Journal of Carcinogenesis最新文献

Pyruvate kinase activity is controlled by a tightly woven regulatory network. The oncofetal isoform of pyruvate kinase (PKM2) is a master regulator of cancer metabolism. PKM2 engages in parallel, feed-forward, positive and negative feedback control contributing to cancer progression. Besides its metabolic role, non-metabolic functions of PKM2 as protein kinase and transcriptional coactivator for c-MYC and hypoxia-inducible factor 1-alpha are essential for epidermal growth factor receptor activation-induced tumorigenesis. These biochemical activities are controlled by a shift in the oligomeric state of PKM2 that includes acetylation, oxidation, phosphorylation, prolyl hydroxylation and sumoylation. Metabolically active PKM2 tetramer is allosterically regulated and responds to nutritional and stress signals. Metabolically inactive PKM2 dimer is imported into the nucleus and can function as protein kinase stimulating transcription. A systems biology approach to PKM2 at the genome, transcriptome, proteome, metabolome and fluxome level reveals how differences in biomolecular structure translate into a global rewiring of cancer metabolism. Cancer systems biology takes us beyond the Warburg effect, opening unprecedented therapeutic opportunities.

Background: Adenocarcinoma, a subgroup of non-small cell lung cancer, is the most frequent form occurring in the non-smokers. Mutation in tyrosine kinase domain of epidermal growth factor receptor (EGFR) has been a common feature observed in lung adenocarcinoma. The study was carried out to detect the prevalence of EGFR mutation in lung adenocarcinoma.

Materials and methods: EGFR mutation status in 166 lung adenocarcinoma patients was obtained retrospectively. Mutation tests were performed on paraffin embedded tissue blocks as a routine diagnostic procedure by polymerase chain reaction followed by direct nucleotide sequencing. Patient's demographics and other clinical details were obtained from the medical records.

Results: EGFR mutation was detected in 43/166 (25.9%) patients. Gender wise mutation was observed as 18/55 (32.7%) in females and 25/111 (22.5%) in males. Overall, EGFR mutation was correlated with never smokers and distant metastasis (P < 0.05), but not associated with the gender, disease stage and pleural effusion. Exon 19 deletions were significantly correlated with females, never smokers, pleural effusion and distant metastasis (P < 0.05). However, point mutation on exon 21 did not show any statistical association with the above variables. Median overall survival was 22 months (95% confidence interval, 15.4-28.6). Female sex, EGFR mutation and absence of metastasis are associated with good prognosis.

Conclusion: EGFR mutation in lung adenocarcinoma was higher in never smokers, females and patients with distant metastasis. However, it was not linked with tobacco smoking. The prevalence of EGFR mutation observed is in range with the previously published reports from the Asian countries.

Introduction: Ovarian cancer is the leading cause of death from gynecological cancer. Non-specific symptoms early in disease and the lack of specific biomarkers hinder early diagnosis. Multi-marker blood screening tests have shown promise for improving identification of early stage disease; however, available tests lack sensitivity, and specificity.

Materials and methods: In this study, pooled deeply-depleted plasma from women with Stage 1, 2 or 3 ovarian cancer and healthy controls were used to compare the 2-dimensional gel electrophoresis (2-DE) protein profiles and identify potential novel markers of ovarian cancer progression.

Results/discussion: Stage-specific variation in biomarker expression was observed. For example, apolipoprotein A1 expression is relatively low in control and Stage 1, but shows a substantial increase in Stage 2 and 3, thus, potential of utility for disease confirmation rather than early detection. A better marker for early stage disease was tropomyosin 4 (TPM4). The expression of TPM4 increased by 2-fold in Stage 2 before returning to "normal" levels in Stage 3 disease. Multiple isoforms were also identified for some proteins and in some cases, displayed stage-specific expression. An interesting example was fibrinogen alpha, for which 8 isoforms were identified. Four displayed a moderate increase at Stage 1 and a substantial increase for Stages 2 and 3 while the other 4 showed only moderate increases.

Conclusion: Herein is provided an improved summary of blood protein profiles for women with ovarian cancer stratified by stage.

Background: Since heavy metal cadmium is an endocrine disrupting chemical, we investigated whether maternal exposure to cadmium during the pregnancy alters mammary tumorigenesis among female offspring.

Methods: From gestation day 10 to day 19, pregnant rat dams were fed modified American Institute of Nutrition (AIN93G) diet containing 39% energy from fat (baseline diet), or the baseline diet containing moderate (75 μg/kg of feed) or high (150 μg/kg) cadmium levels. Some dams were injected with 10 μg 17β-estradiol (E2) daily between gestation days 10 and 19.

Results: Rats exposed to a moderate cadmium dose in utero were heavier and exhibited accelerated puberty onset. Both moderate and high cadmium dose led to increased circulating testosterone levels and reduced the expression of androgen receptor in the mammary gland. The moderate cadmium dose mimicked the effects of in utero E2 exposure on mammary gland morphology and increased both the number of terminal end buds and pre-malignant hyperplastic alveolar nodules (HANs), but in contrast to the E2, it did not increase 7, 12-dimethylbenz (a) anthracene-induced mammary tumorigenesis.

Conclusions: The effects of in utero cadmium exposure were dependent on the dose given to pregnant dams: Moderate, but not high, cadmium dose mimicked some of the effects seen in the in utero E2 exposed rats, such as increased HANs in the mammary gland.

The first discovery of metabolic changes in cancer occurred almost a century ago. While the genetic underpinnings of cancer have dominated its study since then, altered metabolism has recently been acknowledged as a key hallmark of cancer and metabolism-focused research has received renewed attention. The emerging field of metabolomics - which attempts to profile all metabolites within a cell or biological system - is now being used to analyze cancer metabolism on a system-wide scale, painting a broad picture of the altered pathways and their interactions with each other. While a large fraction of cancer metabolomics research is focused on finding diagnostic biomarkers, metabolomics is also being used to obtain more fundamental mechanistic insight into cancer and carcinogenesis. Applications of metabolomics are also emerging in areas such as tumor staging and assessment of treatment efficacy. This review summarizes contributions that metabolomics has made in cancer research and presents the current challenges and potential future directions within the field.

Background: Cardiac glycosides such as digitoxin have been shown to directly cause apoptotic death of cancer cells both in vitro, and in vivo. However, the mechanism connecting cardiac glycoside action to apoptosis is not known. It has been reported that compounds resembling digitoxin are able to reduce c-MYC expression. Furthermore, it has been previously shown that the transcription of c-MYC depends on nuclear factor of activated T-cells (NFAT) binding sites in the c-MYC promoter. We have therefore hypothesized that NFAT might mediate digitoxin effects on c-MYC mRNA message.

Materials and methods: We have chosen to study this process in HeLa cells where structurally intact c-MYC genes in 8q24 co-localize with human papilloma virus 18 at all integration sites.

Results: Here we show that within the 1(st) h following treatment with digitoxin, a significant reduction in c-MYC mRNA occurs. This is followed by a precipitous loss of c-MYC protein, activation of caspase 3, and subsequent apoptotic cell death. To test the NFAT-dependence mechanism, we analyzed the effects of digitoxin on NFAT isoform-dependent auto-activation of a NFAT-luciferase expression system. Drug dependent effects on expression varied according to each of the four canonical NFAT isoforms (1, 2, 3 or 4). The most digitoxin-sensitive NFAT isoform was NFAT1. Using c-MYC chromatin immune precipitation, we find that digitoxin inhibits interaction of NFAT1 with the proximal c-MYC promoter.

Conclusions: These results suggest that the carcinotoxic activity of digitoxin includes suppression of NFAT-driven c-MYC expression.

Lung cancer is a heterogeneous group of diseases. There has been much research in lung cancer over the past decade which has advanced our ability to treat these patients with a more personalized approach. The scope of this paper is to review the literature and give a broad understanding of the current molecular targets for which we currently have therapies as well as other targets for which we may soon have therapies. Additionally, we will cover some of the issues of resistance with these targeted therapies. The molecular targets we intend to discuss are epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), anaplastic large-cell lymphoma kinase (ALK), KRAS, C-MET/RON, PIK3CA. ROS-1, RET Fibroblast growth factor receptor (FGFR). Ephrins and their receptors, BRAF, and immunotherapies/vaccines. This manuscript only summarizes the work which has been done to date and in no way is meant to be comprehensive.

Introduction and hypothesis: Nuclear atypia with features of multi nuclei have been detected in human melanoma specimens. We found that the K type human endogenous retroviral element (HERV K) is expressed in such cells. Since cellular syncytia can form when cells are infected with retroviruses, we hypothesized that HERV K expressed in melanoma cells may contribute to the formation of multinuclear atypia cells in melanoma.

Experiments and results: We specifically inhibited HERV K expression using RNA interference (RNAi) and monoclonal antibodies and observed dramatic reduction of intercellular fusion of cultured melanoma cells. Importantly, we identified loss of heterozygosity (LOH)of D19S433 in a cell clone that survived and proliferated after cell fusion.

Conclusion: Our results support the notion that proteins encoded by HERV K can mediate intercellular fusion of melanoma cells, which may generate multinuclear cells and drive the evolution of genetic changes that provide growth and survival advantages.

Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s) of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell of origin, and cancer stem cells has been hampered by the heterogeneity of the disease, the lack of good in vivo transplantation models to assess stem cell behavior, and an overall incomplete understanding of the epithelial stem cell hierarchy. As such, a systematic computerized literature search of the MEDLINE database was used to identify articles discussing current knowledge about normal lung and lung cancer stem cells or progenitor cells. In this review, we discuss what is currently known about the role of cancer-initiating cells and normal stem cells in the development of lung tumors.

Background: Prostate stem cell antigen (PSCA), an organ-dependent tumor suppressor, is down regulated in gallbladder cancer (GBC). It is anticipated that the missense allele C of the single nucleotide polymorphism (SNP) rs2294008 (T/C) in the translation initiation codon of the gene affects the gene's biological function and has some influence on GBC susceptibility. We examined the biological effect of the C allele on the function of the gene and the relation between the C allele and GBC susceptibility.

Materials and methods: Functional analysis of the SNP was conducted by introducing PSCA cDNA harboring the allele to a GBC cell line TGBC- 1TKB and performing colony formation assays in vitro and tumor formation assays in mice. The effect on transcriptional regulation was assessed by reporter assays. The association study was conducted on 44 Japanese GBC cases and 173 controls.

Results: The PSCA cDNA harboring the C allele showed lower cell growth inhibition activity (20% reduction) than that with the T allele. Concordantly, when injected into subcutaneous tissues of mice, the GBC cell line stably expressing the cDNA with the C allele formed tumors of almost the same size as that of the control cells, but the cell line expressing the cDNA with the T allele showed slower growth. The upstream DNA fragment harboring the C allele had more transcriptional activity than that with the T allele. The C allele showed positive correlation to GBC but no statistical significant odds ratio (OR = 1.77, 95% confidence interval 0.85-3.70, P value = 0.127 in dominant model).

Conclusions: The missense allele was shown to have a biological effect, attenuating antitumor activities of PSCA, and consequently it may be a potential risk for GBC development. An association study in a larger sample size may reveal a significant association between the allele and GBC.