Antioncogenes
by Steven B. Oppenheimer
The answer
to
cancer?
26
hilt causes cancer?
At one. level, we
know some of the
answers-r,,diation,
certain chemicals,
diet, exposure to certilin viruses. And
we can use this knowledge to avoid
exposing ourselves to these dangers
[6]. But the effects of radiatio:1, chemicals, and so on must be understood at
the cellula_r level.
We know that cancer is the result
of seqtiential ·changes in DNAchanges prob,1bly brought on by carcinogens. An initiation event, possibly
a mutation, occurs anrl is followed by
a promotion event, which Ccluses the
initiated cells to divide uncontrollably
[4,5]. Any explanation of cancer must,
then, account for the two-step initiation/promotion scenario.
One mechanism proposed for these
events is the expression of oucogcrres, or
dominant cancer-causing genes. Oncogenes h<1ve been identified in a v,1riety
of c<1ncers. When inserted into some
cell lines, they confe·r on the cells malignilnt ch<1r<1cteristics. Normally re~
pressed, oncogenes could be activated
by mutations, in some cases induced
by external factors such as exposure
to chemicals. But oncogenes have never been proven to cause liUIIIrHI cancer.
Only recently have biologists identified a possible alternate mechanism
in tHlliollcogt'llt'S, or genes whose presence may prevent tumors from developing and, conversely, whose absence
may encourage malignancy. An early ·
hint of the existence of these tumorsuppressor genes Cilme in 1969 when
Henry Harris and his colleagues found
that malignancy was suppressed when
malignant and nonmalignant cells were
fused irr t'ilro, even though the complete genetic complements (including
any cancer-causing genes) of both
groups of cells remained intact [2].
However, the mechanism for the suppression of the cancer remained a
mystery.
Rese<Jrch on familial retinoblilstoma,
a cancer of the eyes, added pieces to
the puzzle. Retinoblastoma .. ,,ff.licts
about 1 in 20 000 infilnts and young
children ilnd is curable only if detected
early. Children of retinoblastoma survivors develop the cancer at rates as
high as 50 percent. This fact indicates
a genetic component to the disease.
As told in a review in Nature [2] in
1986, A. G. Knudson analyzed the histories of 48 retinoblastoma patients ·
and hypothesized thilt filmilial retinoblilstomil develops as a result of double
mutations affecting both alleles at ,,
genetic locus called RB-1. The first
mutation is probably inherited, and a
second occurs spontaneously in the
normal homologous chromosome
sometime after birth. For retinoblastoma carriers, who start life with
one mutilted chromosome, if the normal chromosome is destroyed in any
single cell amtmg the millions of cells
in the retina, then retinoblastoma is
Tilt' Scit'lln' r,mhrrl Ar,ril 198 s
likely to develop.
In the 1970s through the mid 1980s,
a variety of observations suggested
that Knudson's model was correct. It
appeared that the defect was il deletion in chromosome 13 in a region
called q14. The same deletion was
found in osteosarcomil cells, a bone
cancer that frequently develops in
teenagers who have survived retinoblastoma. Researchers eventually concluded that when the normal chromosome 13 spontaneously mutiltes in the
q14 region in eye cells, retinoblastoma
develops; when the mutation occurs
in bone cells, osteosarcoma forms. The
cancers, therefore, appear to be Cilused
by the ilbsence of gene activity in the
q14 region of chromosome 13. Norm,,] cells possess two copies of the
retinoblastomil antioncogene, one in
the q14 region of each chromosome'
13. (See Figure 1.)
Stephen Friend and his colleagues
succeeded in tloning a 70-kilobase
-fragment of DNA that corresponded
to the retinoblastomi1 ilntioncogene,
and reported their findings in 1986
[1]. The ge~e was sequenced, but there
was still no direct demonstration thilt
the absence of RB-1 caused the development of a tumor. Nor was there
proof that the gene, when present,
could prevent cancer. The evidence
that would warrant the label "antioncogene" WiiS still circumstantial.
A direct demonstration that specific
genetic material could revefse c-ancer
was made by Bernard Weissman ilnd
his colleagues in their work with
Wilms' tumor, a cancer of the kidneys
thilt afflicts. small children (71. This
malignancy develops in cells that have
deletions in the p13 region of both
copies of chromosome 11. Working
with mice, Weissman and his coStrom B. Oppmltrimrr is 11 professor iu flrl'
Jrprrrfmmt of f,iology mul lite tlimlor of tlu
u11frr for Crr11ar mul Drvelopmt'flirrl Biolosy
nt CnfifonJill Strrfr Urrivmily, 18111 Nordhoff St., Norl!tridgt', CA 91330.
Tht Scimrt Tt11clttr!Avril1988
Figure 1
no mutation
---normal
mutation in one
- n o cancer
mutation in both
workers inserted a single copy of
normal chromosome 11 into Wilms'
tumor cells and found that the cells
would no longer produce malignancy.
The reseMchers also tried inserting
chromosome .13 kilrrying the retinoblastoma antioncogene) as well as a
second chromosome thought to carry
another ilntioncogene. Neither prevented the Wilms' tumors from developing. These experiments directly
implicated chromosome 11 as the carrier of the antioncogene(s) that blocks
the development of Wilms' tumor.
Weissman's work also failed to support the oncogene mtidel. The expression of a variety of oncogenes was the
same in bdth' the malignant Wilms'
tumor cell lines and in the Wilms' lines
that h,1d received the inserts of normal chromosome 11 and subsequently
lost their malignilncy.
Other cancers have been tentatively
associated with the lack of genes: A
deletion in chromosome 3 is often
found in renal carcinoma and in small
cell carcinoma of the lung, and the loss
of iln allele on chromosorr1e 5 is often
present in cancer of the. colon [3].
Until oncogenes are directly shown
to cause human cancer, the antioncogene model appears very plausible. In
other words, many human cancers
m.1y be c.1used not by the activation oF
<111 oncogene, but by inactiv,1tion or
destruction of tumor-suppressor genes
•
present.iti all healthy cells.
o. •
References
1. F.1il'nd, S.H., et ,,I." A Hum.m DNA 5l'gment
With l'rupertits of the Cent' That Predisposl's to Retinobbstom,, .111d Ostl'os,Hcom,,."
Nnturr, 323:643-646, Octob<•r 1986.
2. H.1rris, H. "M,>lign,>nt Tumors Ct'l1l'r,>tt·d by
Rl'cessive Mut,>tipns-" M'!JJYI', 323:582-583,
Ortobt·r 1986.
3. Klein, C. "The Apf>ro,Khing Era ,,f thl' Tumnr
Suppressor CPm·." Sci,·lrn•. 238:1539-1545,
Decembt•.r-11, 1987.
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,
f,mu.>ry 1987.
5. - - - . Cmr,·r. 2nd l'O. Bust<lll: jones and
B.ntll'tt, 1985.
6. - - - . "Tl'n Str.lt<·gil'S for C.mcl'r l'revl'nti<l11." T/r,· 5.-im(,• Tm(/11-r, 54:38-43, Octnbl'r
1987.
7. WPissm.m, B.E., l'l .1\. "lntroductinn of ,,
Norm.1l Hum.111 Chnmwsomt· 11 Into ,,
Wilms' Tumor Cdl Linl' Controls Its Tumorigl'llic Expn·ssion." xil'll(r·, 236: 175-180, April
1987.
Note
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Stit·nn· progr.1m, which is supportl'd by gr.>nt
TEl 8650081 from the N.>tion,>l Scil'11l"l' Found.1tion .1nd by till' Thon1.1s Eckstrom Trust. Thl'
program is designed to bring the latest advances
in biological science to teachers,
A p.1g<'·Si7l•d copy of thl' figllrl' th.H c.111 bt•
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27
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