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Medical Hypotheses w-r x,r+r-.- inm a n» r t..v... cr... UK 4Y 1M7 THE SIGNIFICARCE OF PR020-ONCOCENES IN CARCrii0CII1LSIS Philip Rosen, llasbrouck Laboratory. University of Msssachusetts, Amherst, Massachusetts, 01003, U.S.A. AbS?RAC7 i A survey of the literature on activated proto-oncogenes shows that they are involved in the development of cancer but apparently not in the initiation process. The review of Klein and Klein cosxs to conclusions in opposition to the review of Duesberg. I favor the latter hera. Active proto-oncogenes my be part of the developmental process of carcinogene- sis but are not Initiators of carcinogenesis.. IPfl'RODUCrION For the past few years, investigators have argued over the signi- ficance of activated proto-oncogenea in carcinogenesis. one review (1), states that the evidence that activated proto-oncogenes are implicated in the development of human cancer is circumstantial. The ways of acti- vation are varied: a)s+utation, b)amplification, c)interaction of two proto-oncogenes, d)translocation and e)insertion of a long terminal repeat, LTR, of a virus adjacent to the proto-oncogene. The general conclusion of the above review relates activated proto-oncogene products with growth factors. In another review (2), Klein and Klein state cancer occurs as a multistep process in which activated proto-oncogenes play the most important role in tumor progression. A similar view is taken by.Land et a1 (3) for 24 known proto-oncogenes.. Duesberj (4), has taken a view opposite to that given in references (2) and (3) and states there is no proof that activated proto-oncosenes are sufficient or even necessary to cause cancer but does concede that they may be necessary for development of cancer. I shall favor the point of view of Duesberg here and attempt to show that activated proto-oncogenes can be related to.grovth lactors or contribute to the development of nmors. 23' NN- I

• SELECTED CASES ? ! . Jne of the interesting cases in the literature is that of transgenic mice (5). A modified version of the eyc proto-oncogene has been intro- duced into the geno line of sice. A hvbrid of normal mice myc and mouse mammary tumor virus (`LKIV) control region was used. The hybrid gene was injected into fertilized mouse eggs and transplanted in foster mothers. The results indicate that the female progeny are tumor prone, but animals that received a copy of mouse sye gene and its own control sequences have not shown any signs of cancer. The mice with the hybrid gene for mice with breast tumors and normal breast show a high expression of the hybrid gene. This suggests that high production of normal myc product contributes to the development of cancer but is not sufficient by itself. Thus, I have reviewed the literature concerning proto-oncogenes whose products act like developmental agents. The most outstanding example in human cancer is the case of human colon cancer (6). The data sugeest that ras p 21 expression is correlated with depth of carcinoma within the bowel wall and is probably a relatively late event in colon carcinogenesis. Another interesting case is that of retinoblaston. (7) where the N-®yc gene may have a role in progression of malignancy. In another embryonic tumor, that of Wila"s tusor as well as retinoblastosss (B)„ it is stated for Wilm's tumor or retinoblastos+a, that the tumors aay arise by another mechanism besides activation of cellular proto-oncogenes. No active transforming sequences have so far been isolated for either disease. Finally (9), Y-syc amplification is correlated with stage III and IV neuroblastoma, and' thus appears to be associated with development. DEVELOPMENT I will now cite places in the literature where activated proto- oncogenes are involved in growth or differentiation. Muller and Wagner (10) show that the transfer of mouse or human c-fos proto-oncogenes into F9 teratocarcinoma stem cells cause the cells to become morphologically altered and express characteristics of differentiated cells. Another case is that of c-fms proto-oncogene in human monocyte differentiation (11). Finally, (12), an outstanding case is the one where c-myc trans- cript is increased up to 10-15 fold of the normal level atter partial hepatectomy in the rat. The liver cells move from a differentiated state, Co phase„ to a proliferative state. SITL'ATIONS WHERE NO PROTO ON"OCE4IES ARE IWOLVED In radiation carcinogenests, no proto-oncogenes seem to be involved. In ultraviolet carcinogenesis of the thyroid in fish (1]), the production of pyrimidine diners are responsible for a mutation leading to thyroid tumors. It i!s necessary to have iodine deficiency and a pituitary thyrotropic hormone as a promoter. 24 r

In careinogenesis by DNA virus (14), early viral proteins, are re- sponsible for cancer in anisrls if the animal's isunme system allows ic. CONCLUSIION In a survey of the literature on the subject of proto-oncogenes, I find that the products of activated proto-oncogenes are not responsible for tumor initiation but are responsible for growth and development. There are situations where proto-oncogenes do not appear to be involved at all. REFERENCES 1. Marx JL. What do oncogenes do. Science 223:673, 1984. 2. Klein G, and Klein E. Evolution of tumors and the impact of molecu- lar oncology. Nature 315: 190,, 1985. 3. Land H, Parada LF, and Weinberg RA. Cellular oncogenes and swltistep carcinogenesis. Science 222: 771, 1983. 4. Duesberg PH. Activated proto-onc genes: sufficient or necessary for cancer. Science 228: 669, 1985. 5. Marx JL. Tumor-prone mice and myc. Science 226: 823, 1984. 6. Thor A, Horan Hand P, Wunderlich D, Ceruso A, Muraro R, and Sch1o. J. Monoclonal antibodies define differential ras gene expression in malignant and benign colonic diseases. Nature 311: 562, 1985. 7. Lee LH, Nurphree AL, and Benedict WF. Expression and amplification of the N-ayc gene in primary retinoblastoma. Nature 309: 458, 1984. 8. tiartinville E, and Francke V. The c-Ha-ras 1, insulin and globin loci map outside the deletion associated with aniridia - Wilm's tumor. Nature 305: 641 1983. ) , 9. Schwab ?S, Varmus HE, and Bishop JH. Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture. Nature 316: 160, 1985. 10. Muller R, and Wagner EF. Differentiation of F9 teratocarcino.a stem eslls after transfer of c-fos proto-oncogenes. Nature 311: 438, 1994. 11. Sariban E, Mitchell T„ and Kufe D. Expression of the c-fsu proto- oncogene during human monocyte differentiation. Nature 316: 64, 1985. 25

r LI. Marino k, Havash K. and Sugimura T. c-myc transcript is induced' in rat live: ac a very early stage of regeneration or by cvclohezimids treatment. Nature 310: 697, 1994. 13. Hart RY, Setlow RB, and Gtoodhead AD. Evidence that pyrimidine dimers in DNA can give rise to tumors. PNAS 74: 5574, 1977. 14. Levis AM, Jr., and Cook JL. A nev role for DNA virus early proteins in viral carcinogenesis. Science 227: 15. 1985. ! 26