Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

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Regulation of cancer cell metabolism

Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.

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Epigenetics in Cancer

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

The regulation of cell growth and survival can be subverted by a variety of genetic defects that alter transcriptional programs normally responsible for controlling cell number. High throughput analysis of these gene expression patterns should ultimately lead to the identification of minimal expression profiles that will serve as common denominators in assigning a cancer to a given category. In the course of defining the common denominators, though, we should not be too surprised to find that cancers within a single category may nevertheless exhibit seemingly disparate genetic defects. The wnt pathway has already provided an outstanding example of this. We now know of three regulatory genes in this pathway that are mutated in primary human cancers and several others that promote experimental cancers in rodents (Fig. 1). In all of these cases the common denominator is the activation of gene transcription by -catenin. The resulting gene expression profile should provide us with a signature common to those cancers carrying defects in the wnt pathway. In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.

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Wnt signaling and cancer

Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences

Proliferation, cell cycle and apoptosis in cancer

To investigate whether the KLF6 gene plays an important role in the development and/or progression of colorectal cancers, we searched for mutations and allelic loss of the KLF6 gene in 123 colorectal adenocarcinomas by performing PCR-SSCP sequencing. We found five somatic missense mutations: S155N, G163S, G163D, P183L and G195S. Three of them affected the activation domain of KLF6 and four mutations were predicted to disrupt the putative phosphorylation sites. On LOH analysis, 63 cases were heterozygous for at least one marker and 27 cases (42.9%) showed allelic loss at these markers. These data further support that the KLF6 gene may be one of the candidate tumor suppressor genes in colorectal cancers and that genetic alteration of the KLF6 gene might play a role in the development of colorectal carcinomas.

Genetic alterations of the KLF6 gene in colorectal cancers.

approach, a 3% increase in microscopic involvement of the bladder neck and a 2% increase in microscopic involvement of the seminal vesicle have been seen. Our approach has not helped us to solve the problem of a true intraprostatic component of the seminal vesicles in addition to the anatomically well-characterized extraprostatic seminal vesicle. The seminal vesicle connects with the prostate ejaculatory duct, and occasionally appears to be invaginated into the prostate (Figure 6). In conclusion, our current approach could contribute to more accurate evaluation of the prognostic morphological elements included by Srigley and his co-authors in their dataset for reporting of prostate carcinoma in RPSs, and also to meaningful comparisons of benchmarking data, epidemiological studies, and clinical trials.

DICER1 exons 25 and 26 mutations are rare in common human tumours besides Sertoli–Leydig cell tumour

AIMS AND BACKGROUND Myeloid differentiation primary response gene 88 (MYD88) is a protein involved in hematopoietic differentiation and innate immunity. Recent studies revealed MYD88 mutation in hematological malignancies and MYD88 overexpression in some solid cancers. The aim of this study was to see whether alterations of MYD88 protein expression and somatic mutation of MYD88 gene are features of common solid cancers. METHODS We analyzed MYD88 mutation in 45 gastric, 45 colorectal, 45 breast, 45 hepatocellular, 45 prostate and 45 lung carcinomas by single-strand conformation polymorphism (SSCP). We also analyzed MYD88 protein expression in 60 gastric, 60 coloretal and 107 prostate carcinomas by immunohistochemistry. RESULTS In the immunohistochemistry results, MYD88 protein was highly expressed in gastric (75%), colorectal (80%) and prostate (83%) cancers. However, MYD88 expression was significantly different among normal tissues (gastric: 58%, colon: 100%, prostate: 86%). MYD88 expression was significantly increased in gastric cancer cells compared with normal cells, whereas it was decreased in colorectal cancer cells compared with normal cells. There were no somatic mutations of the MYD88 gene in gastric, colorectal, breast, hepatocellular, prostate and lung carcinomas. CONCLUSIONS Our data indicate that MYD88 overexpression might be a feature of many solid cancers, but MYD88 expression in normal cells differs depending on the organs. The data suggest that a gain of MYD88 expression in gastric cancers might play a role in cancer pathogenesis by activating oncogenic functions of MYD88.

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Mutational and expressional analyses of MYD88 gene in common solid cancers.

Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)-encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, CDC14A, MTM1, MTMR3, SSH1, and SSH2, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI-H), 12 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI-H, 14 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism (SSCP). We found CDC14A and MTMR3 mutations in five and one cancer (s), respectively. These mutations were detected in MSI-H cancers, but not in MSI-L or MSS cancers. The GC and CRC with MSI-H harbored the mutations in 15% and 6%, respectively. The CDC14A and MTMR3 mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would result in premature stops of the amino acid syntheses. Our data show that frameshift mutations of DPTP genes in MSI-H cancers occur at moderate frequencies. The data suggested that alterations in the CDC14A and MTMR3 genes may play a role in the development of GC and CRC with MSI-H by deregulating phosphatase functions possibly together with mutations of classical PTP genes.

Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability.

To the Editor, Tumor suppressor genes (TSGs) encode proteins that suppress cell proliferation and growth in normal cells. However, inactivation of TSG by mutations or other alterations disrupts the functions and may lead to cancers (1). BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme, has been suggested to be a TSG with a role that inhibits cell proliferation and growth via the BRCA1-related growth control pathway (2–4). BAP1 interacts not only with BRCA1, but also with HCF-1 that binds with histone-modifying complex during cell division. Germline mutation of BAP1 predisposes to uveal melanomas, lung cancers, and meningiomas (5). Frequent somatic mutations of BAP1 gene have been reported in melanomas and malignant mesotheliomas (6, 7). Human BAP1 gene resides at chromosome 3p21 that is frequently deleted in many carcinomas (6). However, to data, the data on BAP1 somatic mutation in other common cancers are lacking. To observe whether BAP1 somatic mutations occur in common human carcinomas as well, we analyzed the entire coding region (exon 1–17) and spicing sites of human BAP1 gene by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) using 19 primer pairs. For this, we used in methacarn-fixed tissues of 45 breast, 45 prostate, 45 gastric, and 45 colorectal carcinomas from Korean patients. In cancer tissues, malignant cells and normal cells were selectively procured from hematoxylin and eosinstained slides using a hypodermic needle affixed to a micromanipulator (8, 9). Radioisotope ([P]dCTP) was incorporated into the PCR products for detection by autoradiogram. The PCR products were subsequently displayed in SSCP gels. After SSCP, direct DNA sequencing reactions were performed in the cancers with mobility shifts in SSCP. Single-strand conformation polymorphism from the carcinomas showed aberrant bands in one colon carcinoma compared with wildtype bands from normal tissues (Fig. 1). Direct DNA sequencing analysis led to identification of a BAP1 somatic mutation (1/45 colon carcinomas; 2.2%). The BAP1 mutation was a missense mutation (c.179G > A), which would result in substitution of Arg by Glu at amino acid residue 60 (p.Arg60Glu) (Fig. 1). This mutation was a novel mutation that had not been detected in earlier studies (6, 7). The colon carcinoma with this mutation was a usual adenocarcinoma with high microsatellite instability (MSI-H) in ascending colon. There was no mutation in the other carcinomas. To confirm the SSCP results, we repeated the experiments twice, including tissue microdissection, PCR and SSCP to ensure specificity of the results, and found that the data were consistent. As a possible inactivation mechanism for BAP1 TSG in human cancers, we analyzed somatic mutation of BAP1 gene in gastric,

Nam Jin Yoo

Papers

Genetic alterations of the KLF6 gene in colorectal cancers.

DICER1 exons 25 and 26 mutations are rare in common human tumours besides Sertoli–Leydig cell tumour

Mutational and expressional analyses of MYD88 gene in common solid cancers.

Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability.

Somatic mutation of a tumor suppressor gene BAP1 is rare in breast, prostate, gastric and colorectal cancers.