Aberrant EGFR signaling strongly promotes glioma malignancy and treatment resistance. The most prevalent mutation, ΔEGFR/EGFRvIII, is an in-frame deletion of the extracellular domain, which occurs in more than 25% of glioblastomas and enhances growth and survival of tumor cells. Paradoxically, the signaling of the potent oncogene ΔEGFR is of low intensity, raising the question of whether it exhibits preferential signaling to key downstream targets. We have observed levels of phosphorylation of STAT5 at position Y699 in cells expressing ΔEGFR that are similar or higher than in cells that overexpress EGFR and are acutely stimulated with EGF, prompting us to investigate the role of STAT5 activation in glioblastoma. Here, we show that in human glioblastoma samples, pSTAT5 levels correlated positively with EGFR expression and were associated with reduced survival. Interestingly, the activation of STAT5b downstream of ΔEGFR was dependent on SFKs, while the signal from acutely EGF-stimulated EGFR to STAT5b involved other kinases. Phosphorylated STAT5b and ΔEGFR associated in the nucleus, bound DNA and were found on promoters known to be regulated by STAT5 including that of the Aurora A gene. ΔEGFR cooperated with STAT5b to regulate the Bcl-XL promoter and knockdown of STAT5b suppressed anchorage independent growth, reduced the levels of Bcl-XL and sensitized glioblastoma cells to cisplatin. Together these results delineate a novel association of nuclear ΔEGFR with STAT5b, which promotes oncogenesis and treatment resistance in glioblastoma by direct regulation of anti-apoptotic gene, Bcl-XL.
nuclear EGFRvIII/ΔEGFR; STAT5b; Bcl-XL; glioma transcriptional regulation
Emerging evidence suggests that the transcription factor Forkhead Box M1 (FoxM1) is associated with aggressive human carcinomas, including breast cancer. Because elevated expression of FoxM1 has been observed in human breast cancers, FoxM1 has attracted much attention in recent years as a potential target for the prevention and/or therapeutic intervention in breast cancer. However, no information is currently available regarding how downregulation of FoxM1 could be achieved for breast cancer prevention and therapy. Here, we report for the first time that 3,3′-diindolylmethane (DIM), a nontoxic dietary chemopreventive agent could effectively downregulate FoxM1 in various breast cancer cell lines. Using gene transfection, real-time reverse transcription-PCR, Western blotting, invasion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, we found that DIM could enhance Taxotere-induced growth inhibition of breast cancer cells, and decreased invasive capacity of breast cancer cells was observed after either treatment alone or the combination. These effects were associated with downregulation of FoxM1. We also found that knock down of FoxM1 expression by small interfering RNA (siRNA) transfection increased DIM-induced cell growth inhibition, whereas over-expression of FoxM1 by cDNA transfection attenuated DIM-induced cell growth inhibition, suggesting the mechanistic role of FoxM1. Most importantly, the combination treatment significantly inhibited tumor growth in severe combined immunodeficiency (SCID) mice, and the results were correlated with the downregulation of FoxM1 in tumor remnants. We conclude that inactivation of FoxM1 and its target genes by DIM could enhance the therapeutic efficacy of Taxotere in breast cancer, which could be a useful strategy for the prevention and/or treatment of breast cancer.
FoxM1; DIM; Taxotere; breast cancer
The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest following UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest following UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis.
Merkel cell carcinoma; polyomavirus; DNA repair; cell cycle; ultraviolet radiation
Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors.
EZH2; Medulloblastoma; Polycomb repressive complex 2; histone lysine methylation; DZNEP
Pancreatic cancer is the one of most common causes of cancer deaths and has the worst prognosis. Clinical observational studies suggest that statins may reduce the risk of pancreatic cancer. The chemopreventive efficacy of the statin atorvastatin (Lipitor®) and the role of the phosphatidyl-inositol 3-kinase(PI3/AKT) signaling pathway were evaluated for the progression of pancreatic intraepithelial neoplasms (PanINs) to pancreatic ductal adenocarcinoma (PDAC) in conditional p48Cre/+-LSL-KrasG12D/+ transgenic mice. Six-week old male p48Cre/+-LSL-KrasG12D/+ (20/group) mice were fed AIN-76A diets containing 0, 200, and 400 ppm atorvastatin for 35 weeks. At termination, pancreata were evaluated histopathologically for PanINs and PDAC, and for various PI3/AKT signaling markers, and inflammatory cytokines, by immunohistochemistry/immunohistoflourscence, ELISA, Western blotting and/or Reverse Transcription-PCR methods. Control diet-fed mice showed 85% incidence of PDAC; whereas, mice fed with atorvastatin showed PDAC incidence of 65 and 35% respectively (p<0.0001). Similarly, significant suppression of PanIN-3 (22.6%) was observed in mice fed 400 ppm atorvastatin. Importantly, pancreata from atorvastatin-treated mice were ~68% free from ductal lesions. Furthermore, pancreas of mice administered with atorvastatin had significantly reduced expressions levels of PCNA, p2X7, p-ERK, RhoA, cyclin D1, survivin, Akt, pAKT, β-catenin, cyclin E, cdK2, and caveolin-1. Also, atorvastatin-treated mice had shown dose-dependent suppression of inflammatory cytokines and a significant increase in tunnel-positive cells, p21 and PARP expression levels in pancreas. Atorvastatin significantly delays the progression of PanIN-1 and -2 lesions to PanIN-3 and PDAC by modulating PI3/AKT signal molecules in a preclinical model, suggesting potential clinical benefits of statins for high risk pancreatic cancer patients.
PI3/AKT; Atorvastatin; Pancreatic cancer; p48Cre/+-LSL- KrasG12D/+ mice
Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. This study aimed to examine toenail trace element status and risk of Barrett’s oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR study (Factors Influencing the Barrett’s Adenocarcinoma Relationship) comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using Instrumental Neutron Activation Analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% CIs were calculated within tertiles of trace element concentrations. A two-fold increased risk of BO was observed, but not OAC, amongst individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI 1.11–4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI 0.44–2.04) or BO OR 0.89 (95% CI 0.37–2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI 1.01–3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case-control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.
trace elements; Barrett’s oesophagus; oesophageal adenocarcinoma; selenium; case-control study
Previous studies report an atypical cancer pattern among patients with Parkinson’s disease. Here, we evaluate the cancer pattern among people diagnosed with Parkinson’s disease in an extension of our previous cohort study. For this Danish population-based cohort study, we identified 20,000 people with Parkinson’s disease diagnosed in 1977–2006, from the National Danish Hospital Register. Cohort members were followed up for cancer in the Danish Cancer Registry until December 31, 2008, and their incidence rates of cancer were compared to age-, sex- and calendar period-specific rates in the general population as standardized incidence rate ratios (SIRs). In subanalyses, we estimated the risk for cancer among patients with early onset Parkinson’s disease and we also compared breast tumor characteristics among women with Parkinson’s disease to that of a control group. The overall cancer risk in our cohort was decreased [SIR = 0.86; 95% confidence interval (CI) = 0.83–0.90], as were those for smoking-related (SIR = 0.65; 95% CI = 0.60–0.70) and nonsmoking-related cancers (SIR = 0.79; 95% CI = 0.71–0.86). The cohort had increased risks for malignant melanoma (SIR = 1.41; 95% CI = 1.09–1.80), nonmelanoma skin cancer (SIR = 1.29; 95% CI = 1.18–1.39) and female breast cancer (SIR = 1.17; 95% CI = 1.02–1.34). Among patients with early onset Parkinson’s disease, the risk for cancer was comparable to that of the general population. Of breast tumor characteristics, only grade of malignancy differed between Parkinson’s disease women and controls. This study confirms a lower cancer risk among people with Parkinson’s disease. Increased risks for malignant melanoma, nonmelanoma skin cancer and breast cancer might be due to shared risk factors with Parkinson’s disease.
Parkinson’s disease; cancer; population-based cohort; Denmark
A human papillomavirus (HPV) was cloned from a patient with multiple squamous cell carcinomas (SCCs) and identified as HPV88, recently categorized into a new species within the genus Gamma. The HPV88 viral load in an SCC of the index patient exceeded 1 million copies/cell. By contrast, a survey of 447 skin lesions (79 actinic keratoses, 73 seborrhoeic keratoses, 169 basal cell carcinomas and 126 SCCs) and 362 healthy skin biopsies found detectable HPV88 DNA in only 7 specimens. All these had very low viral loads (<1 copy/103 cells) implying extreme biological variability in viral load.
tumor virology; infection; diagnostics; real-time PCR
Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of the MLH1 gene, characterized by soma-wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss-of-heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation-associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair–deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1.
colorectal cancer; Lynch syndrome; MLH1 epimutation; microsatellite instability; BRAF
To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual-level pooled data from 12 case-control studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, and 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta-carotene, iron, selenium, and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, and pack-years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR=0.76, 95% CI=0.59-0.96) and with ever use of calcium supplement (OR=0.64, 95% CI=0.42-0.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR=0.72, 95% CI=0.54-0.97) and more than 365 tablets of cumulative calcium intake (OR=0.36, 95% CI=0.16-0.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of head and neck cancer.
vitamin supplement; mineral supplement; head and neck cancer
We recently reported that overexpression of progastrin in embryonic epithelial cells (HEKmGAS-cells) increased proliferation of the cells, compared to that of control HEKC-cells. Here we report the novel finding that tumorigenic and metastatic potential of HEKmGAS cells is also increased significantly, compared to that of HEKC cells. Cell-surface associated annexinA2 (CS-ANXA2) binds progastrin and is over-expressed on cancer-cells, allowing us to successfully use fluorescently-labeled progastrin-peptide for enumerating metastatic lesions of transformed/cancer cells in vivo. Next, we examined the hypothesis that increased tumorigenic/metastatic potential of isogenic HEKmGAS vs HEKC cells maybe due to transformed-phenotype of stem-cells. FACSorting/FACScanning of cells demonstrated significant increases in percent DCLK1/Lgr5 positive stem-cells, co-expressing CD44/CS-ANXA2, in HEKmGAS vs HEKC-cells. Distinct differences were noted in morphology of HEKC vs HEKmGAS spheroidal growths on non-adherent cultures (selective for stem cells). HEKC-spheroids were rounded with distinct perimeters (basement membranes?), while HEKmGAS-spheroids were amorphous, with no perimeters. Relative levels of DCLK1/Lgr5/CD44 and AnnexinA2/β-catenin/pNFκBp65/metalloproteinases were significantly increased in HEKmGAS vs HEKC-cells, growing either as mono-layer cultures, 3D-spheroids (in vitro), or xenografts (in vivo). Interestingly, HEKC-cells enriched for CS-ANXA2, developed amorphous spheroids, while down-regulation of ANXA2 in HEKmGAS-clones, resulted in loss of matrixmetalloproteinases and re-formation of rounded spheroids, suggesting high levels of CS-ANXA2/matrixmetalloproteinases may impact spheroid morphology. Down-regulation of DCLK1 significantly attenuated activation of β-catenin, with loss of proliferation of HEKmGAS and HEKC-cells, suggesting DCLK1 is required for maintaining proliferation of cells.
Our results suggest the novel possibility that transformed stem-cells, unlike non-transformed stem-cells, co-express stem-cell-markers DCLK1 and CD44 with CS-ANXA2.
DCLK1; CD44; β-catenin; Stem-Cells; annexinA2
Greater consumption of red and processed meat has been associated with an increased risk of colorectal cancer in several recent meta-analyses. Heterocyclic amines (HCAs) have been hypothesized to underlie this association. In this prospective analysis conducted within the Multiethnic Cohort Study, we examined whether greater consumption of total, red, or processed meat was associated with the risk of colorectal cancer among 165,717 participants who completed a detailed food frequency questionnaire at baseline. In addition, we examined whether greater estimated intake of HCAs was associated with the risk of colorectal cancer among 131,763 participants who completed a follow-up questionnaire that included a meat-cooking module. A total of 3,404 and 1,757 invasive colorectal cancers were identified from baseline to the end of follow-up, and from the date of administration of the meat-cooking module to the end of follow-up, respectively. Proportional hazards models were used to estimate basic and multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for colorectal cancer associated with dietary exposures. In multivariable models, no association with the risk of colorectal cancer was detected for density-adjusted total meat (RRQ5 vs Q1=0.93 [0.83–1.05]), red meat (RR =1.02 [0.91–1.16]), or processed meat intake (RR =1.06 [0.94–1.19]), or for total (RR =0.90 [0.76–1.05]) or specific HCA intake whether comparing quintiles of dietary exposure or using continuous variables. Although our results do not support a role for meat or for HCAs from meat in the etiology of colorectal cancer, we cannot rule out the possibility of a modest effect.
colorectal cancer; meat; multiethnic population; heterocyclic amines; food frequency questionnaire
Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98–0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93–0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99–1.08; pdifference=0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix.
Alcohol is not an established risk factor for prostate cancer; however, the current work suggests that heavy drinking could cause a small increase in risk of the more aggressive forms. If the results are confirmed to be causal, prostate cancer risk will be added to the many long-term health risks of heavy drinking, and public health strategies will then also reduce high-risk, poorer prognosis prostate cancer. The authors also found that heavy drinkers have lower PSA levels, suggesting that heavy alcohol consumption could be used as a marker to identify men in whom some cancers might be missed.
alcohol; prostate cancer; prostate specific antigen; ProtecT, nested case–control
Even in the era of highly effective HPV prophylactic vaccines, substantial reduction in worldwide cervical cancer mortality will only be realized if effective early detection and treatment of the millions of women already infection and the millions who may not receive vaccination in the next decade can be broadly implemented through sustainable cervical cancer screening programs. Effective programs must meet three targets: 1) at least 70% of the targeted population should be screened at least once in a lifetime, 2) screening assays and diagnostic tests must be reproducible and sufficiently sensitive and specific for the detection of high-grade precursor lesions (i.e., CIN2+), and 3) effective treatment must be provided. We review the evidence that HPV DNA screening from swabs collected by the women in their home or village is sufficiently sound for consideration as a primary screening strategy in the developing world, with sensitivity and specificity for detection of CIN2+ as good or better than Pap smear cytology and VIA. A key feature of a self-collected HPV testing strategy (SC-HPV) is the move of the primary screening activities from the clinic to the community. Efforts to increase the affordability and availability of HPV DNA tests, community education and awareness, development of strong partnerships between community advocacy groups, health care centers and regional or local laboratories, and resource appropriate strategies to identify and treat screen-positive women should now be prioritized to ensure successful public health translation of the technologic advancements in cervical cancer prevention.
Epidemiologic evidence suggests that a diet rich in fruits and vegetables is associated with a reduced risk of prostate cancer (PCa) development. Although several dietary compounds have been tested in preclinical PCa prevention models, no agents have been identified that either prevent the progression of premalignant lesions or treat advanced disease. Momordica charantia, known as bitter melon in English, is a plant that grows in tropical areas worldwide and is both eaten as a vegetable and used for medicinal purposes. We have isolated a protein, designated as MCP30, from bitter melon seeds. The purified fraction was verified by SDS-PAGE and mass spectrometry to contain only 2 highly related single chain Type I ribosome-inactivating proteins (RIPs), α-momorcharin and β-momorcharin. MCP30 induces apoptosis in PIN and PCa cell lines in vitro and suppresses PC-3 growth in vivo with no effect on normal prostate cells. Mechanistically, MCP30 inhibits histone deacetylase-1 (HDAC-1) activity and promotes histone-3 and -4 protein acetylation. Treatment with MCP30 induces PTEN expression in a prostatic intraepithelial neoplasia (PIN) and PCa cell lines resulting in inhibition of Akt phosphorylation. In addition, MCP30 inhibits Wnt signaling activity through reduction of nuclear accumulation of β-catenin and decreased levels of c-Myc and Cyclin-D1. Our data indicate that MCP30 selectively induces PIN and PCa apoptosis and inhibits HDAC-1 activity. These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer.
ribosome inactivating protein; HDAC inhibitor; prostate cancer; tumor suppresive gene; dietary factors
Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate-refractory gastrointestinal stromal tumors). This single-institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma, and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty-eight patients were enrolled, and 35% were heavily pretreated (≥2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression-free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1, and 2.5 and 13.6 months, respectively. The 3-month progression-free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma, and MFH were 75% and 69.2%, 60%, and 62.5%, and and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low-grade disease could have been included and the small numbers, a 3-month progression-free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.
soft tissue sarcoma; targeted therapy; sunitinib malate; progression-free rate; survival; tyrosine kinase inhibitor
The NADPH-oxidase 1 (Nox1) is a homolog of gp91phox, the catalytic subunit of the phagocyte superoxide-generating NADPH-oxidase. Nox1 is expressed in normal colon epithelial cells and in colon tumor cell lines, and overexpression in model cells has been implicated in stimulation of mitogenesis and angiogenesis and inhibition of apoptosis. This suggests that aberrant expression of Nox1 could contribute to the development of colorectal cancer. Herein, we examine the expression of Nox1 mRNA in 24 colon tumors of various stages compared with paired adjacent normal tissue from the same patient, and correlate expression with some common mutations associated with colon cancer. Nox1 was overexpressed compared with paired normal tissue in 57% of tumors as early as the adenoma stage, with no correlation of expression level with tumor stage. Overexpression of Nox1 mRNA correlated with Nox1 protein levels assessed by immunofluorescence and immunohistochemistry with an antibody specific for Nox1. There was a strong correlation between Nox1 mRNA level and activating mutations in codons 12 and 13 of K-Ras. Eighty percent (8/10) of tumors with codons 12 and 13 mutations had a 2-fold or more increase in Nox1 mRNA, and 70% (7/10) had a 5-fold or greater increase. Transgenic mice expressing K-RasG12V in the intestinal epithelium also expressed markedly elevated Nox1 in both small and large intestine. There was no correlation between inactivating mutations in the tumor suppressor p53 and Nox1 expression. We conclude that Nox1 mRNA and protein are overexpressed in colon cancer and are strongly correlated with activating mutations in K-Ras.
K-Ras; Nox1; reactive oxygen species; colorectal cancer
Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of non-oncogenic HPV types in the vagina. In the current investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by PCR. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison group – before versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% versus 12%; P<0.001) and after hysterectomy (56% versus 6%; P<0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence (odds ratio [OR]=0.71; 95% confidence interval [CI]=0.59-0.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR=0.48; 95%CI=0.35-0.66) than non-oncogenic HPV types (OR=0.89; 95%CI=0.71-1.11; Pinteraction=0.002). Overall, we observed greater reductions in oncogenic than non-oncogenic HPV prevalence following hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared with vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer.
vaginal; HPV; hysterectomy; viral tropism; HIV
Cancer stem cells (CSCs) have been successfully isolated from solid tumors and are believed to be initiating cells of primary, metastatic and recurrent tumors. Imaging and therapeutic reagents targeted to CSCs have potential to detect subclinical tumors and completely eradicate the disease. Previously, we have demonstrated that Mab CC188 binds to colon cancer CD133- and CD133+ (CSCs) cells. In this study, we examined the reactivity of Mab CC188 to ovarian cancer cells including CD133+ cells and primary tumor tissues using immunofluorescence staining methods and tissue microarray technique. We also explored the feasibility of using NIR dye-labeled Mab CC188 probe to image ovarian tumors in vivo. Mab CC188 stains both CD133- and CD133+ cells of ovarian cancer. Tissue microarray analysis reveals that 75% (92/123) of ovarian cancer cases are positively stained with Mab CC188. Weak positive (±), positive (+), strong positive (++) and very strong positive (+++) stains are 14.8%, 3.7%, 11% and 24.4% respectively. In contrast, Mab CC188 staining is low in normal cells and tissues. In vivo study show that significant amounts of the probe accumulates in the excretion organs in the early period post injection. At 24 hours, the imaging probes have largely accumulates in the tumor, while the intensity of the imaging probe decreases in the liver. The tumor uptake was still evident at 120 hours post injection. Our work suggests that Mab CC188 based imaging and therapeutic reagents are capable of detecting early stage ovarian tumors and effectively treating the tumor.
Monoclonal antibody; Cancer stem cell; Ovarian cancer; Optical imaging
Diabetes has been consistently associated with an increased risk of liver, pancreas and endometrial cancer and has been implicated as a risk factor for esophageal and gastric cancers, although this association has been less well studied. We sought to determine the role of diabetes in the etiology of esophageal, gastric cardia and distal gastric adenocarcinomas. This analysis included patients with esophageal adenocarcinoma (n=209), gastric cardia adenocarcinoma (n=257) and distal gastric adenocarcinoma (n=382), and 1,309 control participants from a population-based case-control study conducted in Los Angeles County. The study included non-Hispanic whites, African Americans, Hispanics and Asian Americans. The association of diabetes with the three tumor types was estimated using polytomous logistic regression. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. Nine percent of control participants and 13% of the case patients reported a history of diabetes. After adjustment for age, gender, race, birthplace, education, cigarette smoking status and body mass index, diabetes was associated with an increased risk of esophageal adenocarcinoma (OR, 1.48; 95% CI, 0.94–2.32; P=0.089) and distal gastric adenocarcinoma (OR, 1.47; 95% CI, 1.01–2.15; P=0.045), but was not associated with risk of gastric cardia adenocarcinoma (OR, 0.96; 95% CI, 0.59–1.55; P=0.87). However, the association between diabetes and risk of DGA was statistically significant only among patients for whom we interviewed their next-of-kin. This study further investigated the association between diabetes and adenocarcinomas of the esophagus and distal stomach.
diabetes; esophageal adenocarcinoma; gastric adenocarcinoma; case-control study; polychotomous logistic regression
The aim of this study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric non-cardia adenocarcinoma. From 1995–1996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric non-cardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Though apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null (e.g. EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95%CI) 1.66 (1.27–2.18) P for trend <0.01; EAC multivariate adjusted HR (95%CI) 1.17 (0.84–1.64) P for trend=0.58). Similar patterns were also observed for fat subtypes (e.g. EAC saturated fat, energy adjusted HR (95%CI) 1.79 (1.37–2.33) P for trend <0.01; EAC saturated fat, multivariate adjusted HR (95%CI) 1.27 (0.91–1.78) P for trend=0.28). However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5–<25 kg/m2) (HR (95%CI) 0.76 (0.63–0.92)), that was not present in overweight subjects (HR (95%CI) 1.04 (0.96–1.14)), or in unstratified analysis (HR (95%CI) 0.97 (0.90–1.05)). P for interaction=0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; though a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI.
cohort; dietary fat; esophageal neoplasms; stomach neoplasms; prospective
Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that bromo-onoscapine (EM011), a rationally-designed synthetic derivative of a natural non-toxic tubulin-binding alkaloid-noscapine, that reduces the dynamics of microtubules, causes a reversible G2/M arrest in wild type mouse embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs after APC deletion with siRNA. Furthermore, both β-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 prior to caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated ApcMin/+ mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of ApcMin/+ mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients.
Familial Adenomatous Polyposis (AFP); Colon Cancer; bromo noscapine; EM011; Noscapine; β-catenin
Women with high-grade cervical intraepithelial neoplasia (HGCIN) frequently present with multiple cervical lesions, and multiple concomitant Human papillomavirus (HPV) genotype infections. To elucidate HPV genotype attribution in different regions on the cervix, we performed molecular mapping of cervical disease in women with HGCIN. Thirteen subjects referred to colposcopy for abnormal cervical cancer screening results were included. A cervical smear and biopsies from four different areas on the cervix were collected. HPV genotyping using Linear Array (for cytology) or SPF-10-LiPA25 (for histology) were performed in 13 smears, 52 whole sections from biopsies, and 138 tissue regions isolated with laser capture microdissection (LCM). Twelve subjects had a diagnosis of CIN3 and one subject had a diagnosis of CIN2 based on the worst histology found in four biopsies. Eight of the 13 smears (62%) showed multiple genotype infections. Four of 13 women (31%) had multiple HPV infections in their biopsies. After performing LCM-PCR, only one woman (8%) had two different carcinogenic HPV types in morphologically distinct, but colliding HGCIN lesions. HPV16 was identified as the causal type in all women with HPV16 in cytology. A large proportion of other HPV types found in cervical smears were not detected at the tissue level. Using tissue-based genotyping and LCM-PCR analysis, we were able to attribute an individual HPV type to each area of CIN lesions. We demonstrate that HPV16 is even more etiologically dominant than previously thought, based on various genotype attribution models.
CIN; HPV; colposcopy; LCM; genotyping
HMG Co-A reductase inhibitors (statins) have shown inverse associations with cancer risks, but the results have been inconsistent. Since there is no previous published data in brain tumors, we conducted a case-control study to investigate statin therapy and risk of glioma. We also further evaluated the use of nonsteriodal anti-inflammatory drugs (NSAIDs) in the risk of these tumors. We recruited newly diagnosed glioma cases and frequency matched controls at Columbia University and the University of California San Francisco. Standardized questions on statins and NSAIDs were used at both institutions. Intakes of these drugs were defined as > 6 months of at least twice weekly use versus less than this amount or never use. From July 2007 to January 2010, we recruited a total of 517 cases and 400 controls. Simvastatin and lovastatin showed significant inverse associations with glioma (OR = 0.49, 95% CI 0.30, 0.81 and OR = 0.47, 95% CI 0.24, 0.93, respectively). In NSAIDs, aspirin use was also inversely related to glioma risk (OR = 0.68, 95% CI 0.49, 0.96). Both statins and NSAIDs showed significant inverse trends between duration of drug use and glioma risks (trend tests p = 0.03 and p = 0.02, respectively), and drug intake > 120 months demonstrated the most significant associations for both types of medication. The inverse association between statin therapy and risk of glioma supports the roles of Ras/Rho GTPases or inflammatory cytokines in gliomagenesis, and similar relationship between NSAIDs and glioma highlights the importance of cyclo-oxygenase-2 in glioma pathogenesis.
HMG-CoA Reductase Inhibitors; statins; non-steriodal anti-inflammatory drugs; glioma; glioblastoma; pharmaco-epidemiology
Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer, but little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site-specific cancer in a large, regionally diverse cohort (450,934 white, non-Hispanic subjects (50-71 years old) in the prospective NIH-AARP Diet and Health Study) after accounting for individual-level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the U.S. Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HR) and 95% confidence intervals (CI) for quartiles of UVR exposure. Restricted cubic splines examined non-linear relationships. Over 9 years of follow-up, UVR exposure was inversely associated with total cancer risk (N=75,917; highest vs. lowest quartile, HR=0.97 (0.95, 0.99), p-trend<0.001). In site-specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest vs. lowest quartile, HR=1.22 (1.13, 1.32), p-trend<0.001) and decreased risk of Non-Hodgkin’s lymphoma (HR=0.82 (0.74, 0.92)) and colon (HR=0.88 (0.82, 0.96)), squamous cell lung (HR=0.86 (0.75, 0.98)), pleural (HR=0.57 (0.38, 0.84)), prostate (HR=0.91 (0.88, 0.95)), kidney (HR=0.83 (0.73, 0.94)), and bladder (HR=0.88 (0.81, 0.96)) cancers (all p-trend<0.05). We also found non-linear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer.
Ultraviolet radiation; cancer; vitamin D; prospective