Showing papers in "International Journal of Cancer in 2007"

Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update.

Abstract: Data on human papillomavirus (HPV) type distribution in invasive and pre-invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV-based screening tests. A meta-analyses of HPV type distribution in invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74-77%) than in Africa, Asia and South/Central America (65-70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under-represented, and other high-risk HPV types significantly over-represented in HSIL compared to ICC, suggesting differences in type-specific risks for progression. Data on HPV-typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.

Inflammation and cancer: an ancient link with novel potentials.

Abstract: Infection and chronic inflammation contribute to about 1 in 4 of all cancer cases. Mediators of the inflammatory response, e.g., cytokines, free radicals, prostaglandins and growth factors, can induce genetic and epigenetic changes including point mutations in tumor suppressor genes, DNA methylation and post-translational modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer. Recent discovery of an interaction between microRNAs and innate immunity during inflammation has further strengthened the association between inflammation and cancer.

Chronic inflammation and oxidative stress in human carcinogenesis.

Abstract: A wide array of chronic inflammatory conditions predispose susceptible cells to neoplastic transformation. In general, the longer the inflammation persists, the higher the risk of cancer. A mutated cell is a sine qua non for carcinogenesis. Inflammatory processes may induce DNA mutations in cells via oxidative/nitrosative stress. This condition occurs when the generation of free radicals and active intermediates in a system exceeds the system's ability to neutralize and eliminate them. Inflammatory cells and cancer cells themselves produce free radicals and soluble mediators such as metabolites of arachidonic acid, cytokines and chemokines, which act by further producing reactive species. These, in turn, strongly recruit inflammatory cells in a vicious circle. Reactive intermediates of oxygen and nitrogen may directly oxidize DNA, or may interfere with mechanisms of DNA repair. These reactive substances may also rapidly react with proteins, carbohydrates and lipids, and the derivative products may induce a high perturbation in the intracellular and intercellular homeostasis, until DNA mutation. The main substances that link inflammation to cancer via oxidative/nitrosative stress are prostaglandins and cytokines. The effectors are represented by an imbalance between pro-oxidant and antioxidant enzyme activities (lipoxygenase, cyclooxygenase and phospholipid hydroperoxide glutathione-peroxidase), hydroperoxides and lipoperoxides, aldehydes and peroxinitrite. This review focalizes some of these intricate events by discussing the relationships occurring among oxidative/nitrosative/metabolic stress, inflammation and cancer.

Diabetes mellitus and risk of breast cancer: a meta-analysis.

Abstract: Diabetes mellitus has been associated with an increased risk of several types of cancers, but its relationship with breast cancer remains unclear. We conducted a meta-analysis of case-control and cohort studies to assess the evidence regarding the association between diabetes and risk of breast cancer. Studies were identified by searching MEDLINE (1966-February 2007) and the references of retrieved articles. We identified 20 studies (5 case-control and 15 cohort studies) that reported relative risk (RR) estimates (odds ratio, rate ratio/hazard ratio, or standardized incidence ratio) with 95% confidence intervals (CIs) for the relation between diabetes (largely Type II diabetes) and breast cancer incidence. Summary RRs were calculated using a random-effects model. Analysis of all 20 studies showed that women with (versus without) diabetes had a statistically significant 20% increased risk of breast cancer (RR, 1.20; 95% CI, 1.12-1.28). The summary estimates were similar for case-control studies (RR, 1.18; 95% CI, 1.05-1.32) and cohort studies (RR, 1.20; 95% CI, 1.11-1.30). Meta-analysis of 5 cohort studies on diabetes and mortality from breast cancer yielded a summary RR of 1.24 (95% CI, 0.95-1.62) for women with (versus without) diabetes. Findings from this meta-analysis indicate that diabetes is associated with an increased risk of breast cancer.

A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen.

Abstract: Human papillomavirus type 16 (HPV16) plays a role in the development of a subgroup of head and neck squamous cell carcinomas (HNSCC). However, uncertainty exists about the true impact of HPV in this tumor type as conflicting reports have been published with prevalence rates from 0 to 100%. We aimed to find a detection algorithm of a biologically and thus clinically meaningful infection, applicable for high-throughput screening of frozen and formalin-fixed paraffin embedded (FFPE) specimens. By considering detection of HPV E6 oncogene expression in frozen biopsies as gold standard for a meaningful HPV infection, the value of several assays was evaluated on FFPE tumor specimens and sera of 48 HNSCC patients. The following assays were evaluated on FFPE tissue samples: HPV DNA general primer (GP)5+/6+ PCR, viral load analysis, HPV16 DNA FISH detection, HPV16 E6 mRNA RT-PCR, p16 immunostaining, and on corresponding serum samples detection of antibodies against the HPV16 proteins L1, E6 and E7. Comparing single assays on FFPE tissue samples detection of E6 expression by RT-PCR was superior, but application remains at present limited to HPV16 detection. Most suitable algorithm with 100% sensitivity and specificity appeared p16 immunostaining followed by GP5+/6+ PCR on the p16-positive cases. We show that clinically meaningful viral HPV infections can be more reliably measured in FFPE HNSCC samples in a standard and high throughput manner, paving the way for prognostic and experimental vaccination studies, regarding not only HNSCC, but possibly also cancer types with HPV involvement in subgroups such as penile and anal cancer.

Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis.

Abstract: Human papillomavirus (HPV) has been associated with head and neck squamous cell carcinomas (HNSCC), especially of the oropharynx, with highest distribution in the tonsils. HPV infection has been associated with improved outcome, although not all the studies show consistent results. The reason for this is not clear. We reviewed all published articles and conducted a meta-analysis on the overall relationship between HPV infection and overall survival (OS) and disease-free survival (DFS) in HNSCC. Patients with HPV-positive HNSCC had a lower risk of dying (meta HR: 0.85, 95% CI: 0.7-1.0), and a lower risk of recurrence (meta HR: 0.62, 95%CI: 0.5-0.8) than HPV-negative HNSCC patients. Site-specific analyses show that patients with HPV-positive oropharyngeal tumours had a 28% reduced risk of death (meta HR: 0.72, 95%CI: 0.5-1.0) in comparison to patients with HPV-negative oropharyngeal tumours. Similar observations were made for DFS (meta HR: 0.51, 95% CI: 0.4-0.7). There was no difference in OS between HPV-positive and negative non-oropharyngeal patients. The observed improved OS and DFS for HPV-positive HNSCC patients is specific to the oropharynx; these tumours may have a distinct etiology from those tumours in non-oropharyngeal sites.

Nanomedicine for drug delivery and imaging : A promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles

Abstract: The diagnosis and treatment of cancer or tumor at the cellular level will be greatly improved with the development of techniques that enable the delivery of analyte probes and therapeutic agents into cells and cellular compartments. Organic and inorganic nanoparticles that interface with biological systems have recently attracted widespread interest in the fields of biology and medicine. The new term nanomedicine has been used recently. Nanoparticles are considered to have the potential as novel intravascular or cellular probes for both diagnostic (imaging) and therapeutic purposes (drug/gene delivery), which is expected to generate innovations and play a critical role in medicine. Target-specific drug/gene delivery and early diagnosis in cancer treatment is one of the priority research areas in which nanomedicine will play a vital role. Some recent breakthroughs in this field recently also proved this trend. Nanoparticles for drug delivery and imaging have gradually been developed as new modalities for cancer therapy and diagnosis. In this article, we review the significance and recent advances of gene/drug delivery to cancer cells, and the molecular imaging and diagnosis of cancer by targeted functional nanoparticles.

CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity

Abstract: Recently increasing reported data have suggested that only a small subset of cancer cells possess capability to initiate malignancies including leukemia and solid tumors, which was based on investigation in these cells displaying a distinct surface marker pattern within the primary cancers. CD133 is a putative hematopoietic and neuronal stem-cell marker, which was also considered as a tumorigenic marker in brain and prostate cancer. We hypothesized that CD133 was a marker closely correlated with tumorigenicity, since it was reported that CD133 expressed in human fetal liver and repairing liver tissues, which tightly associated with hepatocarcinogenesis. Our findings showed that a small population of CD133 positive cells indeed exists in human hepatocellular carcinoma (HCC) cell lines and primary HCC tissues. From SMMC-7721 cell line, CD133+ cells isolated by MACS manifested high tumorigenecity and clonogenicity as compared with CD133− HCC cells. The implication that CD133 might be one of the markers for HCC cancer stem-like cells needed further investigation. © 2006 Wiley-Liss, Inc.

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound.

Abstract: The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 +/- 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 +/- 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r = 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRI-guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies.

Risk‐based selection from the general population in a screening trial: Selection criteria, recruitment and power for the Dutch‐Belgian randomised lung cancer multi‐slice CT screening trial (NELSON)

Abstract: A method to obtain the optimal selection criteria, taking into account available resources and capacity and the impact on power, is presented for the Dutch-Belgian randomised lung cancer screening trial (NELSON). NELSON investigates whether 16-detector multi-slice computed tomography screening will decrease lung cancer mortality compared to no screening. A questionnaire was sent to 335,441 (mainly) men, aged 50-75. Smoking exposure (years smoked, cigarettes/day, years quit) was determined, and expected lung cancer mortality was estimated for different selection scenarios for the 106,931 respondents, using lung cancer mortality data by level of smoking exposure (US Cancer Prevention Study I and II). Selection criteria were chosen so that the required response among eligible subjects to reach sufficient sample size was minimised and the required sample size was within our capacity. Inviting current and former smokers (quit 15 cigarettes/day during >25 years or >10 cigarettes/day during >30 years was most optimal. With a power of 80%, 17,300-27,900 participants are needed to show a 20-25% lung cancer mortality reduction 10 years after randomisation. Until October 18, 2005 11,103 (first recruitment round) and 4,325 (second recruitment round) (total = 15,428) participants have been randomised. Selecting participants for lung cancer screening trials based on risk estimates is feasible and helpful to minimize sample size and costs. When pooling with Danish trial data (n = +/-4,000) NELSON is the only trial without screening in controls that is expected to have 80% power to show a lung cancer mortality reduction of at least 25% 10 years after randomisation.

Risk factors for prostate cancer incidence and progression in the health professionals follow-up study

Abstract: Risk factors for prostate cancer could differ for various sub-groups, such as for "aggressive" and "non-aggressive" cancers or by grade or stage. Determinants of mortality could differ from those for incidence. Using data from the Health Professionals Follow-Up Study, we re-examined 10 factors (cigarette smoking history, physical activity, BMI, family history of prostate cancer, race, height, total energy consumption, and intakes of calcium, tomato sauce and alpha-linolenic acid) using multivariable Cox regression in relation to multiple subcategories for prostate cancer risk. These were factors that we previously found to be predictors of prostate cancer incidence or advanced prostate cancer in this cohort, and that have some support in the literature. In this analysis, only 4 factors had a clear statistically significant association with overall incident prostate cancer: African-American race, positive family history, higher tomato sauce intake (inversely) and alpha-linolenic acid intake. In contrast, for fatal prostate cancer, recent smoking history, taller height, higher BMI, family history, and high intakes of total energy, calcium and alpha-linolenic acid were associated with a statistically significant increased risk. Higher vigorous physical activity level was associated with lower risk. In relation to these risk factors, advanced stage at diagnosis was a good surrogate for fatal prostate cancer, but high-grade (Gleason >/= 7 or Gleason >/= 8) was not. Only for high calcium intake was there a close correspondence for associations among high-grade cancer, advanced and fatal prostate cancer. Tomato sauce (inversely) and alpha-linolenic acid (positively) intakes were strong predictors of advanced cancer among those with low-grade cancers at diagnosis. Although the proportion of advanced stage cancers was much lower after PSA screening began, risk factors for advanced stage prostate cancers were similar in the pre-PSA and PSA era. The complexity of the clinical and pathologic manifestations of prostate cancer must be considered in the design and interpretation of studies.

Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer

Abstract: Molecular prognostic indicators for oropharyngeal squamous cell carcinoma (OSCC), including HPV-DNA detection, epidermal growth factor receptor (EGFR) and p16 expression, have been suggested in the literature, but none of these are currently used in clinical practice. To compare these predictors, 106 newly diagnosed OSCC for the presence of HPV-DNA and expression of p16 and EGFR were analyzed. The 5-year disease-free survival (DFS) and overall survival (OS) were calculated in relation to these markers and a multivariate Cox analysis was performed. Twenty-eight percent of the cases contained oncogenic HPV-DNA and 30% were positive for p16. The p16 expression was highly correlated with the presence of HPV-DNA (p < 0.001). Univariate analysis of the 5-year DFS revealed a significantly better outcome for patients with p16-positive tumors (84% vs. 49%, p = 0.009). EGFR-negative tumors showed a tendency toward a better prognosis in DFS (74% vs. 47%, p = 0.084) and OS (70% vs. 45%, p = 0.100). Remarkable and highly significant was the combination of p16 and EGFR expression status, leading to 5-year DFS of 93% for p16+/EGFR- tumors vs. 39% for p16-/EGFR+ tumors (p = 0.003) and to a 5-year OS of 79% vs. 38%, respectively (p = 0.010). In multivariate analysis p16 remained a highly significant prognostic marker for DFS (p = 0.030) showing a 7.5-fold increased risk for relapse in patients with p16-negative tumors. Our data indicate that p16 expression is the most reliable prognostic marker for OSCC and further might be a surrogate marker for HPV-positive OSCC. HPV+/p16+ tumors tended to have decreased EGFR expression, but using both immunohistological markers has significant prognostic implications.

Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals.

Abstract: Biological, biochemical and physical stimuli activate inflammatory leukocytes, such as macrophages, resulting in induction and synthesis of proinflammatory proteins and enzymes, together with free radicals, as innate immune responses. On the other hand, chronic and dysregulated activation of some inducible enzymes, including NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, have been shown to play pivotal roles in the development of certain inflammatory diseases such as oncogenesis. While the use of synthetic agents, especially those targeting molecules, is an attractive and reasonable approach to prevent carcinogenesis, it should be noted that traditional herbs and spices also exist along with their active constituents, which have been demonstrated to disrupt inflammatory signal transduction pathways. In this mini-review, the molecular mechanisms of activation or induction of NOX, iNOS and COX-2, as well as some food phytochemicals with marked potential to regulate those key inflammatory molecules, are highlighted. For example, 1'-acetoxychavicol acetate, which occurs in the rhizomes of the subtropical Zingiberaceae plant, has been shown to attenuate NOX-derived superoxide generation in macrophages, as well as lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production through the suppression of iNOS and COX-2 synthesis, respectively. Notably, this phytochemical has exhibited a wide range of cancer prevention activities in several rodent models of inflammation-associated carcinogenesis. Herein, the cancer preventive potentials of several food phytochemicals targeting the induction of NOX, iNOS and COX-2 are described.

Microrna expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma

Abstract: Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that accounts for nearly 40% of all lymphoid tumors. This heterogeneous disease can be divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes by gene expression and immunohistochemical profiling. Using microarray analysis on prototypic cell lines, we identified microRNAs (miR-155, miR-21 and miR-221) that were more highly expressed in ABC-type than GCB-type cell lines. These microRNAs were over-expressed in de novo DLBCL (n = 35), transformed DLBCL (n = 14) and follicular center lymphoma cases (n = 27) compared to normal B cells. Consistent with the cell line model, expression levels were higher in DLBCL cases with an ABC-type immunophenotype than those that were GCB-type (p < 0.05). Moreover, using multivariate analysis we found that expression of miR-21 was an independent prognostic indicator in de novo DLBCL (p < 0.05). Interestingly, expression levels of both miR-155 and miR-21 were also higher in nonmalignant ABC than in GCB cells. As we also demonstrate that expression of microRNAs can be measured reliably from routine paraffin-embedded biopsies of more than 8-years-old (p < 0.001), we suggest that microRNAs could be clinically useful molecular markers for DLBCL as well as other cancers.

Dietary polyphenolic phytochemicals—promising cancer chemopreventive agents in humans? A review of their clinical properties

Abstract: Epidemiological and preclinical evidence suggests that polyphenolic phytochemicals exemplified by epigallocatechin gallate from tea, curcumin from curry and soya isoflavones possess cancer chemopreventive properties. Whilst such naturally occurring polyphenols have been the subject of numerous mechanistic studies in cells, information on their clinical properties, which might help assess their promise as human cancer chemopreventive agents, is scarce. Therefore, we present a review of pilot studies and trials with a cancer chemoprevention-related rationale, in which either healthy individuals or patients with premalignant conditions or cancer received polyphenolic phytochemicals. The review identifies trial design elements specifically applicable to polyphenolic phytochemicals. The available evidence for tea polyphenols tentatively supports their advancement into phase III clinical intervention trials aimed at the prevention of progression of prostate intraepithelial neoplasia, leukoplakia or premalignant cervical disease. In the case of curcumin and soya isoflavones more studies in premalignacies seem appropriate to optimise the nature and design of suitable phase III trials. The abundance of flavonoids and related polyphenols in the plant kingdom makes it possible that several hitherto uncharacterised agents with chemopreventive efficacy are still to be identified, which may constitute attractive alternatives to currently used chemopreventive drugs.

The non‐Hodgkin lymphomas: A review of the epidemiologic literature

Abstract: The non-Hodgkin lymphomas (NHL) are a heterogeneous group of B-cell and T-cell neoplasms that arise primarily in the lymph nodes NHL incidence rates in the US doubled between about 1970 and 1990, and stabilized during the 1990s NHL accounts for approximately 34% of cancer deaths in the US Although some of the observed patterns in NHL have been related to HIV/AIDS, these conditions cannot fully explain the magnitude of the changes; neither do changes in classification systems nor improved diagnostic capabilities Studies of occupational and environmental exposures (eg, pesticides, solvents) have produced no consistent pattern of significant positive associations Inverse associations with ultraviolet radiation exposure and alcohol and fish intake, and positive associations with meat and saturated fat intake have been reported in several studies; additional studies are needed to confirm or refute these associations Family history of NHL or other hematolympho-proliferative cancers and personal history of several autoimmune disorders are associated with increased risk of NHL, but are not likely to account for a large proportion of cases HIV and other infectious agents, such as human herpesvirus 8 and Epstein-Barr, appear to be associated with differing types of NHL, such as some B-cell lymphomas Future epidemiologic studies should evaluate associations by NHL type, enhance exposure information collected, and elucidate factors that may identify susceptible (or resistant) subpopulations because of genetic, immunologic or other characteristics The extent to which the etiology of NHL types may differ is important to resolve in ongoing and future studies

Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies.

Abstract: Squamous cell carcinomas account for about 80% of cancers of the uterine cervix, and the majority of the remainder are adenocarcinomas. There is limited evidence on the extent to which these histological types share a common etiology. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 8,097 women with invasive squamous cell carcinoma, 1,374 women with invasive adenocarcinoma and 26,445 women without cervical cancer (controls) from 12 epidemiological studies. Compared to controls, the relative risk of each histological type of invasive cervical cancer was increased with increasing number of sexual partners, younger age at first intercourse, increasing parity, younger age at first full-term pregnancy and increasing duration of oral contraceptive use. Current smoking was associated with a significantly increased risk of squamous cell carcinoma (RR = 1.50, 95% CI: 1.35-1.66) but not of adenocarcinoma (RR = 0.86 (0.70-1.05)), and the difference between the two histological types was statistically significant (case-case comparison p < 0.001). A history of screening (assessed as having had at least one previous nondiagnostic cervical smear) was associated with a reduced risk of both histological types, but the reduction was significantly greater for squamous cell carcinoma than for adenocarcinoma (RR = 0.46 (0.42-0.50) and 0.68 (0.56-0.82), respectively; case-case comparison, p = 0.002). A positive test for cervical high-risk HPV-DNA was a strong risk factor for each histological type, with 74% of squamous cell carcinomas and 78% of adenocarcinomas testing positive for HPV types 16 or 18. Squamous cell and adenocarcinoma of the cervix share most risk factors, with the exception of smoking.

Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies.

Abstract: A number of studies have examined the association between body mass index (BMI) and risk of pancreatic cancer, but uncertainty about the relationship remains. We performed a meta-analysis to summarize the evidence from prospective studies investigating this association. We searched MEDLINE for studies published in any language from 1966 to November 2006. Prospective studies were included if they reported relative risks (RRs) with 95% confidence intervals (CIs) for the association between BMI and pancreatic cancer incidence or mortality. Study-specific RR estimates were combined by use of a random-effects model. A total of 21 independent prospective studies, involving 3,495,981 individuals and 8,062 pancreatic cancer cases, met the inclusion criteria. The estimated summary RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.12 (95% CI, 1.06–1.17; p-heterogeneity = 0.13) in men and women combined, 1.16 (95% CI, 1.05–1.28; p-heterogeneity = 0.001) in men, and 1.10 (95% CI, 1.02–1.19; p-heterogeneity = 0.12) in women. There was no evidence of publication bias (p = 0.58). Findings from this meta-analysis of prospective studies support a positive association between BMI and risk of pancreatic cancer in men and women. © 2007 Wiley-Liss, Inc.

Activation of PI3K‐Akt signaling pathway promotes prostate cancer cell invasion

Abstract: Activated phosphoinositide 3-kinase (PI3K) and its downstream target Akt/PKB are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis and oncogenesis. We investigated the role of the PI3K-Akt signaling pathway in the invasion of prostate cancer cell lines and activation of this pathway in primary human prostate tumors. Treatment of human prostate cancer cells viz. LNCaP, PC-3 and DU145 with PI3K pharmacological inhibitor, LY294002, potentially suppressed the invasive properties in each of these cell lines. Restoration of the PTEN gene to highly invasive prostate cancer PC-3 cells or expression of a dominant negative version of the PI3K target, Akt also significantly inhibited invasion and downregulated protein expression of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9, markers for cell invasion, indicating a central role of the PI3K-Akt pathway in this process. Immunoblot analysis of PI3K and total/activated levels of Akt showed increased protein levels of catalytic (p110α/β) and regulatory (p85) subunits of PI3K and constitutive Akt activation in high-grade tumors compared to low-grade tumor and benign tissue. Immunohistochemical analyses further confirmed a progressive increase in p-Akt (p-Ser473) levels but not of total-Akt (Akt1/2) in cancer tissues compared to benign specimens. A successive increase in p-Akt expression was further noted in specimens serially obtained from individuals with time-course disease progression. Taken together, these results suggest that aberrant activation of PI3K-Akt pathway may contribute to increased cell invasiveness and facilitate prostate cancer progression. © 2007 Wiley-Liss, Inc.

Multiple myeloma: A review of the epidemiologic literature

Abstract: Multiple myeloma, a neoplasm of plasma cells, accounts for approximately approximately 15% of lymphatohematopoietic cancers (LHC) and 2% of all cancers in the US. Incidence rates increase with age, particularly after age 40, and are higher in men, particularly African American men. The etiology is unknown with no established lifestyle, occupational or environmental risk factors. Although several factors have been implicated as potentially etiologic, findings are inconsistent. We reviewed epidemiologic studies that evaluated lifestyle, dietary, occupational and environmental factors; immune function, family history and genetic factors; and the hypothesized precursor, monoclonal gammopathies of undetermined significance (MGUS). Because multiple myeloma is an uncommon disease, etiologic assessments can be difficult because of small numbers of cases in occupational cohort studies, and few subjects reporting exposure to specific agents in case-control studies. Elevated risks have been reported consistently among persons with a positive family history of LHC. A few studies have reported a relationship between obesity and multiple myeloma, and this may be a promising area of research. Factors underlying higher incidence rates of multiple myeloma in African Americans are not understood. The progression from MGUS to multiple myeloma has been reported in several studies; however, there are no established risk factors for MGUS. To improve our understanding of the causes of multiple myeloma, future research efforts should seek the causes of MGUS. More research is also needed on the genetic factors of multiple myeloma, given the strong familial clustering of the disease.

Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis.

Abstract: The purpose of this study was to document the prevalence of diabetes among newly diagnosed cancer patients and to evaluate the influence of diabetes on stage at diagnosis, treatment and overall survival. We performed a population-based analyses of all 58,498 cancer patients newly diagnosed between 1995 and 2002 in the registration area of the Eindhoven Cancer Registry. Stage of cancer, cancer treatment and comorbidities were actively collected by hospital medical records review. Follow-up of all patients was completed until January 1, 2005. Nine percent of all cancer patients had diabetes at the time of cancer diagnosis. The prevalence of diabetes was highest among patients with cancer of the pancreas (19%), uterus (14%) and among young men with kidney cancer (8%). Colon, breast and ovarian cancer patients with diabetes were more often diagnosed with a higher tumour stage (p < 0.05). Patients with diabetes and cancer of the oesophagus, colon, breast and ovary were treated less aggressively compared to those without diabetes (p < 0.05). During the follow-up period 3,902 of 5,555 cancer patients with diabetes died and 29,909 of 52,943 cancer patients without diabetes died. For all cancers combined, in a multivariate cox-regression model, adjusting for age, gender, stage, treatment and cardiovascular disease, patients with diabetes experienced a significant increase in overall mortality (HR = 1.44, 95% CI 1.40-1.49), ranging however from 0 to 40% for different types of cancer, compared to those without diabetes. In conclusion, diabetic cancer patients frequently were treated less aggressively and had a worse prognosis compared to those without diabetes.

OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer

Abstract: OCT-4 (also known as POU5F1) is a key regulator of self-renewal in embryonic stem cells. Regarding the new cancer stem cell concept, the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of tumor behavior, such as tumor recurrence or resistance to therapies. Although OCT-4 has been introduced as a molecular marker for germ cell tumors, little is known about its expression in somatic cancers. Here, we have investigated the potential expression of OCT-4 in bladder cancer. We used semiquantitative RT-PCR to examine the expression of OCT-4 in 32 tumors, 13 apparently nontumor tissues taken from the margin of tumors and 9 normal urothelial tissues. The expression of OCT-4 at protein level was further determined by Western blotting and immunohistochemical (IHC) analysis. OCT-4 expression was detected in almost all examined tumors (31/32), but at much lower level (p<0.001) in some nonneoplastic samples (6/22). A significantly strong correlation of 0.6 has been observed between OCT-4 expression and the presence of tumors (p<0.001). Western blot analysis further confirmed the expression of OCT-4 in tumor biopsies. According to IHC results, OCT-4 is primarily localized in the nuclei of tumor cells, with no or low immunoreactivity in nontumor cells. Our study demonstrated, for the first time, the expression of OCT-4 in bladder cancer and a further clue to the involvement of embryonic genes in carcinogenesis.

Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC).

Abstract: Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC).

A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer.

Abstract: Flavonoids are antioxidant compounds found in plants, including fruits, vegetables and tea. No prior prospective studies have examined the association between intake of flavonoids in the flavonol and flavone subclasses and ovarian cancer risk. We analyzed the association between intake of 5 common dietary flavonoids and incidence of epithelial ovarian cancer among 66,940 women in the Nurses' Health Study. We calculated each participant's intake of myricetin, kaempferol, quercetin, luteolin and apigenin from dietary data collected at multiple time points, and used Cox proportional hazards regression to model the incidence rate ratio (RR) of ovarian cancer for each quintile of intake. Our analysis included 347 cases diagnosed between 1984 and 2002, and 950,347 person-years of follow-up. There was no clear association between total intake of the 5 flavonoids examined and incidence of ovarian cancer (RR = 0.75 for the highest versus lowest quintile, 95% confidence interval [CI] = 0.51-1.09). However, there was a significant 40% decrease in ovarian cancer incidence for the highest versus lowest quintile of kaempferol intake (RR = 0.60, 95% CI = 0.42-0.87; p-trend = 0.002), and a significant 34% decrease in incidence for the highest versus lowest quintile of luteolin intake (RR = 0.66, 95% CI = 0.49-0.91; p-trend = 0.01). There was evidence of an inverse association with consumption of tea (nonherbal) and broccoli, the primary contributors to kaempferol intake in our population. These data suggest that dietary intake of certain flavonoids may reduce ovarian cancer risk, although additional prospective studies are needed to further evaluate this association. If confirmed, these results would provide an important target for ovarian cancer prevention.

Depletion of CD4+CD25+ human regulatory T cells in vivo: Kinetics of Treg depletion and alterations in immune functions in vivo and in vitro

Abstract: The aim of this study was to investigate whether depletion of CD4(+)CD25(+) regulatory T cells (Treg) from melanoma patients affects immune responses against tumors. By application of recombinant IL-2-diphteria toxin fusion protein, also known as ONTAK, we were able to significantly reduce the frequency of Treg in peripheral blood, whereas other cell populations remained unaffected. The reduction of Treg started immediately after the first bolus of ONTAK with a dose of 5 microg ONTAK per kg bodyweight and lasted for 13 days with subsequent recovery thereafter. Successive ONTAK treatments further reduced the number of circulating Treg. Using the contact sensitizer DCP we show that all patients developed vast eczema after Treg depletion, whereas no or only mild eczematous reactions were detectable before ONTAK treatment. Corresponding induction of DCP-specific CD4(+) and CD8(+) T cells were detectable. Moreover, after immunization of ONTAK treated patients with tumor antigen peptides, MelanA/MART-1 and gp100, significant induction of peptide specific CD8(+) T cells could be observed in 90% of the patients treated. These cells displayed effector functions, as they were able to lyse peptide-pulsed target cells and secreted IFNgamma upon restimulation. In aggregate, our data indicate that ONTAK depletes Treg in vivo significantly, resulting in enhanced immune functions and substantial development of antigen-specific CD8(+) T cells in vaccinated individuals.

Androgen receptor coregulators and their involvement in the development and progression of prostate cancer

Abstract: The androgen receptor signaling axis plays an essential role in the development, function and homeostasis of male urogenital structures including the prostate gland although the mechanism by which the AR axis contributes to the initiation, progression and metastatic spread of prostate cancer remains somewhat enigmatic. A number of molecular events have been proposed to act at the level of the AR and associated coregulators to influence the natural history of prostate cancer including deregulated expression, somatic mutation, and post-translational modification. The purpose of this article is to review the evidence for deregulated expression and function of the AR and associated coactivators and corepressors and how such events might contribute to the progression of prostate cancer by controlling the selection and expression of AR targets.

Trends in oesophageal cancer incidence and mortality in Europe.

Abstract: To monitor recent trends in mortality from oesophageal cancer in 33 European countries, we analyzed the data provided by the World Health Organization over the last 2 decades, using also joinpoint regression. For selected European cancer registration areas, we also analyzed incidence rates for different histological types. For men in the European Union (EU), age-standardized (world population) mortality rates were stable around 6/100,000 between the early 1980s and the early 1990s, and slightly declined in the last decade (5.4/100,000 in the early 2000s, annual percent change, APC = −1.1%). In several western European countries, male rates have started to level off or decline during the last decade (APC = −3.4% in France, and −3.0% in Italy). Also in Spain and the UK, which showed upward trends in the 1990s, the rates tended to level off in most recent years. A levelling of rates was observed only more recently in countries of central and eastern Europe, which had had substantial rises up to the late 1990s. Oesophageal cancer mortality rates remained comparatively low in European women, and overall EU female rates were stable around 1.1–1.2/100,000 over the last 2 decades (APC = −0.1%). In northern Europe a clear upward trend was observed in the incidence of oesophageal adenocarcinoma, and in Denmark and Scotland incidence of adenocarcinoma in men is now higher than that of squamous-cell carcinoma. Squamous-cell carcinoma remained the prevalent histological type in southern Europe. Changes in smoking habits and alcohol drinking for men, and perhaps nutrition, diet and physical activity for both sexes, can partly or largely explain these trends. © 2007 Wiley-Liss, Inc.

Folate receptor overexpression is associated with poor outcome in breast cancer.

Abstract: The high affinity folate receptor is a membrane-associated glycoprotein that is preferentially expressed in cancers of epithelial origin and rarely expressed in normal cells. We examined its expression pattern in breast cancer, utilizing a tissue microarray containing samples from 63 invasive breast cancers from women with divergent clinical outcomes. Thirty-three women comprised the poor outcome group with a median time to recurrence of 1.9 years. Thirty women, the good outcome group, were free of recurrence for a minimum of 7 years after diagnosis. The intensity of folate receptor staining was strongly correlated with outcome. There were two summary categories of staining intensity: weak (n = 42) or strong (n = 21). In the strong staining group, 17 of 21 women (81%) have recurred and their median survival is 2.4 years. In the weak staining group, 16 of 42 women (38%) have recurred. Their median survival is not estimable. After adjustment for tumor size, nodal status, ER status, adjuvant therapy, histology and tumor grade, strong staining for the folate receptor remained significantly associated with poor outcome, p < 0.001. Our work requires validation in a larger cohort, but supports the possibility of using folate receptor-targeted approaches in the management of breast cancer.

Statins and risk of cancer: a systematic review and metaanalysis.

Abstract: We conducted a systematic review of the association between HMG-CoA reductase inhibitor (statin) use and cancer risk We searched MEDLINE, EMBASE, Web of Science, ISI Proceedings and BIOSIS Previews bibliographic databases, electronic trials registers and reference lists for potentially eligible randomized trials and observational studies Thirty-eight individual studies (26 randomized trials involving 103,573 participants and 12 observational studies with 826,854 participants) were included Median follow-up was 36 and 62 years for trials and observational studies, respectively In metaanalyses of randomized trials, there was no evidence that statin therapy was associated with incidence of all-cancers (26 trials; pooled risk ratio = 100; 95% CI 095-105; I(2) = 0%) or the following site-specific cancers: breast (7 trials; risk ratio = 101; 079-130; I(2) = 43%), prostate (4 trials; risk ratio = 100; 085-117; I(2) = 0%), colorectum (9 trials; risk ratio = 102; 089-116; I(2) = 0%), lung (9 trials; risk ratio = 096; 084-109; I(2) = 0%), genito-urinary (5 trials; risk ratio = 095; 083-109; I(2) = 0%), melanoma (4 trials; risk ratio = 086; 062-120; I(2) = 17%) or gastric (1 trial; risk ratio = 100; 035-285) There was no evidence of differential effects by length of follow-up, statin type (lipophilic vs lipophobic) or potency Trial results were generally consistent with observational studies We conclude that statin use is not associated with short-term cancer risk, but longer-latency effects remain possible