Oncogenes: Clues to carcinogenesis

European Journal of Eur J Pediatr (1984) 141 : 134-142 �9 �9

Pediatrics �9 Springer-Verlag 1984

Reviews

Oncogenes: Clues to carcinogenesis *

C. R. Bartram

Department of Cell Biology and Genetics, Erasmus University Rotterdam, Postbox 1738, NL-3000 DR Rotterdam, The Netherlands

Curriculum vitae. Claus R. Bartram was born in 1952 in Hamburg (Ger- many). 1972-1978 student in medicine and philosophy. He graduated and received the Doctor degree in medicine from the University of Hamburg in 1978. 1979-1982 postgraduate train- ing in pediatrics at the University Children's Hospital Diisseldorf (Di- rectors: Profs. G.A. vonHarnaek, E. Sehmidt, H.J. Bremer). Since 1982 recipient of a fellowship from the Deutsche Forschungsgemeinschaft at the Department of Cell Biology and Genetics, Erasmus University Rotter- dam (Prof. Dr. D. Bootsma).

Abstract. Recent applications of recombinant DNA techniques in cancer research led to the detection of cellular genes with potential transforming activity, called oncogenes (c-onc). Regularly they seem to be involved in normal cell differentiation and proliferation: a number of oncogene-encoded proteins specifically phosphorylates tyrosine, a key reaction in growth control. Certain human tumors exhibit activated forms of these genes and DNA fragments isolated from these neoplasms transform nonneoplastic cells (transfection assay). Oncogenes were first discovered and defined in a number of retroviruses; these viral oncogenes (v-onc) are thought to have been derived from the cellular oncogeiaes (c-onc). By integration of the v-onc genes into the host genome acute neoplastic transformation of the cell may occur. Several modes of oncogene activation are discussed that lead either to an increased dosage ofgene product or to the formation of an altered gene product. The localization of oncogenes in the human genome near the breakpoints of specific chromosome aberrations involved in various neoplasms like Burkitt lymphoma and several leukemias emphasizes the importance of these genes in carcinogenesis.

Key words: Oncogene - Recombinant DNA techniques - Carcinogenesis - Retrovirus - Chromosomal aberrations

Introduction

At the turn of this century Eltermann and Bang as well as Rous [30b,92a] reported that leukemia and sarcomas could be

* Dedicated to my wife, Ilse Bartram, M.D.

induced in chicken by transmissible agents. Since then the oncogenic potential of many animal viruses has become well established. These viruses are taxonomically diverse including those with a DNA or RNA genome. RNA tumor viruses (oncorna viruses) after cell infection copy their RNA genome by an enzyme (reverse transcriptase) into double stranded DNA, which is integrated into the host genome without impairing the viability of the host cell. These retroviruses can be subdivided into two general groups based on their biological activity [42, 57, 60]; slow transforming viruses do not appear to transform cells in culture and induce neoplastic diseases in infected animals only after long latency periods of 4-12 months; acute transforming retroviruses, however, efficiently transform tissue culture cells and induce tumors in vivo within 2-3 weeks. These different properties are a reflection of differences in the viral genome. Thus, acute transforming viruses contain, beside sequences required for virus replication, specific genes responsible for their oncogenicity [30,37,53, 69,113], called viral oncogenes (v-onc). Approximately 20 viruses of this type isolated from different species have been characterized (Table 1).

However, the identification of viral oncogenes about 13 years ago was also a turning point in human cancer research, as I will discuss in this article. The question to date is not solely whether viruses cause human tumors (they may occasionally) but rather, what can be learned from tumor virology about principal mechanisms of carcinogenesis. Answers in this field were made possible mainly because the powerful techniques of genetic engineering allowed a more precise definition of oncogenes and their possible role in the development of tumors in

Table 1. Oncogenes localized on human chromosomes

Name Virus strain Isolation source

myb Avian myeloblastosis virus Chicken

mos Moloney murine sarcoma virus Mouse

myc Avian myelocytomatosis virus Chicken

abl Abelson murine leukemia virus Mouse

ras H Harvey murine sarcoma virus Rat

ras ~ Kirsten murine sarcoma virus Rat

fes Feline sarcoma virus Cat

src Rous sarcoma virus Chicken

sis Simian sarcoma virus Woolly monkey

The gene name is composed from letters (underlined) of virus strains that picked up these cellular genes from the host genomes (isolation sources) [151

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RETROVIRUS \ ] REVERSE TRANSCRIPTASE

/ / \

ACUTE TRANSFORMING RETROYIRUS

Fig. 1. Simplified scheme of acute transforming retrovirus origin. A retrovirus infects a cell, copies it's RNA genome via reverse transcriptase into DNA and integrates into the host genome close to a cellular oncogene (c-onc). This gene, like most genes in mammals, is interrupted by noninforma- tional intervening sequences. Coding sequences are spliced together at the level of the primary transcript to form a coherent message. When host DNA is transcribed into RNA, the viral DNA is also transcribed together with the c-oncogene that is now inserted into the viral genome (v-onc), thus providing the retrovirus with acute transforming properties

general. Until recently it was impossible to isolate and analyze individual human genes because they are linked together into 46 huge DNA molecules, the chromosomes. Genes were de- scribed in terms of their manifestations and the behavior of their mutations. For a decade, however, recombinant DNA technology has made genes remarkably accessible. The discovery of restriction endonuclease, for example, makes it possible to break DNA molecules reproducibly into small pieces that can be further investigated [3, 26,116, 117]. In this article I discuss different approaches that give evidence for the potential role of the regulation of oncogenes and their possible importance in the development of some human cancers.

Detection of cellular oncogenes

The discovery that retroviruses induce tumors in animals and transform cultured cells in vitro led to the identification of viral oncogenes. However, it came as a surprise that these oncogenes are not only present in retroviruses, but are homologous to DNA sequences in normal, uninfected cells [8,105]. The cellular counterparts (c-onc) of viral transforming genes are highly conserved during evolution, found in all vertebrate species [81, 104,111, 120], and could be traced back even to Drosophila [52, 99, 101,103] and yeast [35, 112]. Transforming retroviruses thus represent recombinants in which a cellular gene sequence has been inserted into a virus genome during previous rounds of infection [9, 42,107,113]. By adding DNA sequences of this foreign gene to their own DNA these viruses

obtain transforming activity. Thus in contrast to an older hypo- thesis [53] the host genome supplies acute transforming retroviruses with a gene functioning from now on as an oncogene (Fig. 1). Unlike acute transforming viruses chronic ones appear to exert their oncogenic potential by integrating their viral DNA in the vicinity of a cellular gene resulting in abnormal expression of this gene within the host cell as a consequence of the activity of the viral transcription promotor [47, 48,113]. This mode seems to be, for example, the effect of the recently discovered first human retrovirus, known as human T-cell leukemia-lymphoma virus (HTLV). This virus is highly suspected to be etiologically associated with certain types ofT- cell neoplasms, including adult T-cell leukemia [12a, 38, 51, 66, 86, 90,119].

The discovery that cellular oncogenes constitute a group of normal cellular genes with potential oncogenic activity is further supported by gene transfection experiments. Transfer of purified, biologically active DNA fragments to recipient cells, termed transfection, is commonly performed by expo- sure of cell cultures to donor DNA by means of calcium phosphate precipitation [43]. It could be demonstrated that DNA fragments from a broad spectrum of different human tumor cell lines (Table 2) were able to transform nonneoplastic cells (e.g. NIH/3T3 mouse cells) with high efficiency [17,18]. Simi- lar results were obtained with DNA fragments derived from fresh tumor tissues [34, 63, 87,115]. DNA fragments isolated from normal cells (e.g. human lung fibroblasts) lacked detect- able transforming activity [18], although after fragmentation to small pieces this DNA induced transformation with low effi-

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Table 2. Human tumor cell lines" and solid tumors b containing activated transforming genes

Carcinoma: Bladder ",b Lymphoma: Pre-B cell a'b

Lung " b B-cell a

Breast" T-cell "'b

Colon a'b T-helper cell a'b

Pankreas b Sarcoma: Fibros."

Gall bladder a Rhabdomyos b

Neuroblastoma a Acute promyelocytic leukemia a'b

References: [34, 61-63, 68, 71, 76, 84, 87,102,115]

ciency [17,18]. These results suggest that potentially transforming genes can be activated as a consequence of DNA rearrangements (e.g. dissociation of genes from their normal regulatory sequences) and that many neoplasms contain activated forms of those genes.

Moreover it could be demonstrated that some transforming genes of DNA transfection assays and oncogenes are homologues. An example is the homology between the human bladder carcinoma transforming gene and the oncogene of Harvey sarcoma virus (ras H ) first isolated from rats [14, 28, 82, 98]. Although the great majority of transfected oncogenes investigated to date are members of the ras group, there are several exceptions [40, 62,100]. However, it is possible that the NIH 3T3 assay is biassed for the identification of ras oncogenes. The frequent detection o f ras genes by transfection may on the other hand reflect their widespread activation in a large propor- tion oftumors, perhaps because different oncogenes perform functionally distinct steps any of which are required for the full oncogenic conversion.

Thus cancers of viral and nonviral origin have more in common than was previously thought and they may be related to inappropriate activation of homologous cellular genes.

Enemies within?

A growing body of evidence indicates that transformation of cells may, in fact, occur by activation of otherwise dormant cellular genes. This immediately prompts the question about their regular function. Although these genes are called oncogenes, their primary role is by no means to cause cancer. To the contrary, their normal function must be important enough to have these genes conserved during vertebrate evolution. However, little is known about their role in normal cell metab- olism. Some oncogenes are expressed on a low level in all normal celt strains examined, others are only transcribed in some cell types or at certain stages of maturation [19, 63, 72-74,120].

H Recently it was demonstrated that the c-ras oncogene in rats is expressed at an elevated level in damaged liver tissue during regeneration and returned to basal level immediately there- after [41]. This stage- and tissue-specific manner of expression suggests that these genes participate in normal cell proliferation and differentiation.

Oneogenes in tumor specific chromosomal aberrations

Theodor Boveri [11] advanced the theory that mutation in the genetic constitution of cells, particularly in the chromosomes,

may play a crucial role in the development of the malignant process. Until recently technical limitations have restricted most of the work in cancer cytogenetics to the analysis of con- tracted and poorly banded chromosomes; moreover, solid tumor research was hampered by limitations in the ability to disaggregate tumor cells. New techniques are now making feasible the routine cytogenetic study of various neoplasms. Particular progress has recently been made in the application of high resolution chromosome analysis to visualize up to several thousand bands in the human genome [122]. It is now generally accepted that chromosomal abnormalities are the rule rather than the exception in malignant diseases. More- over, approximately 20 types of tumors have been found to exhibit a specific chromosome defect [4,94,97,123,124]. Among these, a distinct chromosomal band deletion has been discovered in Wilms tumor and retinoblastoma, while Burkitt lymphoma and some types of leukemia exhibit a tumor-specific reciprocal translocation between two chromosomes (Table 3). The remarkable concordance between the chromosomal localization of some human cellular oncogenes and the breakpoints of chromosomal aberrations involved in various forms of cancer again suggests an important role of these genes in carcinogenesis (Table 3). However, an involvement in tumor- specific translocations has only been proved for the human oncogenes c-myc and c-abl, localized on chromosomes 8 and 9, respectively; therefore, in the following I will concentrate on them.

In most cases of Burkitt lymphoma (900/0), tumor cells exhibit a translocation between chromosomes 8 and 14, t(8;14)(q24;q32). This abnormality (Fig. 2) has been found in both the African and the non-African forms [7, 97,123]. In approximately 8% of these patients the distal part of chromosome 8 (8q24) is translocated to chromosome 2 (2p12) or 22 (qll) instead of 14. c-myc is located at the very band (q24) on chromosome 8 that is consistently involved in these rearrangements [23,78] and transferred to chromosome 14 in several patients [67,110]. This reciprocal translocation is of special interest because band q34 on chromosome 14 contains the immunoglobulin heavy chain gene cluster [20]. Moreover, the other chromosomes involved with chromosome 8 in translocation events in Burkitt lymphoma, 2 (p12) and 22 (qll), contain the sites for the immunoglobulin ~ and 2 light chain genes, respectively [31,65]. Interestingly, lymphomas with t(8;2) express u chains and those with t(8;22) express 2 chains [64]. However, not in all patients investigated thus far is c-myc translocated [25, 32, 67,110]. Apparently in some cases the breakpoint is a little off the locus of this oncogene. On the other hand, variable sequences of the heavy chain gene cluster are involved in t(8;14) from different cases of Burkitt lymphoma [1, 33, 46]. These differences in breakpoint sites can only be demonstrated by recombinant DNA techniques, not under the microscope. Nevertheless, because these translocations are reciprocal, c-myc comes close to immunoglobulin genes, either by translocation to chromosomes 2,14 or 22 or by translocation of these genes to chromosome 8 [271. It is possible therefore, that as a consequence of translocation either the level of c-myc expression is affected by the neighboring active immunoglobulin genes or that an exchange in regulatory sequences of these genes lead to a derangement in the schedule of c-myc expression during the course of lymphocyte maturation [25, 33, 83].

Almost 25 years ago chronic myelocytic leukemia (CML) was the first malignant disease discovered to be associated with a consistent chromosomal defect [79]. In approximately 92% of

Table 3. Some human cellular oncogenes are localized on chromosomes involved in tumor-specific aberrations

Oncogene Chromosome no. Chromosomal Tumor (band) aberration

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ras N 1 lp-- Neuroblastoma

myb 6(q21-q24) t(6;14)(q22;q24) Ovarian carcinoma

ras K1 6

mos 8(q22) t(8;21)(q22;q22) ANLL (M2)

myc 8(q24) t(8;2)(q24;p12) Burkitt lymphoma

t(8;14)(q24;q32) Burkitt lymphoma

t(8;22)(q24;q11) Burkitt lymphoma

abl 9(q34) t(9;22)(q34;ql 1) CML

ras m 1 l(p 13) del l lp 13 Wilms tumor

ras x2 12 + 12 CLL

f e s 15(q24-q25) t(15;17)(q25;q22) APL

src 20 20q- MPD

sis 22(q12.3-q13.1) del 22q- Meningioma

ras H2 X

p indicates the short arm and q the long arm of a chromosome; t, translocation; del, deletion. E.g. read t(9;22)(q34;q11), translocation of chromosomal material distal to band 11 on the long arm of chromosome 22 to band 34 on the long arm of chromosome 9. ANLL, acute nonlymphocytic leukemia, M2 subset; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelocytic leukemia; MPD, myeloproliferative disorder. References: [5-7, 21-23, 39, 45, 49, 70, 78, 80, 94-97,123,124]

N.B. an involvement in tumor-specific translocations is to date only proven for c-abl (CML) and c-rnyc (Burkitt lymphoma)

2 N O R M A L C M L 9 22 9q + 22q- (Ph 1)

8 p 12 ~- L-CH

P

. . . . H-CH q 2 4 . . . . c -

22

q l l . . . . A-L-CH

Fig. 2. Chromosomes involved in Burk i t t l ymphoma translocations. C-myc is localized at the breakpoint band q24 on chromosome 8. Note that the immunoglobulin genes are localized at the breakpoints on chromosomes 2, i4 and 22, respectively. H-Ch, immunoglobulin heavy chain, x-L-CH and 2-L-CH, x and 2 light chain

adult patients suffering from CML the distal part of chromosome 22 in leukemic cells is translocated to chromosome 9 (Fig. 3); this translocation t(9;22)(q34;q11) is called Philadel- phia translocation [93], the remaining part of chromosome 22, Philadelphia chromosome (22q- or phi). Recently it could be demonstrated that the c - a b l oncogene is translocated the other

q l l - - c - a b [ ~ r - - q l l

q

q 3 4 -]i- ctbl q34

Fig. 3. The Philadelphia translocation t(9;22)(q34;qll) in CML is reciprocal; c-abl i s translocated from chromosome 9 to the Philadelphia chromosome (22q-)

way around, from the terminal part of chromosome 9 to the Philadelphia chromosome [581. The significance of this reciprocal translocation for the generation of CML was further underlined by the discovery that in variant forms of CML, in which the distal part of chromosome 22 is translocated to other chromosomes than 9, c - a b l is also found on the Philadelphia chromosome [5]. Moreover, in CML patients c - a b l is localized adjacent to the translocation breakpoint, which itself is hetero- genous in different patients [50]. As c - m y c in Burkitt lym-

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phoma, c-ablis translocated in the neighborhood of the immunoglobulin 2 light chain genes on chromosome 22qll [50], possible consequences were discussed above.

Mechanisms of oneogene activation

The relationships between chromosomal aberrations and human tumors on one hand and oncogenes on the other suggest that DNA rearrangements might be an important mechanism for tumor induction by affecting the activity of these genes. Some mechanisms of oncogene activation are investigated in more detail. For example, in some patients suffering from Burkitt lymphoma c-myc in tumor cells is transcribed at higher levels than in normal cells. As already mentioned, this may be due to the influence ofpromotors or enhancers of the immunoglobulin genes under whose influence c-myc has followed the translocation [33]. Another mechanism resulting in increased gene expression is the presence of multiple copies of relevant sequences within the genome; such a gene amplifi- cation has recently been demonstrated (a) for c-mycin a patient suffering from acute promyelocytic leukemia [24] as well as in endocrine tumor cell lines derived from a colon carcinoma patient [2], and (b) for c-abl in an erythroleukemic cell line established from a CML patient in blast crisis [50]. Both mechanisms demonstrate a gene dosage effect, i.e., the over- production of oncogene encoded proteins is thought to be responsible for malignant transformation.

It is of considerable interest that the mutant oncogene (c-ras H1) in cells from human bladder carcinoma cell lines dif- fers from the wild-type gene in the simplest possible way, i.e., the replacement of one specific nucleotide in the DNA sequence by another [88,108,109]. A similar alteration is signifi- cant in the oncogenic activation of the viral analogue (v-rasH). This point mutation results in the incorporation of valine instead of glycine as the 12th amino acid residue of the oncogene-coded protein. Such a simple substitution was not expected to effect a drastic functional change. However, glycine is unique among.the amino acids because it has no side chain and therefore is able to bend and fold within the poly- peptide chain quite readily; thus a replacement of glycine indeed represents a profound change in local sterochemistry that probably affects interactions of the protein with cellular

Table 4. Some characteristics of viral oncogene-coded proteins

targets [118]. This consideration is supported by a similar alteration known from sickle-cell anemia, in which the substitution of glutamine by valine in position 6 of the/?-chain profoundly alters the solubility of adult hemoglobulin within erythrocytes thereby causing the sickling phenomenon [75, 85]. A different mutation in the same oncogene has been found in a human lung carcinoma cell line [121]. In this case the c-ras H1 gene has a substitution of leucine for glutamine at amino acid 61.

However, it should be emphasized that these discoveries are a valuable model for carcinogenesis, but by no means an explanation why individual patients develop carcinomas of the bladder or lung. None of ten primary bladder carcinomas exhibited the point mutation affecting the 12th amino acid of c-ras H1 [36]. These data support the view that it is important at least to examine primary human tumor tissues before general- izing results obtained with established culture cell lines.

Nevertheless, alterations of oncogene DNA sequences expressed at normal levels and an increased transcription of these genes are two possible final causes leading to the same disasterous result [13, 56]. It might be possible, however, that a cascade of several oncogenes is required for the full oncogenic conversion; a case in point is the combined activation ofc-ras N and c-myc in hematopoietic malignancies [77].

Some of the proteins encoded by oncogenes have been analyzed (Table 4). One class represent members of a diverse family [44, 89] of phosphoproteins with an associated protein kinase activity. Protein kinases regulate the activity of many enzymes by adding phosphate ions to amino acids, mainly serine and threonine [16]. However, most of the oncogene coded proteins exclusively phosphorylate tyrosine. During the last months tyrosine specific phosphorylation turned out to be a key reaction for growth control in general. Binding of epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) to their cell surface receptors results in immediate tyrosine phosphorylation [12,106]. The same was demonstrated for insulin [54, 92] and one of the main actions of this hormone is to stimulate cell growth. One important difference between the phosphorylation induced by growth factors and oncogenic proteins is that normally the phosphorylation signal is transient, while with oncogenes the signal is turned on all the time and the cells lose control of proliferation.

Very recently a striking link between growth factors and oncogene-coded proteins was discovered: simian sarcoma

Oncogene Name Protein

Phospho- Phospho- Phosphorylates Located protein kinase

abl p120 gag'abl + + Tyrosine Cell surface

ras H p21 rash + + Tyrosine Cell surface

ras x p21 rasK + + Tyrosine Cell surface

f e s p85 gag-feS + + Tyrosine Cell surface

src p60 src + + Tyrosine Cell surface

myc p l l 0 gag'myc -I- NN Se r ine / theon ine Nucleus

mos p 85 gag-mos -t- + Se r ine / theon ine NN

sis p28 sis - - NN NN

myb p45 myb NN NN NN NN

The different names of proteins are abbreviations: p (protein), number (molecular weight in kilodaltons) and name of coding oncogen; e.g. p120 gag-abl is the 120.000 Dalton protein coded by the abl-gene. NN: not known. References: [15, 59, 60, 91]

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virus acquired its tranforming gene (v-sis) from the gene or genes which encode PDGF [29,114]. Thus the cellular homologue of v-sis (c-sis) is in all probabibility the gene for PDGF. This growth factor is thought to be synthesized within bone marrow megakaryocytes, the platelet progenitor cell. However, recent data [106] suggest that a paracrine production of PDGF results in the development of some connective tissue neoplasms. As a matter of fact, high c-sis expression has been found in various human tumor cell lines derived from sarcoma and glioblastoma [34]. It will be of interest to determine whether PDGF is involved with the pathology of these tumors.

Perspectives

Medical geneticists detected the effects of cancer genes years ago, when they identified families whose members inherit a predisposition to some particular forms of cancer. Until recently, however, the vast size of the mammalian genome prevented any direct search for cellular genes involved in the genesis of tumors. Recombinant DNA techniques have over- come these problems and application of these techniques to cancer research led to unexpected answers concerning prin- ciple mechanisms of cancer development. The main conclu- sions suggested by recent discoveries are: 1) Retroviruses can cause neoplasia (a) by transducing viral

oncogenes incorporated into the viral genome from cellular genes during previous rounds of infection or (b) by activat- ing resident cellular oncogenes by proximal integration,

2) cellular oncogenes appear to be regulators of normal cell differentiation and proliferation,

3) any disturbance of this well balanced system causes uncon- trolled cell growth,

4) the function of oncogenes can be modified by different mechanisms, examples are complex rearrangements within the genome (specific chromosomal translocations), or minimal modifications of crucial sequences (point mutation as in a bladder carcinoma cell line).

Beside all enthusiasm about these discoveries combining so many different areas of cancer research, it should not be forgotten that these are just the first insights rather than an universal explanation of cancer. Moreover, as yet there is no unequivocal evidence that cellular oncogenes directly initiate and maintain cancer like the oncogenes ofretroviruses [30a]. Complete genetic definition and assays for the biological function of cellular oncogenes are necessary to define exactly their role in normal and mutated states. Carcinogenesis is a multi- step process, it is likely that activation of oncogenes is only one of several events involved. We still do not know the rate limit- ing steps toward cancer or which of them are sensitive to environmental influences and thus may be preventable. Moreover, approximately 40% of the human tumors tested so far exhibit no transforming activity. Is the development of these neoplasms caused by epigenetic changes or do these tumors contain activated genes that simply do not induce transformation in the recipient (mouse) cells used in transfection assays? Another important question is the relation of oncogenes to mutagens. Are the sites of oncogenes in the genome 'hot spots' for mutagenic, i.e., carcinogenic, events inducing alterations in gene sequences as demonstrated for c-ras I4 in human bladder and lung carcinoma cell lines? And finally, is there any possible way to bring these discoveries to the bedside? Speculations, especially in the field of cancer research should be handled with great caution. However, the

fact that cells from patients suffering from the same type of tumor may differ from each other on a molecular basis (different chromosomal breakpoints, different types of oncogenes involved) may lead to new classifications that will be of prog- nostic and therapeutic help to clinicians. Cytogenetic differentiation of certain leukemias is a case in point [10]. Recent applications of monoclonal antibodies to cancer therapy have initiated preliminary attempts to produce antibodies against altered oncogene-coded proteins and drugs interfering with tyrosine phosphorylation. Whether these approaches will turn out to be helpful will be seen in the future.

Considering the rapidity with which important recent discoveries have been made, the field as discussed in this review may warrant an optimistic view of cancer research since a relatively long time of standstill seems to have come to an end.

Acknowledgements. I thank Prof. Dr. D. Bootsma, Drs. Anne Hage- meijer, Annelies deKlein, G. Grosveld and A. GeurtsvanKessel (Rotterdam) for stimulating discussions and helpful suggestions; Prof. E. Passarge (Essen) and Prof. Dr. H.W. Rfidiger (Hamburg) for reading the manuscript. The help of Rita Boucke and P. Visser with the preparation of this manuscript is gratefully acknowledged. C.R.B. is a recipient of a fellowship from the Deutsche Forschungsgemein- schaft.

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Received May 20, 1983 / Accepted September 1, 1983

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Oncogenes: Clues to carcinogenesis