = 36, 51) In adolescents, age-specific incidence rate of renal tumours was 14 per million (95% CI = 13, 15) WT accounted for over 90% of all renal tumours in each age from 1 to 7 years and the proportion of renal carcinomas increased gradually with age From 1996 to 2010, incidence remained mostly stable for WT (average annual percent change, AAPC = 01) and increased for renal carcinomas in children (AAPC = 37) and adolescents (AAPC = 32) Our findings warrant further monitoring

Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort

Abstract: Endocrine-disrupting chemicals are proposed to increase breast cancer (BC) incidence. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), two perfluorinated alkylated substances (PFASs), are suspected to be ubiquitously present in the blood of human population worldwide. We investigated the associations between serum concentrations of these substances and BC risk. Etude Epidemiologique aupres de femmes de l'Education Nationale is a cohort of 98,995 French women born in 1925-1950 and followed up since 1990. We sampled 194 BC cases and 194 controls from women with available blood samples. Serum concentrations of PFASs were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Adjusted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two sided. While PFASs concentrations were not associated with BC risk overall, we found positively linear associations between PFOS concentrations and the risk of ER+ (3rd quartile: OR = 2.22 [CI = 1.05-4.69]; 4th quartile: OR = 2.33 [CI = 1.11-4.90]); Ptrend = 0.04) and PR+ tumors (3rd quartile: OR = 2.47 [CI = 1.07-5.65]; 4th quartile: OR = 2.76 [CI = 1.21-6.30]; Ptrend = 0.02). When considering receptor-negative tumors, only the 2nd quartile of PFOS was associated with risk (ER-: OR = 15.40 [CI = 1.84-129.19]; PR-: OR = 3.47 [CI = 1.29-9.15]). While there was no association between PFOA and receptor-positive BC risk, the 2nd quartile of PFOA was positively associated with the risk of receptor-negative tumors (ER-: OR = 7.73 [CI = 1.46-41.08]; PR-: OR = 3.44 [CI = 1.30-9.10]). PFAS circulating levels were differentially associated with BC risk. While PFOS concentration was linearly associated with receptor-positive tumors, only low concentrations of PFOS and PFOA were associated with receptor-negative tumors. Our findings highlight the importance of considering exposure to PFASs as a potential risk factor for BC.