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
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
Tht Scimrt Tt11clttr!Avril1988 27