Encyclopedia of Cancer 2016
An oncogene is a derivative of any gene that has the ability to stimulate cellular growth. In experimental assays, oncogene products can, alone or in cooperation with another gene, transform eukaryotic cells so that they grow in a way analogous to tumor cells. The definition was originally applied to the transforming genes acquired by RNA tumor viruses through transduction of oncogenes. Today, the term may be used rather broadly and includes functional aspects. Oncogenes, or in general genes having oncogenic functions, contribute to tumorigenesis by any positive modulation of cellular growth; they act by their presence (this in contrast to tumor suppressor genes), an activity that is often referred to as “dominant.” Tumorigenic activation of oncogenes can result from mutational/structural/numeric changes in a gene and possibly from regulatory enhancement of gene expression, such as by hormones.
Oncogenes were originally isolated from RNA tumor viruses, where they are responsible for the ability of rapid tumor induction after infection of an animal host. In the viral genome, the oncogene was referred to as a viral oncogene or v-onc (Bishop 1982, 1987).
It was soon established that the v-oncs are actually derived from the genome of the host cell. They are captured by the virus after infection of the cell by a process called transduction (Fig. 1; transduction of oncogenes). Transduction appears in a wide range of animal species from chickens to monkeys (Table 1); it has not been observed in humans. The cellular counterparts, from which the v-oncs are derived, are referred to as proto-oncogene or cellular oncogenes (c-onc). Proto-oncogenes are normal constituents of the cellular genome and are highly conserved among all eukaryotic organisms.
Broadly speaking, the term oncogene now includes any gene that has a growth stimulatory effect on cells, with the result of:
- Conferring sustained cellular multiplication
- Advancement of cell cycle progression
- Decreased requirement for growth factors
- Focus formation under conditions of cell culture
- Ability of cells to grow under more restricted experimental conditions, such as in soft agar
- Tumorigenic conversion, such as in experimental animals
- Conversion of cells to form tumors that undergo metastasis
- Escape from apoptosis
Fig. 1. Model for the transduction by retroviruses. The process begins when the provirus of a retrovirus integrates into the vicinity of a cellular oncogene. The characteristic “long terminal repeats” (LTR) are drawn as black and white boxes. A deletion enables the c-onc and the provirus to fuse into a single genetic unit; one of the proviral LTR plus regions of both the provirus and the c-onc is deleted. Transcription from the hybrid unit generates a hybrid RNA; introns have been removed by splicing. This RNA can be packaged, together with a wild-type retroviral RNA, to form a virion (retroviruses have two RNA molecules). Infection of a cell initiates reverse transcription of viral RNA. Beginning at the 50-end, the reverse transcriptase can jump to the 30-end to continue chain propagation along the retroviral genome. Reverse transcriptase can also jump to the hybrid RNA and generate a new retrovirus genome, containing the c-onc
Table 1. Oncogene. Retroviral genes in different animal species and oncogenes
|Harvey murine sarcoma||Ha-MuSV||Rat||Sarcoma||H—ras|
|Kirsten murine sarcoma||Ki-MuSV||Rat||Erythroleukemia||K—ras|
|Moloney murine sarcoma||Mo-MuSV||mouse||Sarcoma||mos|
|FBJ murine osteosarcoma||FBJ-MuSV||Mouse||Chondrosarcoma||fos|
|Avian myelocytomatosis||MC29||Chicken||Carcinoma, sarcoma, and myelocytoma||myc|
|Abelson leukemia||MuLV||Mouse||B cell lymphoma||abl|
|Avian erythroblastosis||AEV||Chicken||Erythroleukemia and ﬁbrosarcoma||erbB (erbA)|
|Avian myeloblastosis||AMV||Chicken||Myeloblastic leukemia||myb|
Fig. 2. Molecular pathways for activating the oncogenic potential of cellular oncogenes. Translocation defines exchange of genetic material between two nonhomologous chromosomes. Historically, the activity of point mutations was discovered through transfection assays, where total DNA from cancer cells was introduced into non-tumorigenic tester cells, either of murine or human origin. Cells that have incorporated the mutationally activated oncogene have acquired the ability to form tumors when transplanted into an animal host. Nonrandom translocations had been known for many years, particularly in lymphoblastoid cells. The availability of cloned retroviral oncogenes has allowed rapid determination of the molecular identity of the genetic information altered through the translocation event. The significance of oncogene amplification was established by the first application of array technology, using what in today’s terminology is referred to as an “oncochip” (Fig. 3). Oncogene expression profiling of human and animal tumor cells carrying conspicuous cytogenetic manifestations of amplified DNA, “double minutes” (DMs), or “homogeneously staining chromosomal regions” (HSR) revealed the enhanced expression of an individual oncogene, such as RAS K in a murine cell line or, more significantly, MYCN in human neuroblastoma. Subsequent analysis of the gene copy number showed that the enhanced expression is the consequence of the amplification (up to 500 additional gene copies) of the otherwise unchanged gene
The precursors of oncogenes (proto-oncogenes) are present in their normal structure and expression activities in at least all higher animal cells. They represent what has been referred to as “enemies within,” but perform normal, usually vital, functions. Their oncogenic potential can be activated by any one of the following genetic changes (Fig. 2):
- Point mutation, resulting in an exchange of a base with the consequence of an amino acid change. The first example was the RAS H oncogene from a human gastric cancer that can convert in vitro established cells to tumorigenicity.
- Expression deregulation, by which the normal expression pattern is altered by a variety of mechanisms.
- Mutation within the gene, which results in an abnormal protein that has a different biological activity (e.g., RAS).
- Translocation, in which DNA from two genes on two different chromosomes can recombine, resulting in a fusion gene and a fusion protein (e.g., BCR/ABL [? BCR-ABL1]) in chronic myelogenous leukemia or deregulated gene expression, when normal gene expression signals are replaced by other DNA sequences, for example, the juxtaposition of MYC and active Ig promoters in different types of lymphomas.
- Amplification, where the number of gene copies multiplies, with consequent enhanced gene expression; prototypic for this is the MYCN gene in neuroblastomas, which has emerged as the first molecular marker for patient prognosis and is a paradigm for the clinical usefulness of an oncogene alteration (Schwab et al. 2003; Savelyeva and Schwab 2001).
Additionally, activation may be achieved through regulatory enhancement of gene expression, although such a type of activity is more difficult to establish, due to the lack of suitable counterpart cells for a faithful comparison of expression signatures.
Fig. 3. Early low-tech oncogene array for expression profiling of tumor cells. Retroviral oncogenes were spotted as a template onto a filter membrane (Schwab et al. 1983; note that the cellular homologs had not been isolated at that time); polyadenylated RNA was extracted from tumor cells and reverse transcribed into cDNA, which then was radioactively labeled and hybridized under conditions of reduced stringency to allow for interspecies cross-hybridization. These principles of array technology involving, as a hallmark, the reverse hybridization of a complex cDNA probe to a gene array were first described in Schwab et al. (1983); they are the same as those used in today’s high volume arrays with thousands of genes (Khan et al. 2001)
Experimental approaches have shown that the expression of a single activated oncogene is insufficient to achieve full tumorigenic conversion of a normal cell. Only when at least two altered oncogenes or, alternatively, a single altered oncogene under the control of a strong heterologous promoter is introduced can a normal cell assume a tumorigenic phenotype. Oncogene cooperation is well in line with the multiple genetic changes that a tumor acquires during its evolution to metastatic disease (? Multistep development). In the development of naturally developing tumors, oncogenes can also cooperate with tumor suppressor genes during cellular evolution towards the malignant phenotype.
Bishop JM (1982) Retroviruses and cancer genes. Adv Cancer Res 37:1–32 Bishop JM (1987) The molecular genetics of cancer. Science 235:305–311
Khan J, Wei JS, Ringnйr M et al (2001) Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7:673–679
Savelyeva L, Schwab M (2001) Amplification of oncogenes revisited: from expression profiling to clinical application. Cancer Lett 167:115–123
Schwab M, Alitalo K, Varmus HE et al (1983) A cellular oncogene (c-Ki-ras) is amplified, overexpressed, and located within karyotypic abnormalities in mouse adrenocortical tumour cells. Nature 303:497–501
Schwab M, Westermann F, Hero B et al (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472–480
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