AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.

p21 in cancer: intricate networks and multiple activities

Commensal and pathogenic microorganisms must resist the deleterious actions of bile in order to survive in the human gastrointestinal tract. Herein we review the current knowledge on the mechanisms by which Gram-positive and Gram-negative bacteria contend with bile stress. We describe the antimicrobial actions of bile, assess the variations in bile tolerance between bacterial genera and examine the interplay between bile stress and other stresses. The molecular mechanisms underlying bile tolerance are investigated and the relationship between bile and virulence is examined. Finally, the potential benefits of bile research are briefly discussed.

The interaction between bacteria and bile

Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes—most prominently the APC, KRAS, and p53 genes—are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target protein...

Molecular Genetics of Colorectal Cancer

Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

Introduction: JC Virus (JCV), a human polyomavirus, is frequently present in colorectal cancers (CRCs). JCV large T-Ag (T-Ag) expressed in approximately half of all CRC’s, however, its functional role in CRC is poorly understood. We hypothesized that JCV T-Ag may mediate metastasis in CRC cells through increased migration and invasion. Material and Methods: CRC cell lines (HCT116 and SW837) were stably transfected with JCV early transcript sequences cloned into pCR3 or empty vectors. Migration and invasion assays were performed using Boyden chambers. Global gene expression analysis was performed to identify genetic targets and pathways altered by T-Ag expression. Microarray results were validated by qRT-PCR, protein expression analyses and immunohistochemistry. Matching primary CRCs and liver metastases from 33 patients were analyzed for T-Ag expression by immunohistochemistry. Results: T-Ag expressing cell lines showed 2 to 3-fold increase in migration and invasion compared to controls. JCV T-Ag expression resulted in differential expression of several genetic targets, including genes that mediate cell migration and invasion. Pathway analysis suggested a significant involvement of these genes with AKT and MAPK signaling. Treatment with selective PI3K/AKT and MAPK pathway inhibitors resulted in reduced migration and invasion. In support of our in-vitro results, immunohistochemical staining of the advanced stage tumors revealed frequent JCV T-Ag expression in metastatic primary tumors (92%) as well as in their matching liver metastasis (73%). Conclusion: These data suggest that JCV T-Ag expression in CRC associates with a metastatic phenotype, which may partly be mediated through the AKT/MAPK signaling pathway. Frequent expression of JCV T-Ag in CRC liver metastasis provides further clues supporting a mechanistic role for JCV as a possible mediator of cellular motility and invasion in CRC.

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/105702/1/T200905045.pdf

JC virus mediates invasion and migration in colorectal metastasis

Mechanisms of sulindac-induced apoptosis and cell cycle arrest

Gastrointestinal (GI) cancers are mainly linked to environmental factors that cause somatic mutations in the tumors. However, a modest proportion of GI cancers (no more than 5%) can be linked to germline mutations in a variety of genes, including a tumor suppressor gene (the APC gene, which causes the dominant form of familial adenomatous polyposis, or FAP) and DNA repair genes (the DNA mismatch repair genes that cause Lynch syndrome, and the base excision repair gene MUTYH, which causes the recessive form of FAP). There are several recognizable familial syndromes that are associated with hamartomatous polyps of the GI tract and an increased risk for GI cancers, including Peutz–Jeghers syndrome (STK11/LKB1 gene), juvenile polyposis syndrome (associated with SMAD4, BMRPR1A, and ENG), Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome—jointly known as the PTEN hamartoma tumor syndrome (associated with PTEN, and also KLLN), and others. The CDH1 gene has been associated with hereditary diffuse gastric cancer (HDGC), and multiple genes have been associated with an increased risk for pancreatic cancer, most of which produce a phenotypically identifiable disease, including familial pancreatitis (PRSS1), the familial atypical multiple mole/melanoma syndrome, FAMMM (p16), Peutz–Jeghers syndrome, hereditary breast and ovarian cancer (BRCA2 and BRCA1), Lynch syndrome and FAP.

Cancer of the Colon and Gastrointestinal Tract

Colorectal cancer causes significant morbidity and mortality and remains the second most common cause of cancer-related death in the United States. A number of screening approaches have been shown to decrease colon cancer‐related mortality and are cost-effective. In this review, we discuss available screening approaches and suggest strategies to implement effective screening using the current tools available.

Screening for Colorectal Cancer: Analysis of Evidence and Cost-Effectiveness

The roles in colon cancer pathogenesis of the transforming growth factor family members bone morphogenetic protein (BMP) and activin have only recently been studied but are increasingly recognized as key. Like their more heavily investigated relative, transforming growth factor β, both BMP and activin are growth-suppressive in normal colonocytes, and their canonical intracellular SMAD signaling is disrupted to abate this suppression. For BMP, there is evidence that non-SMAD signaling pathways may mediate cell proliferation and contribute to the metastatic behavior of colon cancer. BMP signaling in particular is disrupted in the germline of patients with familial juvenile polyposis, an autosomal dominant syndrome with a 12-fold increase in risk for colon cancer over the general population. Researchers are actively investigating cellular and signaling mechanisms by which BMP and activin may initiate and drive proliferation and allow cells to exhibit metastatic properties.

Barbara H. Jung

Papers

JC virus mediates invasion and migration in colorectal metastasis

Mechanisms of sulindac-induced apoptosis and cell cycle arrest

Cancer of the Colon and Gastrointestinal Tract

Screening for Colorectal Cancer: Analysis of Evidence and Cost-Effectiveness

Bone Morphogenetic Protein and Activin Signaling in Colorectal Cancer