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

Aims and background Mounting evidence indicates that deregulated cell adhesion is involved in the mechanisms of cancer pathogenesis. A recent study showed that the paxillin gene (PXN) encoding a focal adhesion protein was somatically mutated in lung cancers. The aim of this study was to confirm the presence of PXN mutations in lung cancers as well as in other common solid cancers. Methods We analyzed somatic PXN mutations in 45 lung, 45 gastric, 45 colorectal, 45 breast, 45 liver and 45 prostate cancers by polymerase chain reaction and single-strand conformation polymorphism assay. Results Neither lung nor other cancers were found to be associated with somatic mutations of PXN. Conclusions In contrast to the previous report, our study revealed that PXN mutation was absent in lung cancers and other common solid cancers, suggesting that PXN mutation may not play a principal role in solid cancer development.

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Absence of paxillin gene mutation in lung cancer and other common solid cancers.

Mutational analysis of FLASH and PTPN13 genes in colorectal carcinomas

To the Editor, Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that reduces errors in gene expression by eliminating mRNA transcripts that contain premature stop codons [1]. Without the NMD, translation of such aberrant mRNAs could lead to deleterious gain-of-function or dominant-negative activity of the resulting proteins. As for tumors, suppressed NMD can either promote or inhibit tumors depending on the natures of NMD-candidate transcripts. For example, NMD shows a tumor suppressor activity in the cancers with truncated forms of BRCA1 [2]. By contrast, it shows an oncogenic role in those with truncated forms of CDH1 [3]. In humans, NMD depends on UPF1 and six other proteins SMG1, UPF2, UPF3, SMG6, SMG5 and SMG7 [1]. The SMG7 coordinates with UPF1 to degrade NMD-candidate transcripts [4]. NMDinactivating mutation of UPF1 gene is common in pancreatic adenosquamous carcinoma [5], indicating that NMD inhibition by somatic mutations of NMD machinery could possibly contribute to tumorigenesis. However, mutational status of the other genes is largely unknown. There is a mononucleotide repeat (A9) in the coding sequence of SMG7 that could be a target for frameshift mutation in cancers with microsatellite instability (MSI) such as gastric (GCs) and colorectal (CRCs) cancers [6]. To see whether SMG7 gene harbored frameshift mutations within the repeat in GC and CRC, we analyzed the A9 repeat in exon 17 of SMG7 in 34 GCs with high MSI (MSI-H), 45 GCs with microsatellite stable/low MSI (MSS/MSI-L), 79 CRCs with MSI-H and 45 CRCs with MSS/MSI-L by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) assay as described previously [7]. Radioisotope ([P]dCTP) was incorporated into the PCR products for detection by autoradiogram. The PCR products were subsequently displayed in SSCP gels. After SSCP, Sanger DNA sequencing reactions were performed in the cancers with mobility shifts in the SSCP as described previously [8]. In the SSCP, we found aberrantly migrating bands in two GCs and six CRCs, but not in their normal samples. DNA sequencing analysis confirmed that the aberrant bands represented SMG7 somatic mutations, which consisted of frameshift mutations by a deletion (c.2454delA (p. Met849fsx1)) and a duplication (c.2545dupA (p. Met849Asnfsx10)) within the repeat (Fig. 1). The mutations were detected in GCs (2/34, 5.9 %) and CRCs (6/79, 7.6 %) with MSI-H, but not in GCs (0/45) and CRCs (0/45) with MSS/MSI-L (Fisher’s exact test, p = 0.008). Clinical and histopathological parameters, however, could not distinguish SMG7 mutation (+) and (−) cancers. Of the 79 CRCs with MSI-H analyzed, we analyzed multiregional areas in 16 CRCs (96 areas, 4–7 areas per case). One of the 16 CRCs (6.3 %) showed the deletion (c.2454delA) in two of the six regional fragments, indicating intratumoral heterogeneity (ITH) of the SMG7 frameshift mutation. We could not find any significant histological difference among the ITH regions. Earlier identification of NMD-inactivating mutation of UPF1 gene [5] led us to further analyze frameshift mutations of SMG7, another NMDmachinery gene. In the present study, we found that eight cases (7.1%) of GCs and CRCswithMSIH harbored SMG7 frameshift mutations, indicating that SMG7 gene is not uncommon in GCs and CRCs with MSI-H. The N* Sug Hyung Lee suhulee@catholic.ac.kr

Frameshift Mutations of SMG7 Essential for Nonsense-Mediated mRNA Decay in Gastric and Colorectal Cancers.

Mutational analysis of EZH2 codon 641 in non-Hodgkin lymphomas and leukemias.

Chloride channel calcium-activated (CLCA) genes encode regulators for chloride transport across the cell membrane. As for cancer development, some CLCA genes are considered putative tumor suppressor genes. The aim of this study was to explore whether CLCA4 gene would have mutations in its nucleotide repeats in colorectal cancer (CRC). In a public database, we found that CLCA4 gene had mononucleotide repeats in the coding sequences that might be mutational targets in the cancers with microsatellite instability. For this, the current study studied 146 CRCs for mutation and expression analyses by single-strand conformation polymorphism analysis, DNA sequencing, and immunohistochemistry. Overall, we found CLCA4 frameshift mutations in 12/101 (11.8%) CRCs with high-microsatellite instability (MSI-H), but none in microsatellite stable CRCs (0/45) (P<0.01). In addition, we analyzed intratumoral heterogeneity of the CLCA4 frameshift mutations and found that 1 CRC harbored regional intratumoral heterogeneity of the CLCA4 frameshift mutation. Loss of CLCA4 protein expression was identified in 50% of CRCs. Also, cancers with MSI-H harboring CLCA4 frameshift mutations showed lower CLCA4 immunostaining than those with the wild-type. Our data indicate that the CLCA4 gene harbors alterations both in somatic mutation and expression, suggesting their roles in tumorigenesis of CRC with MSI-H.

Nam Jin Yoo

Papers

Absence of paxillin gene mutation in lung cancer and other common solid cancers.

Mutational analysis of FLASH and PTPN13 genes in colorectal carcinomas

Frameshift Mutations of SMG7 Essential for Nonsense-Mediated mRNA Decay in Gastric and Colorectal Cancers.

Mutational analysis of EZH2 codon 641 in non-Hodgkin lymphomas and leukemias.

Frameshift Mutations and Loss of Expression of CLCA4 Gene are Frequent in Colorectal Cancers With Microsatellite Instability.