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The Answer Cancer? Antioncogenes by Steven B. Oppenheimer hilt causes cancer? may encourage malignancy. An early · At one. level, we hint of the existence of these tumor­ The answer know some of the suppressor genes Cilme in 1969 when answers-r,,diation, Henry Harris and his colleagues found to certain chemicals, that malignancy was suppressed when diet, exposure to certilin viruses. And malignant and nonmalignant cells were cancer? we can use this knowledge to avoid fused irr t'ilro, even though the com­ exposing ourselves to these dangers plete genetic complements (including [6]. But the effects of radiatio:1, chemi­ any cancer-causing genes) of both cals, and so on must be understood at groups of cells remained intact [2]. the cellula_r level. However, the mechanism for the sup­ We know that cancer is the result pression of the cancer remained a of seqtiential ·changes in DNA­ mystery. changes prob,1bly brought on by car­ Rese<Jrch on familial retinoblilstoma, cinogens. An initiation event, possibly a cancer of the eyes, added pieces to a mutation, occurs anrl is followed by the puzzle. Retinoblastoma .. ,,ff.licts a promotion event, which Ccluses the about 1 in 20 000 infilnts and young initiated cells to divide uncontrollably children ilnd is curable only if detected [4,5]. Any explanation of cancer must, early. Children of retinoblastoma sur­ then, account for the two-step initia­ vivors develop the cancer at rates as tion/promotion scenario. high as 50 percent. This fact indicates One mechanism proposed for these a genetic component to the disease. events is the expression of oucogcrres, or As told in a review in Nature [2] in dominant cancer-causing genes. Onco­ 1986, A. G. Knudson analyzed the his­ genes h<1ve been identified in a v,1riety tories of 48 retinoblastoma patients · of c<1ncers. When inserted into some and hypothesized thilt filmilial retino­ cell lines, they confe·r on the cells ma­ blilstomil develops as a result of double lignilnt ch<1r<1cteristics. Normally re~ mutations affecting both alleles at ,, pressed, oncogenes could be activated genetic locus called RB-1. The first by mutations, in some cases induced mutation is probably inherited, and a by external factors such as exposure second occurs spontaneously in the to chemicals. But oncogenes have nev­ normal homologous chromosome er been proven to cause liUIIIrHI cancer. sometime after birth. For retino­ Only recently have biologists iden­ blastoma carriers, who start life with tified a possible alternate mechanism one mutilted chromosome, if the nor­ in tHlliollcogt'llt'S, or genes whose pres­ mal chromosome is destroyed in any ence may prevent tumors from devel­ single cell amtmg the millions of cells oping and, conversely, whose absence in the retina, then retinoblastoma is 26 Tilt' Scit'lln' r,mhrrl Ar,ril 198 s likely to develop. Weissman's work also failed to sup­ In the 1970s through the mid 1980s, Figure 1 port the oncogene mtidel. The expres­ a variety of observations suggested sion of a variety of oncogenes was the that Knudson's model was correct. It same in bdth' the malignant Wilms' appeared that the defect was il dele­ no mutation tumor cell lines and in the Wilms' lines tion in chromosome 13 in a region that h,1d received the inserts of nor­ .- called q14. The same deletion was mal chromosome 11 and subsequently found in osteosarcomil cells, a bone lost their malignilncy. cancer that frequently develops in ---normal Other cancers have been tentatively teenagers who have survived retino­ associated with the lack of genes: A blastoma. Researchers eventually con­ deletion in chromosome 3 is often cluded that when the normal chromo­ found in renal carcinoma and in small some 13 spontaneously mutiltes in the cell carcinoma of the lung, and the loss q14 region in eye cells, retinoblastoma of iln allele on chromosorr1e 5 is often develops; when the mutation occurs present in cancer of the. colon [3]. in bone cells, osteosarcoma forms. The Until oncogenes are directly shown cancers, therefore, appear to be Cilused mutation in one to cause human cancer, the antionco­ by the ilbsence of gene activity in the gene model appears very plausible. In q14 region of chromosome 13. Nor­ other words, many human cancers m,,] cells possess two copies of the m.1y be c.1used not by the activation oF retinoblastomil antioncogene, one in -no cancer <111 oncogene, but by inactiv,1tion or the q14 region of each chromosome' destruction of tumor-suppressor genes 13. (See Figure 1.) present.iti all healthy cells. • Stephen Friend and his colleagues succeeded in tloning a 70-kilobase o. • References 1. F.1il'nd, S.H., et ,,I." A Hum.m DNA 5l'gment -fragment of DNA that corresponded With l'rupertits of the Cent' That Predis­ to the retinoblastomi1 ilntioncogene, posl's to Retinobbstom,, .111d Ostl'os,Hcom,,." and reported their findings in 1986 Nnturr, 323:643-646, Octob<•r 1986. mutation in both [1]. The ge~e was sequenced, but there 2. H.1rris, H. "M,>lign,>nt Tumors Ct'l1l'r,>tt·d by Rl'cessive Mut,>tipns-" M'!JJYI', 323:582-583, was still no direct demonstration thilt Ortobt·r 1986. the absence of RB-1 caused the de­ 3. Klein, C. "The Apf>ro,Khing Era ,,f thl' Tumnr velopment of a tumor. Nor was there Suppressor CPm·." Sci,·lrn•. 238:1539-1545, proof that the gene, when present, Decembt•.r-11, 1987. could prevent cancer. The evidence 4. Oppenh~inwr, S.B. "Adv.>nn·s in C.li1Ct·r Bi< >logy." T/r,• Jlmcri.-.r11 Bialogy Tmrha•.. 4 9:11-1 5, that would warrant the label "anti­ f,mu.>ry 1987. oncogene" WiiS still circumstantial. 5. --- . Cmr,·r. 2nd l'O. Bust<lll: jones and A direct demonstration that specific B.ntll'tt, 1985. genetic material could revefse c-ancer 6. ---. "Tl'n Str.lt<·gil'S for C.mcl'r l'revl'n­ ti<l11." T/r,· 5.-im(,• Tm(/11-r, 54:38-43, Octnbl'r was made by Bernard Weissman ilnd 1987. his colleagues in their work with workers inserted a single copy of 7. WPissm.m, B.E., l'l .1\. "lntroductinn of ,, Wilms' tumor, a cancer of the kidneys normal chromosome 11 into Wilms' Norm.1l Hum.111 Chnmwsomt· 11 Into ,, thilt afflicts. small children (71. This tumor cells and found that the cells Wilms' Tumor Cdl Linl' Controls Its Tumor­ would no longer produce malignancy. igl'llic Expn·ssion." xil'll(r·, 236: 175-180, April malignancy develops in cells that have 1987. deletions in the p13 region of both The reseMchers also tried inserting copies of chromosome 11. Working chromosome .13 kilrrying the retino­ Note blastoma antioncogene) as well as a This Mticll' is p.1rt ,,f tlw Adv,111Cl'S in Bi<•logic,11 with mice, Weissman and his co- Stit·nn· progr.1m, which is supportl'd by gr.>nt second chromosome thought to carry TEl 8650081 from the N.>tion,>l Scil'11l"l' Foun­ another ilntioncogene. Neither pre­ d.1tion .1nd by till' Thon1.1s Eckstrom Trust. Thl' Strom B. Oppmltrimrr is 11 professor iu flrl' vented the Wilms' tumors from de­ program is designed to bring the latest advances Jrprrrfmmt of f,iology mul lite tlimlor of tlu veloping. These experiments directly in biological science to teachers, A p.1g<'·Si7l•d copy of thl' figllrl' th.H c.111 bt• implicated chromosome 11 as the car­ u11frr for Crr11ar mul Drvelopmt'flirrl Biolosy liS<·d "" .111 liVl'rhe.ld pn•il't'tor ,111d lltllt'r A<1- nt CnfifonJill Strrfr Urrivmily, 18111 Nord­ rier of the antioncogene(s) that blocks Vtll1f(.'S in Biolt)~k.,f Scil'nce tl't\chin~ ,1ids \,r.t' hoff St., Norl!tridgt', CA 91330. the development of Wilms' tumor. ,1V,1il,,blt• frl'l' from tlw ,1uth<1r. Tht Scimrt Tt11clttr!Avril1988 27 .
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