Multistage carcinogenesis and the concept of oncogene addiction. A view on egfrtargeted therapies from the oncogeneaddiction perspective article pdf available in frontiers in pharmacology 4. Request pdf oncogene addiction tumors induced in conditional oncomice can show remarkable different responses to subsequent oncogene deprivation. Oncogene addiction provides a satisfying explanation for much of what has been observed experimentally. The compelling concept proposed to account for these evidences is known as oncogene addiction. Microrna17, or mir17, is a member of the oncomir1 family and one of the first mirna to be identified as an oncogene. It is published weekly and covers all aspects of the structure and function of oncogenes. In our fight against this dreaded disease, casualties abound and successes are few and far between. A corollary to oncogene addiction is the recently proposed concept of lineagesurvival oncogenes in which specific types of cancer are dependent on the expression of an altered form of a gene that normally plays an essential role in the development of. Most examples of oncogene addiction fall within the first two categories. Myc inactivation elicits oncogene addiction through both. Oncogene addiction describes the phenomenon in which some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities remain dependent on addicted to one or a few genes for both maintenance of the malignant phenotype and cell survival.
Oncogene definition of oncogene by medical dictionary. Does an activated oncogene that initiates tumor growth need to remain activated to maintain the cancer phenotype. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Oncogene addiction refers to the phenomenon by which tumor cells develop a dependency on a driver oncogenic product that assumes the role of buttressing and fueling the malignant phenotype, thus setting the basis for the conception of anticancer therapies targeting single oncoproteins in defined populations of cancer patients. This phenomenon has been demonstrated in vivo for several oncogenes. Why addiction is a disease, and why its important resource guide educational pages addiction 101. An axiom in cancer research is that the multistage process of tumor formation 12 is driven by progressive acquisition of activating mutations in dominant growthenhancing genes oncogenes. Sep 21, 2007 by definition, genes involved in such pathways will evade detection by sequencing. After serial growth of the transformed nih 3t3 cells, the human tumor oncogene can be cloned by its association with human repetitive dna sequences. There are now multiple examples supporting the notion that cancer cells in vitro are dependent on or addicted to certain activated oncogenes. This is because the proteins encoded by these genes often have multiple roles in.
Mechanisms of oncogene addiction we proposed that the phenomenon of oncogene addiction is a consequence of the fact that the multistage process of carcinogenesis is not simply a summation of the individual effects of activation of multiple oncogenes and inactivation of multiple tumor suppressor genes 5. Tumor dormancy, oncogene addiction, cellular senescence. Modeling oncogene addiction using rna interference pnas. This questionhas been answered affirmatively by experiments in which doxycyclineregulated oncogene activation induces growth oflarge tumors that regress completely upon oncogene inactivationa phenomenon called oncogene addiction. The concept of oncogene addiction has been demonstrated in a variety of mouse tumorigenesis models in which continued expression of the transforming oncogene is required for tumor maintenance. Discussion lsf is a ubiquitously expressed transcription factor in mammalian cells, whose substantially enhanced expression in hepatocellular carcinoma can promote oncogenesis. Other genes which have been found to be amplified in some tumor cells include ckiras, cmyb, cabl and cerb b. Oct 14, 2019 oncogene plural oncogenes oncology, genetics any gene that contributes to the conversion of a normal cell into a cancerous cell when mutated or expressed at high levels. Experimental oncogene addiction since the discovery of oncogenes and tumor suppressor genes, a fundamental question has emerged. The oncogeneaddicted phenotype is not unique to mutated kinases. Oncogene addiction as a foundation of targeted cancer.
In its simplest embodiment, oncogene addiction refers to the curious observation that a tumor cell, despite its plethora of genetic alterations, can seemingly exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation andor survival. Tumor death, dormancy, differentiation, or relapse. These originate from a variety of settings, including human cancer cell lines, mouse tumor models, and clinical cancer studies table 1. Identification of oncogenic genes in retroviruses 3. Mar 10, 2017 oncogene addiction describes the phenomenon in which some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities remain dependent on addicted to one or a few genes for both maintenance of the malignant phenotype and cell survival. The inactivation of myc may be a general and effective therapy for human cancer. Oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the achilles heel of the successful molecular targeted therapies in cancer. Mar 07, 2011 fourth, it evolves over time oncogene addiction tumor suppressor hypersensitivity multistage theory of carcinogenesis and other expressions were brand new to me and i thought i share what. Indeed, the first experimental demonstrations of oncogene addiction were in the setting of myc or ras. Targeting molecular addictions in cancer british journal. Viral oncogenes are responsible for the rapid tumor formation and efficient in vitro transformation activity characteristic of acutely transforming retroviruses. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. In human cancer, the clinical efficacy of imatinib confirms the essential role for bcrabl in chronic myelogenous leukemia, whereas the dramatic.
A single cancer cell frequently contains mutations in multiple genes, gross chromosomal abnormalities, and widespread changes in its gene expression profile hn11. But it is difficult to define oncogene addiction in numerous conditions. However, the role of oncogene addiction in gliomas has not been elucidated systematically. Oncogene addiction as a foundation of targeted cancer therapy. We proposed that the phenomenon of oncogene addiction is a consequence of the fact that the multistage process of carcinogenesis is not simply a summation of the individual effects of activation of multiple oncogenes and inactivation of multiple tumor suppressor genes 5, 6. The nci dictionary of cancer terms features 8,568 terms related to cancer and medicine. Oncogene addictiona rationale for molecular targeting. Based on studies with cell line culture models, oncogenic shock. Nononcogene addiction and the stress phenotype of cancer cells. With knowledge gained through clinical trials, the oncogene addiction model was revised 71. Elledge1, 1howard hughes medical institute, department of genetics, harvard medical school, department of medicine, division of genetics, brigham and womens hospital, boston, ma 02115, usa correspondence. Oncogene is one of the worlds leading cancer journals. Nononcogene addiction and the stress phenotype of cancer. Homologous sequences in transformed and untransformed cells 4 methods of transforming cells with oncogenes4.
This is an open access article distributed in accordance with the creative commons attribution non commercial cc bync 4. Sep 30, 2014 oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally. While in vitro and in vivo examples abound documenting the existence of this phenomenon, the mechanistic underpinnings that govern oncogene addiction are just beginning to emerge. Cancers free fulltext targeting nononcogene addiction. Any of a family of genes that normally encodes proteins that are involved in cell growth or regulation e. When we and others first described that myc inactivation reversed tumorigenesis, our explanation was somewhat prosaic not because we did not have an idea of the possible mechanisms, of which we proposed several, but we were aware that, at the time, it was hard enough to be certain of the observation. Some cells, such as cml stem cells, may not be oncogene addicted and tumor. In tumor cells, these genes are often mutated, or expressed at high levels most normal cells will undergo a programmed form of rapid cell death when critical functions are altered and malfunctioning. Identified oncongenes include ras, originally noted in bladder tumors, and p53.
Implications for molecular targeted therapy wei yan, wei zhang and tao jiang abstract oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the achilles heel of the successful molecular targeted. Definition of subsets of patients, which would benefit from a given therapy, with a shared biological. However, the development of drugs that inhibit the function of such proteins such as myc and ras can be substantially more challenging than it has been for the kinases. Oncogene addiction is the phenomenon by which tumor cells, through the consequence of a multitude of genetic and epigenetic changes, remain exquisitely dependent upon a single oncogenic lesion for the persistence of their neoplastic phenotype figure 1,2 2, 14. Essentially, mirnas specifically target certain messenger rnas mrnas to prevent them from coding for a specific protein. The phrase oncogene addiction was coined to describe the observation that tumor maintenance often depends upon the continued activity of certain oncogenes weinstein, 2002.
Definition of addiction short definition of addiction. Although noa genes are acknowledged to be potential drug. Micrornas are short rna molecules about 22 nucleotides in length. This definition was first introduced by bernard weinstein in 2000, with particular reference to the observation that some cyclin doverexpressing cancers reverse their malignant phenotype upon cyclind depletion by means of rna interference rnai. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally. Oncogene addiction is the dependence of a cancer cell on one overactive gene or pathway for the cells survival and growth. Feb, 2015 clinical evidence for oncogene addiction.
The first human oncogene isolated by the gene transfer technique was derived from a bladder carcinoma. Adaptation to hypoxia versus oncogene addiction an oncogene panel is a targeted nextgeneration sequencing ngs approach, which can take a patient sample from tumor tissue, not unaffected tissue and simultaneously sequence all of these hundreds of understood genes on cell division control pathways. In retrospect, the earliest evidence of oncogene addiction can be traced back to studies using human tumorderived cell lines. Definition of oncogene nci dictionary of cancer terms.
The majority of tc are characterized by a good prognosis, even though cases with aggressive forms not cured by standard therapies are also present. We assemble here the evidence that oncogene addiction is angiogenesisdependent. The term oncogene addiction was first coined by bernard weinstein to describe the dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties, despite the likely accumulation of multiple gain and lossoffunction mutations that contribute to tumorigenicity. Oncogene and nononcogene addiction ji luo,1 nicole l.
Moreover, target therapies have led to low rates of partial response and prompted the emergence of resistance. Oncogene addiction as a foundational rationale for targeted anti. Cancer is, an old adage goes, actually a hundred diseases masquerading as one. This definition was first introduced by bernard weinstein in 2000, with particular reference to the observation that some cyclin d. For the purpose of organizing the data presented here, we use the term endothelial centric hypothesis of oncogene addiction. Transcriptional targeting of oncogene addiction in medullary thyroid cancer anisley valenciaga, 1 motoyasu saji, 1 lianbo yu, 2 xiaoli zhang, 2 ceimoani bumrah, 3 ayse s. Fourth, it evolves over time oncogene addiction tumor suppressor hypersensitivity multistage theory of carcinogenesis and other expressions were brand new to me and i thought i share what. Oncogene amplification may be associated with tumor progression as seen with nmyc in neuroblastomas and with cmyc in small cell lung carcinomas. Mutated oncogenes and inactivated tumor suppressors can increase the dependency of cancer cells on gphase cyclindependent kinases, augment replication stress and dna. A cardinal feature of cancer cells is the deregulation of cell cycle controls. Addiction to oncogenesthe achilles heal of cancer science.
Dominant mutations in proto oncogenes contribute to deregulated cell growth. Oncogene definition of oncogene by the free dictionary. One of the most common oncogenic events in human cancer is the activation of the myc oncogene. Oncogene addiction as a foundational rationale for.
The term nononcogene addiction was first coined by steve elledge in the context of findings by susan. In this issue, lindquist and her colleagues illustrate an example of non. Transcriptional targeting of oncogene addiction in medullary thyroid cancer anisley valenciaga, gilbert j. In every case, these retroviral oncogenes are derived from normal cellular genes captured from the genome of the host. Mechanisms of oncogene activation oncogenes are mutant or overexpressed forms of normal cellular genes proto oncogenes. Oncogene addiction an overview sciencedirect topics. The dysregulation of certain micrornas oncomirs has been associated with specific cancer.
Pdf a view on egfrtargeted therapies from the oncogene. The use of selective epidermal growth factor receptor egfr kinase inhibitors in lung cancer treatment represents yet another example of oncogene addiction that. A view on egfrtargeted therapies from the oncogeneaddiction. Over the last decade, researchers have accumulated evidence for oncogene addiction, and they are now teasing out exactly how such addiction takes placeand how tumors might escape it. We offer a widget that you can add to your website to let users look up cancerrelated terms. Oncogenes are altered forms of normal cellular genes called proto oncogenes that are involved in pathways regulating cell growth, differentiation, and survival. Targeting molecular addictions in cancer british journal of.
Oncogene article about oncogene by the free dictionary. The tumorspecific effect of this smallmolecule inhibitor of the oncogene lsf in mice fits the classic definition of oncogene addiction. It is now an axiom in oncology that human cancers often evolve through a. Immune checkpoint inhibitor treatment in patients with. Oncogene addiction appears to provide an exploitable therapeutic opportunity in which targeted inhibition of the addicting oncoprotein can have profound effects on. An oncogene is a gene that has the potential to cause cancer. A gene that played a normal role in the cell as a proto oncogene and that has been altered by mutation and now may contribute to the growth of a tumor. American society of addiction medicine public policy statement. May 17, 2011 oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the achilles heel of the successful molecular targeted therapies in cancer. Thyroid carcinoma tc is the most common malignancy of endocrine organs with an increasing incidence in industrialized countries. Transcriptional targeting of oncogene addiction in. Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Oncogene definition is a gene having the potential to cause a normal cell to become cancerous.
Oncogene and non oncogene addiction ji luo,1 nicole l. Oncogene addiction as a foundational rationale for targeted. A prime clinical example of oncogene addiction is in cml. The recovery research institute provides a comprehensive overview of the epidemiology prevalence, etiology causes, phenomenology experience, impact and the latest terminology on addiction. One of the earliest examples of targeted therapy albeit one where clinical. Retroviral integration of proto oncogene sequences in. An oncomir also oncomir is a microrna mirna that is associated with cancer. Ringel published august 23, 2018 citation information. However, cell culture and animal tumor studies have demonstrated a likely role for oncogene addiction for other important cancer genes, such as cmyc and ras. Among the best examples defined thus far is the demonstration that some melanomas. It was obvious from the start what kinds of genes oncogenes would turn out to be genes that encourage cells to.
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