抗癌治疗：1989年诺贝尔医学生理奖：癌症的起源

抗癌治疗：1989年诺贝尔医学生理奖：癌症的起源The Nobel Prize in Physiology or Medicine 1989J. Michael Bishop, Harold E. VarmusShare this: Press ReleaseNOBELF?RSAMLINGEN KAROLINSKA INSTITUTET THE NOBEL ASSEMBLY AT THE KAROLINSKAINSTITUTE9 October 1989SummaryThe discovery awarded with this year's Nobel Prize in Physiology or Medicine concerns the identification of alarge family of genes which control the normal growth and division of cells. Disturbances in one or some ofthese so-called oncogenes (Gk ónco(s) bulk, mass) can lead to transformation of a normal cell into a tumorcell and result in cancer. Michael Bishop and Harold Varmus used an oncogenic retrovirus to identify thegrowth-controlling oncogenes in normal cells. In 1976 they published the remarkable conclusion that theoncogene in the virus did not represent a true viral gene but instead was a normal cellular gene, which the virushad acquired during replication in the host cell and thereafter carried along. Bishop's and Varmus' discovery ofthe cellular origin of retroviral oncogenes has had an extensive influence on the development of our knowledgeabout mechanisms for tumor development. Until now more than 40 different oncogenes have beendemonstrated. The discovery has also widened our insight into the complicated signal systems which governthe normal growth of cells.Cellular Oncogenes Discovered by the Use of RetrovirusThe term oncogene was introduced in the middle of the 1960s to denote special parts of the genetic material ofcertain viruses. It was believed that this part of the genetic material could direct the transformation of a normalcell into a tumor cell under the influence of other parts of the viral genetic material, alternatively via chemical orphysical effects. The favourite theory of the time was that virus-mediated cell-to-cell transmittance ofoncogenes was the origin of all forms of cancer. This view was later proven to be incorrect. The originaldiscovery of an oncogenic virus was made in 1916 by Peyton Rous working at the Rockefeller Institute in NewYork. Fifty years later Rous received the Nobel Prize in Physiology or Medicine. Rous virus, as the infectiousagent later was named, is a member of a large virus family named retroviruses. The genetic material of theseviruses is RNA (ribonucleic acid). This RNA can be transcribed into DNA (deoxyribonucleic acid) by a uniqueenzyme in the virus, reverse transcriptase. The 1975 Nobel Prize in Physiology or Medicine was awardedto David Baltimore, Renato Dulbecco and Howard Temin partly for the discovery of this enzyme. Reversetranscription of the genetic material of the virus into DNA has the important consequence that it can becomeintegrated into the chromosomal DNA in the cells. It was through investigations of Rous virus that this year'slaureates Michael Bishop and Harold Varmus in 1975 could demonstrate the true origin of oncogenes. Theyused one variant of Rous virus which contained an oncogenic gene (Figure 1) and another variant which lackedthis gene. By use of these viruses they managed to construct a nucleic acid probe which selectively identifiedthe oncogene. This probe was used to search for the corresponding genetic material in DNA from differentcells. It was then found that oncogene-like material could be detected in different species throughout the animalkingdom, in fact even in simple organisms comprising only a few cells. Furthermore, it was shown that the genehad a fixed position in the chromosomes of a certain species, and that the gene, when it constituted part of thecellular genetic material, was divided into fragments (a mosaic gene) (Figure 1).Figure 1. The difference between an oncogene in a virus and in a cell. In retroviruses causing tumors there is aseparate segment of transforming nucleic acid which has been derived from a cell. The cellular gene is split (amosaic gene) whereas the oncogene in the virus is continuous. These findings led to the remarkableconclusion that the oncogene in the virus did not represent a true viral gene but a cellular gene which the virushad picked up far back during its replication in cells and carried along. This cellular gene was found to have acentral function in the cells. It controlled their growth and division. Through these studies of the abnormal, i.e. thediseased state, it was possible to elucidate critical normal cellular functions - a not uncommon situation inbiomedical research. The original discovery of a cellular oncogene led to an intensive search for further similargenes. The explosive development of this field of research has led to the identification of more than 40 differentoncogenes which direct different events in the complex signal systems that regulate the growth and division ofcells. Changes in any one or more of these oncogenes may lead to cancer.

Balanced Cellular Interactions - A Biological Wonder

Symmetrical and asymmetrical, multicellular structures develop from the fertilized ovum by a process ofdifferentiation about which only limited knowledge is available. In the fully developed individual carefullybalanced conditions prevail. Damage of an organ elicits sophisticated repair processes which lead torestitution of the original condition of the organ. However, if a single cell escapes the network of growth controlthe result may be an abnormal local proliferation of cells or in the worst case a cancer implying the

dissemination of cells running amok. The development of a cancer is a complicated process involving severalconsecutive changes of the genetic material. Studies of cellular genes (proto-oncogenes) corresponding to theviral oncogenes, has started to shed light on the intricate systems which control normal cellular growth anddivision.

Cellular Oncogene Products Constitute Links in Signal Chains which Regulate Growth andDivision of Cells

The regulation of growth and division of cells has turned out to be much more complicated than originallybelieved. Cellular oncogene products with different properties act in different positions of elaborate signalsystems (Figure 2). In order to transmit signals from one cell to the other or from one cell to itself there aregrowth factors. These factors appear in the fluids surrounding cells. There are examples of oncogene products,viz. proteins produced in the cytoplasm, which can act as growth factors. Thus, it was found that the product ofthe sis1) gene was closely related to a previously identified growth factor PDGF (Platelet Derived GrowthFactor).

Figure 2. Oncogene products are links in signal chains that stretch from the cell surface to the genetic materialin the cell nucleus. This chain is composed of (1) growth factors, (2) growth factor receptors, (3) signal

transducing proteins in cell membranes, (4) phosphokinases in the cytoplasm and (5) proteins transported fromthe cytoplasm into the nucleus where they bind to DNA. The localization of different oncogene products (Sis,ErbB, Ras, Src, Myc) is schematically indicated. In order for a growth factor to be able to interact with a cellthere has to be membrane structures, receptors, to which they can bind. There are several oncogene productswhich represent receptors in the cytoplasmic membrane of the cells, e.g. ErbA, Fms, Kit. These receptors havea unique enzymatic activity. They are so-called kinases with a capacity to phosphorylate (=add a phosphategroup) the amino acid tyrosine. There are two more groups of oncogene products with phosphokinase activity;firstly tyrosine/phosphokinase which lack receptor function and is located at the inside of the cytoplasmicmembrane, and secondly serine/threonine phosphokinase which is found in the cytoplasm. Thus, oncogeneproducts function as links in signal chains stretching from the surface of the cell to the genetic material in thenucleus. In the cytoplasm there is one more group of oncogene products. These are called Ras and arerelated to important cellular signal factors called G-proteins. Finally, there is a large number of oncogeneproducts which are located in the nucleus of the cell, i.e. Myc, Myb, Fos, ErbA and others. These productsdirect the transcription of DNA into RNA and therefore play a critical role in the selection of proteins to besynthesized by the cell.

Cancer - A Complex, Biological Sequence of Events

Changes in the genetic material constitute the basis for the development of all cancer. Generally there areseveral consecutive such changes which influence different steps in the signal chains described above.Therefore, one should à priori not expect to find one single clue to the mechanism of origin of cancer. However,application of the expanding knowledge in the oncogene field allows us to start comprehending the

disharmonic orchestration behind abnormal cellular growth. It is conceptually incorrect to speak about \"cancergenes\". However, historical circumstances explain why the oncogene terminology was introduced before adesignation of the corresponding normal cellular genes was proposed. From the point of view of cancer theimportant matter is to compare oncogenes in normal cells and in tumor cells.

Oncogenes as a Cause of Cancer

The majority of oncogenes have been discovered in experimental studies using retroviruses. However, in a fewcases oncogenes were identified by the use of an alternative technique, i.e. genetic material was isolated fromtumor cells of non-viral origin and transferred (transfected) to other cells prapagated in culture. The cellsreceiving the DNA changed growth pattern, and further characterization of the transfected genetic materialrevealed the presence of oncogenes. Two principally different forms of activation of oncogenes can bedistinguished. Firstly, the normal cellular oncogene is hyperactive, and secondly the oncogene product isaltered so that it can no longer be regulated in a normal way. There are several examples of these types ofactivation of oncogenes. The discovery of oncogenes was as mentioned originally made by the use ofretroviruses. This infers that genetic control elements in the virus itself can be responsible for the abnormalexpression of the oncogene. However, in many cases it was found that alterations of the transferred oncogene

contributed to its accentuated expression. There are retroviruses which lack oncogenes but still can inducecancer. This is due to the fact that the virus has inserted its genetic material (in the form of DNA) very close to anormally occurring oncogene in the genetic material of the cell. This may result in an increased turn-over of theoncogene which may lead to abnormal cellular growth. The corresponding phenomenon can also occur in theabsence of retroviruses. In this case there is a reorganization of the genetic material in the cell. Such areorganization may occur within a single chromosome or by exchange of material between chromosomes.Repeated copying of a normal oncogene can lead to itsamplification in the chromosome and consequently toincreased amounts of the oncogene product. In certain brain tumors, glioblastomas, an amplifiederbB-genehas been found, and a correspondingly increased neu-gene activity was shown in some forms of breastcancer. The same effect can be seen when there is a reciprocal exchange of segments betweenchromosomes (translocation). Thus the normal myc-gene on chromosome 8 has been translocated to

chromosome 14 in many patients with Burkitt's lymphomas (Figure 3). The insertion of the myc-gene containingchromosome segment is such that it becomes located close to hyperactive genes directing the synthesis ofantibody protein. As a consequence the myc-gene becomes activated. Chromosome translocations occur inmany different tumors. Chromosome analysis can therefore be of considerable value for localization of geneticchanges in the genome critical for tumor development.

Figure 3. Chromosome translocation in Burkitt's lymphoma. Segments have been exchanged betweenchromosomes 8 and 14 which has activated the oncogene myc. Oncogenes with point mutations have beenobserved in many tumors. These mutations may cause alterations in the amino acid composition of the geneproduct. A well-known example of such a modification is the exchange of amino acid 12 from glycine to valinein the ras gene product which has been observed in human tumor material. The mutation may also besomewhat more extensive leading to the absence of part of the protein (deletion). Different examples ofmodified oncogenes in human tumor material are given in Table I.

The Importance of Viruses for Cancer in Man

Cancer is not a contagious disease. However, infectious agents like viruses can contribute to the origin ofcancer. Thus, it is by use of retroviruses that most oncogenes were identified, the starting materials in suchinvestigations often being highly specialized, experimentally derived tumors. It seems likely that retrovirusesplay a relatively limited role for the development of cancer under natural conditions. The only known example inman in which a retrovirus infection contributes to the origin of cancer is the HTLV-1 associated lymphomaswhich occur in Japan. However, there are other kinds of viruses which can contribute to the development oftumors in man. All these viruses have DNA as their genetic material. As examples can be mentioned papillome(wart) viruses and Epstein-Barr virus, a type of herpes virus. Certain types of papillome viruses play a role forthe development of cervical cancer in the genital tract, while Epstein-Barr virus is an important factor for thedevelopment of Burkitt's lymphomas in Africa and nasopharyngeal cancer in Asia. However, in all these casesfactors in addition to the virus infections are required for the cancer to develop.

References J.M. Bishop: Oncogenes. Scientific American, 1982, 246, 68-78. T. Hunter: The Proteins of

Oncogenes. Scientific American, 1984, 251, 60-69. C-H. Heldin & B. Westermark: Tillv?xtfaktorer och onkgener.L?kartidningen 1988, 85, 497-499. E. Norrby: I: V?ra virus. Virus och cancer. Allm?nna F?rlaget, 1987, sid. 66-74.

1) All oncogenes are identified by the use of three letter abbreviations. In addition cellular and viral oncogenes aresometimes distinguished by c- and v- prefixes, respectively, e.g. c-src and v-src.