Discovery Of Tumor Suppressor Genes Research Articles

Virology and cancer biology: DNA viruses associated with transformation and tumor formation. The discovery of tumor suppressor genes

Virology and cancer biology: DNA viruses associated with transformation and tumor formation. The discovery of tumor suppressor genes

A History of Cancer Research: Tumor Suppressor Genes.

Tumor suppressor genes encode critical intracellular regulators, such as the retinoblastoma protein. They control processes including cell proliferation, cell survival, and responses to DNA damage and are frequently mutated in cancer. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the discovery of tumor suppressor genes, covering the early work on cell fusion by Henry Harris, Knudson's two-hit hypothesis, the genetic mapping studies that first identified the RB gene, and subsequent work on silencing.

APPROACH TO EVALUATE THE RISK OF CANCER FOR DIFFERENT NUMBER OF TUMOR SUPPRESSOR GENES IN THE INDIVIDUAL

Significant progress in understanding the mechanisms of carcinogenesis is associated with the discovery of tumor suppressor genes (or antioncogenes). It is known that in the human population, the number of normally functioning suppressor genes varies in different individuals at birth. The aim of the study was to assess the probability of cancer development in an individual with a different initial number of undamaged normally functioning antioncogenes. On the basis of the probabilistic mathematical model of carcinogenesis, the most probable age of cancer development depending on the number of intact antioncogenes was assessed. As a result of the studies, the probability of cancer development depending on the age of the patient is estimated. The dependence of the probability of cancer development in an individual on the number of undamaged antioncogenes is also investigated. The analysis of the significance of the number of tumor suppressor genes, the damage of which may be the cause of initiation of cell malignancy, has been carried out.

Genetics and epigenetics in human cancer

Gene expression regulation by synergistic epigenetic modifications and genetic elements has gain substantial attention for ten years. However, epigenetic and genetic alterations have also been considered to participate in carcinogenesis. The recent development of next-generation sequencing to explore various human cancers has uncovered many mutations in genes that control the epigenome and many epigenetic patterns that control the genome. The genetic alterations tend to change the epigenetic patterns including DNA methylation, histone modifications and ultimately to change gene expression. The epigenetic alterations contribute to cancer by inducing genetic mutations and impairing DNA repair functions. The development of next-generation high-throughput technologies makes the discovery of tumor-suppressor genes and oncogenes more easily. With the aid of Bioinformatics, a large number of studies have suggested that cancer is a multilayer and complex disease involving both genetic mutations and epigenetic changes. We illustrate the recent progress of cancer pathogenesis and explain why cancer genome and epigenome complement each other in cancer progression. The crosstalk between genome and epigenome is a new viewpoint that may be useful in cancer therapy.

A Comparison of DNA Copy Number Profiling Platforms

The accurate mapping of recurring DNA copy number aberrations (CNAs), a hallmark feature of the cancer genome, has facilitated the discovery of tumor suppressor genes and oncogenes. Microarray-based assays designed to detect these chromosomal copy number alterations on a genome-wide and high-resolution scale have emerged as a cornerstone technology in the genomic era. The diversity of commercially available platforms prompted a systematic comparison of five copy number profiling assays for their ability to detect 2-fold copy number gain and loss (4n or 1n, respectively) as well as focal high-amplitude CNAs. Here, using a collection of established human melanoma cell lines, we defined the reproducibility, absolute signals, signal to noise, and false-positive and false-negative rates for each of the five assays against ground truth defined by spectral karyotyping, in addition to comparing the concordance of CNA detection by two high-resolution Agilent and Affymetrix microarray platforms. Our analyses concluded that the Agilent's 60-mer oligonucleotide microarray with probe design optimized for genomic hybridization offers the highest sensitivity and specificity (area under receiver operator characteristic curve >0.99), whereas Affymetrix's single nucleotide polymorphism microarray seems to offer better detection of CNAs in gene-poor regions. Availability of these comparison results should guide study design decisions and facilitate further computational development.

Making Waves in Cancer Research: New Models in the Zebrafish

The zebrafish (Danio rerio) has proven to be a powerful vertebrate model system for the genetic analysis of developmental pathways and is only beginning to be exploited as a model for human disease and clinical research. The attributes that have led to the emergence of the zebrafish as a preeminent embryological model, including its capacity for forward and reverse genetic analyses, provides a unique opportunity to uncover novel insights into the molecular genetics of cancer. Some of the advantages of the zebrafish animal model system include fecundity, with each female capable of laying 200-300 eggs per week, external fertilization that permits manipulation of embryos ex utero, and rapid development of optically clear embryos, which allows the direct observation of developing internal organs and tissues in vivo. The zebrafish is amenable to transgenic and both forward and reverse genetic strategies that can be used to identify or generate zebrafish models of different types of cancer and may also present significant advantages for the discovery of tumor suppressor genes that promote tumorigenesis when mutationally inactivated. Importantly, the transparency and accessibility of the zebrafish embryo allows the unprecedented direct analysis of pathologic processes in vivo, including neoplastic cell transformation and tumorigenic progression. Ultimately, high-throughput modifier screens based on zebrafish cancer models can lead to the identification of chemicals or genes involved in the suppression or prevention of the malignant phenotype. The identification of small molecules or gene products through such screens will serve as ideal entry points for novel drug development for the treatment of cancer. This review focuses on the current technology that takes advantage of the zebrafish model system to further our understanding of the genetic basis of cancer and its treatment.

The quest for a tumor suppressor gene phenotype.

Our current definitions of the tumor suppressor gene (TSG) have been guided by the identification of the prototypical gene, RB1, a TSG that is implicated in the development of both the inherited and sporadic forms of retinoblastoma. The hallmark feature of this TSG is loss of function in tumoral cells, which can be restored by reintroduction of a normally functioning protein with concomitant reversion of tumorigenicity. Key to this discovery was that loss of function is often achieved by deletion of a normal copy of the TSG and retention of a mutated allele, which was either inherited or acquired. Suppression of tumorigenicity and the loss-of-function concept of TSGs was also demonstrated in early studies where normal cellular growth was achieved when tumorigenic cells were fused with normal cells. Thus loss of genetic content and restoration of gene function has guided studies aimed at the discovery of novel TSGs. Here we review the successes of TSG discovery using three approaches that are based on the genetic analysis of inherited predisposition to cancer, tumors that display chromosome loss, and tumorigenic cells that display a suppression of tumorigenicity as a result of transfer of normal chromosomes. Based on a review of the literature we conclude that the discovery of TSGs has been highly successful in the genetic analysis of inherited predisposition to cancer with a dominant mode of inheritance. In contrast, the latter two approaches have yielded a paucity of TSGs that exhibit features similar to the prototypical RB1 in that they are rarely inactivated by somatic mutations in tumors displaying LOH, although decreased gene expression is observed. Nevertheless, some of these genes have been shown to suppress tumorigenicity when normal function is restored in tumorigenic cells consistent with the loss-of-function concept. These observations continue to challenge our current definition of TSG.

A paradigm for cancer treatment using the retinoblastoma gene in a mouse model.

Discovery of tumor suppressor genes has provided a rational approach to cancer prevention and treatment. Loss of retinoblastoma susceptibility gene (Rb) function is a rate-limiting event in the development of human and mouse cancers. Establishment of animal models of cancer associated with Rb deficiency allowed us to develop and test long-awaited approaches to genetic correction for treating tumors in vivo. Recent studies demonstrated that (1) prevention of carcinogenesis is achieved by correction of gene copy number in Rb+/- mice, and (2) reconstitution of Rb gene functions is sufficient for suppression of neoplasia in immunocompetent mice. These results fulfill a promise of cancer treatment by reconstitution of tumor suppressor function.

In Vivo Gene Therapy of Human Lung Cancer Using Wild-Type p53 Delivered by Retrovirus

Lung cancer presents a major therapeutic problem. The mortality rate from lung cancer approaches 90%, and treatment of inoperable non-small-eell lung cancer only occasionally results in cures (7). In this setting, a new therapy yielding a significant clinical partial tumor response rate or any apparently complete tumor regressions is all that it takes to warrant large-scale clinical trials. Different therapeutic approaches are clearly needed, especially rationally designed approaches based on our emerging understanding of molecular abnormalities in cancer cells. It is now thought that cancer is the end result of an accumulation of genetic lesions in key regulatory molecules, and the identity and function of these molecules are the subjects of intense ongoing research (2). With the discovery of tumor suppressor genes whose function is missing in cancer cells came the idea of gene-replacement therapy: putting back into cancer cells a gene that is missing or damaged to return growth control. It is entirely possible, however, that several of the multiple lesions would have to be corrected before any antitumor effect could be seen. Because p53 (also known as TP53) is one such tumor suppressor gene that is missing or defective in the majority of human lung cancers as well as in other human cancers, it was a prime candidate for gene therapy (5-5). As a first step, several groups were able to show that the stable transfection (6) or retroviral transduction (7) of wild-type p53 into p53 mutant or null lung cancer cells dramatically inhibits cell growth in vitro despite the presence of multiple other genetic lesions. The immediate problem with application of this approach in patients is the in vivo delivery of the therapeutic gene to sufficient numbers of tumor cells to produce a clinically observable effect. In theory, nearly every clonogenic tumor cell would have to be effectively transduced (receive, integrate, and express the gene) for us to see a significant antitumor response. With a variety of gene transfer methods under optimal conditions in tissue culture, a 30%-50% rate of transduction and expression of a tumor suppressor gene in human cancer cells would be considered extremely good. This rate, however, would probably be of limited clinical signficance and barely detectable in vivo, where logs of tumor cell kill are required. Despite all of these negative hypotheticals, in this issue of the Journal, Fujiwara et al. (8) report the in vivo retroviral transduction of wild-type p53 into human lung cancer cells in an orthotopic nude mouse model. They convincingly demonstrate that intratracheal human lung cancer cell growth can be eliminated or greatly reduced by intratracheal treatment, beginning 3 days after tumor cell inoculation, with a wild-type p53 recombinant retrovirus (but not with a retrovirus containing a mutant p53 or the retrovirus vector alone). The biological effectiveness in this model system of in vivo gene transfer is surprising, especially given the high level of expression of endogenous mutant p53 protein that has been shown to act in a dominant negative fashion to inhibit the transcriptional function of the wild-type p53 protein (9). As is true with all interesting studies, these data raise a series of questions for future experiments. Which human clinical situations would be best approached with this treatment? In those mice cured by this treatment, was there a bystander effect (70) whereby neighboring tumor cells that were not transduced with wild-type p53 somehow had their growth suppressed? Did the growth suppression in transfected cells result from the induction of apoptosis (programmed cell death) reported in other systems (77) and, if so, did the bystander cells undergo the same fate? Is there a bystander effect in more distant, metastatic tumor cells? Does this therapeutic approach work at other sites in the body, for other p53 mutations, and for other human tumors? Why did some of the tumors grow even with the wild-type p53 incorporated? Fundamental practical problems are still apparent as well. Clinically evident human lung cancers are seldom only a few cell layers thick and confined to a closed surface, as is the case in this intratracheal orthotopic model. In addition, these experiments do not attempt to address the major clinical problem of metastases in lung cancer. However, these studies suggest several potential clinical applications. One application could be the treatment of the pleural space and/or the bronchial tree after surgical removal of the primary tumor in an attempt to reduce the incidence of pleural effusions and local recurrences. Another application could be the treatment of patients with small lesions involving the trachea or carina; these lesions could be debulked

Tumor Suppressor Genes: New Prospects for Cancer Research

Cancer is thought to arise from the accumulation of several genetic mutations in a single cell. Until recently, the only tumorigenic mutations that have been studied in detail are those that activate oncogenes. The discovery of tumor suppressor genes, for which inactivating mutations elicit tumorigenesis, has added a new dimension to our understanding of neoplasia. The retinoblastoma susceptibility gene RB is the prototype tumor suppressor gene and has been shown to suppress the transformed phenotype for several different cancers. Additional studies have revealed other tumor suppressor genes that may operate in a variety of tissues through a variety of mechanisms. These mechanisms may regulate the choice between cellular proliferation and differentiation and appear to involve such processes as the initiation of DNA replication, regulation of expression of certain genes, intercellular communication and adhesion, and the transduction of external signals to intracellular effectors. The elucidation of these mechanisms will enhance our understanding of both oncogenesis and the fundamental operations of the cell.

Tumor Suppressor Genes: A Key to the Cancer Puzzle?

Research Article| January 01 1991 Tumor Suppressor Genes: A Key to the Cancer Puzzle? Steven B. Oppenheimer Steven B. Oppenheimer Search for other works by this author on: This Site PubMed Google Scholar The American Biology Teacher (1991) 53 (1): 22–24. https://doi.org/10.2307/4449207 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Steven B. Oppenheimer; Tumor Suppressor Genes: A Key to the Cancer Puzzle?. The American Biology Teacher 1 January 1991; 53 (1): 22–24. doi: https://doi.org/10.2307/4449207 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentThe American Biology Teacher Search This content is only available via PDF. Copyright 1990 National Association of Biology Teachers Article PDF first page preview Close Modal You do not currently have access to this content.