Current Genomics - Volume 3, Issue 4, 2002

Chromosomal translocations entail the generation of gene fusions in solid mesenchymal tumors. Despite the successful identification of these specific and consistent genetic events, the nature of the intimate association between the gene fusion and the resulting phenotype is pending to understand. Herein these studies are reviewed using FUS-CHOP as a model to illustrate how the manipulation of their loci in the mouse has contributed to the current understanding in unique and unexpected ways. FUS-CHOP is a chimeric oncogene generated by the most common chromosomal translocation t(12;16)(q13;p11) associated to liposarcomas. The application of transgenic methods to the study of this sarcoma-associated FUS-CHOP gene fusion has provided insights into their in vivo functions and suggested mechanisms by which lineage selection may be achieved.

Understanding the molecular events that commit to the cell cycle has important implications for cancer. Available evidence, mostly derived from human tumors, has revealed frequent alterations in genes involved in the control of the G1 restriction point and the progression from G1 to S phase. Many of the players that participate in these events have been characterized at the biochemical level. They include, among others the cyclin-dependent kinases (Cdk), Cdk4, Cdk6 and Cdk2 and their cognate D- and E-type cyclins, Cdk inhibitors (CKI), and the main Cdk downstream substrates, the retinoblastoma (pRb) family of proteins. Yet, there is little information as how these molecules regulate cell cycle commitment in vivo. The development of mouse strains carrying targeted mutations in these loci is opening new ways to explore the network of molecular pathways that control passage through G1 into the S phase in complex multicellular organisms such as mammals. These strains are also providing new insights as of how misregulation of these processes may lead to cancer development. In this review, we attempt to summarize our current knowledge of the molecular mechanisms that control the G1 / S transition with particular emphasis in those studies carried out in vivo using gene targeted mice.

The p53 pathway is inactivated in essentially all human tumors p53 is lost or mutated in over 50% of all human cancers, and the majority of the remaining tumors carry mutations in other components of the pathway. It appears that the main biological function of p53 in vivo is to suppress tumorigenesis, because mice with homozygous deletion of the p53 gene are normal, but develop multiple tumors at an early age. p53 plays a central role in cell cycle control and apoptosis in response to DNA damage and other stresses, and in response to oncogenic activation. Loss of p53 function leads to excessive proliferation due to an inappropriate cell cycle control, or to a reduced apoptosis and an excess survival. This allows propagation of cells with damaged DNA resulting in increased genetic instability and enhanced risk of cancer. The contribution of each of the p53 functions, or the lack thereof, to tumor initiation and progression has been studied in vivo, in genetically modified mice. Mice with deletions of one or both p53 alleles have been crossed with mice expressing dominant oncogenes, or lacking other tumor suppressor genes, in order to analyse the genetic interaction between different tumorigenic pathways in vivo. These studies have defined how oncogenic mutations can cooperate in tumorigenesis in tissue and the tumor-specific ways.

In Drosophila, Sprouty was originally identified as an antagonist of tracheal branching and shown to be a general inhibitor of receptor tyrosine kinase. Recently, four mammalian homologues have been isolated. All Sprouty proteins exhibit a unique, highly conserved, cysteinerich C-terminal domain. Genetic and biochemical data indicate that Sprouty proteins antagonize receptor tyrosine kinase signaling through specific inhibition of the Ras / Raf / MAP Kinase pathway by preventing Ras activation. Expression of sprouty genes is regulated by FGF in a negative autoregulatory loop and is localized to known domains of FGF signaling in the developing embryo. Overexpression studies suggest that vertebrate sprouty genes may be important regulators of several developmental processes. In particular, sprouty may play a role during the branching morphogenesis involved in angiogenesis, or the formation of the lung and the kidney, but also during gastrulation or limb formation.

The human ras genes (Nras, Hras, and Kras) code for closely related small GTPases possessing a molecular size of about 21 KDa. Ras proteins operate as molecular switches in signal transduction cascades controlling cell proliferation, differentiation or apoptosis. As for all G proteins, the function of the ras gene protein products is controlled through a regulated GDP / GTP cycle. Each of the three human ras proto-oncogenes can give rise to a transforming oncogene via single base pair mutations. Mutations at codons 12, 13 or 61 significantly downgrade the GTPase ability of the resulting mutant Ras proteins, which are thus rendered constitutively active and able to transform mammalian cells. Indeed, the detection of such mutations in various human tumors indicates that deregulated GTP binding to Ras is involved in the development of up 30% of all human cancers. Specific members of the Ras family are mutated in different tumor types, with mutations in Kras appearing most frequently. Some tumor cell lines harbor amplified ras genes and transfection studies have shown that a 20-fold increase in the level of expressed normal Ras protein is sufficient to induce transformation of some recipient cells. Studies with knockout mice strains have revealed that Kras (but not Nras or Hras) is necessary and sufficient for the development of the animals to the adult stage. It remains unclear whether the different Ras family members play totally specific or overlapping functional roles in the cell. Recent data on localization to different plasma membrane subdomains, marked quantitative differences of effector activation levels and new roles for some docking / scaffold proteins point to signaling specificities of the different Ras proteins. This review analyzes the current understanding of Ras function focusing on the possible physiological and oncogenic specificities of each Ras family member.

Hematopoiesis is a complex process during which hematopoietic stem cells (HSC) proliferate and differentiate to constitute both the myeloid and lymphoid branches of the hematopoietic system. Hematopoiesis occurs in successive organs beginning in the yolk sac and aorto-gonads-mesonephros (AGM) region, then migrate from the AGM region to the fetal liver and subsequently to the bone marrow. Hematopoiesis is regulated by a multitude of signals from the microenvironment that control expansion and proper differentiation of blood progenitors. Modifications in gene expression or protein function, as those occurring by chromosome translocations have an oncogenic potential. Over the last decade an increasing number of recurrent chromosomal translocations has been described that are associated with hematologic malignancies. Cloning of the partner genes in these translocations and molecular abnormalities characterization has provided new insights in the processes involved in both normal and malignant hematopoiesis. We review here some of the translocations involved in the pathogenesis of hematologic malignancies with emphasis on what is known regarding the mechanisms of malignant transformation.

The epidermis is a model particularly well suited to the study of cell proliferation and differentiation, and of alterations of these processes such as carcinogenesis. Compartmentalization exists in this tissue, with the proliferative, less differentiated cells confined to the basal layer and the terminally differentiating, non-proliferative cells moving upwards to the surface through distinct layers. Different genes are expressed throughout this process in a stage-of-differentiationspecific manner, and their promoters have been very useful in directing precise gene expression in transgenic mice. Other attractive characteristics of the epidermis include its external localization, which facilitates manipulation and observation, the possibility of obtaining primary keratinocytes that can be easily cultured and manipulated in vitro, and the existence of well-established protocols for chemical and UV carcinogenesis. The latter are invaluable tools for assessing the in vivo functions of the genes targeted in transgenic mice. These characteristics have made the epidermis a widely used model system in recent years for the study of molecular mechanisms of carcinogenesis. A wealth of transgenic mice generated using epidermal-specific promoters, as well as knockout animals, have been used to examine the role of genes involved in processes such as cell cycle control, cell signaling, cell growth and differentiation, and angiogenesis in tumor and metastasis growth. Cre / loxP technology will allow a new generation of mice that allows the study of cancer genetics in a cell type-and time-controlled manner, more closely resembling the conditions found in the development of neoplasms.

More than 90% of malignant tumors arising in humans are of epithelial origin. The loss of epithelial morphology and the acquisition of mesenchymal characteristics are important early events in tumor progression. This type of morphological transformation is termed an epithelial-mesenchymal transition. These transitions occur normally during embryonic development, as well as pathologically during tumor progression. This review will encapsulate our understanding of the role that epithelial-mesenchymal transitions play during tumor progression and metastasis, and we also summarize recent results describing the roles played by such genes as E-cadherin, Snail, and TGFβ in regulating epithelial-mesenchymal transitions and metastasis.

The development, refinement and increasingly widespread use of high-density DNA microarrays have been important responses to the explosion of sequence information produced by genome science. Principal among the application of microarrays is the large-scale analysis of gene expression, often referred to as expression profiling. The power of this application lies in its ability to determine the expression patterns of thousands of genes in a single experiment. Microarray use is becoming widespread in many biomedical research fields, including the study of carcinogenesis, in which expression profiling has found a number of important applications. Broadly speaking, these applications can be described as gene and pathway discovery, gene functional assignment, and tumor classification. A number of early gene expression studies using tumor cell lines and tumors have shown that DNA microarrays are powerful tools, both for identifying new genes and assigning roles to known genes involved in carcinogenesis as well as for classifying tumors subtypes. In this review, we describe the major types of DNA microarrays, discuss some practical considerations for their use, and present examples of how they are being applied to the investigation of cancer.

Human cancers are consequence of mutations in genes that encode proteins involved in the control of cellular homeostasis. Most human cancers are sporadic and gene mutations may be induced by a large number of environmental agents. Cell response to carcinogens is regulated by genes involved in liver metabolism. Variability in liver metabolism has been associated with polymorphisms in genes that code for phase I and phase II detoxification enzymes. These polymorphisms are relatively common in the population and may be associated with a higher risk of developing cancer. Moreover, as carcinogens act inducing changes in the DNA, there is a link between DNA repair genes and cancer susceptibility, such that mutations in these genes are associated with cancer susceptibility. Finally, oncogenes and tumor suppressor genes also can present allelic variants that are not directly imply in cancer development but can modify individual susceptibility to cancer. Here we review the most frequent polymorphisms described in genes involved in carcinogen metabolism, DNA repair and in oncogenes and tumor suppressor genes that have been associated with modification in cancer susceptibility.