Læknablaðið - 15.10.1983, Blaðsíða 37

LÆKNABLADID
257
tumorigenesis, are also known to act through
specific receptors (8).
The demonstration of specific receptors for
a selective group of tumor promoters pro-
vides a potentially important link between
promotion and the large number of molecular,
biochemical and biological responses. Experi-
mental tools developed in studies of both
receptor-dependent mechanisms and regula-
tion of normal cellular function should prove
valuable in elucidation of the mechanism of
tumor promotion. However, tumor promotion
by other agents or conditions such as dietary
fat, may be an indirect result of physiological
changes. In these cases, we have little informa-
tion about how an initiated cell grows into a
tumor. Nevertheless, it is suspected that all
tumor promoters confer a selective advantage
to the initiated cell leading to an altered
growth potential compared to surrounding
cells. Study of cells in culture offers one
method of examining such alterations (16).
Many cellular functions are altered in vitro
after treatment with promoters, but cause and
effect relationships in tumorigenesis have not
been demonstrated. While cell culture me-
thods offer possibilities for the screening of
tumor promoters, it will be necessary to
determine which functions altered in vitro are
critical to the promotion process in vivo.
IV. PROGRESSION
The distinction between the promotion and
progression phases in carcinogenesis is un-
clear. However, progression has been defined
as »that stage of neoplastic development
characterized by visible karyotypic alterations
as evidenced by light microscopic techniques
within the majority of the neoplastic cells that
make up the tumor. These karyotypic altera-
tions in turn are associated with increased
growth rate, increased invasiveness, metasta-
ses, and alterations in the biochemical and
morphological characteristics of the neo-
plasm« (54). While the definition of progres-
sion is arbitrary, many neoplasms, when exa-
mined, are aneuploid and exhibit high rates of
growth, invasiveness and glycolysis.
The classical mouse skin promoter, 12-0-
tetradecanoyl-phorbol-13-acetate (TPA) has
been reported to induce chromosomal aber-
rations such as sister chromatid exchange.
However, the reproducibility of these studies
is low and the concentrations required to
induce such changes are high (46, 75). Further-
more, since TPA induces changes in a cell
within minutes and its effects are reversible,
any permanent chromosomal changes induced
by TPA would presumably have to be associat-
ed with prolonged exposure to this promoter
(74). Also, skin papillomas that are induced by
TPA treatment and other types of benign
tumors are primarily associated with a diploid
karyotype whereas malignant tumors have
karyotypic alterations (25, 35).
The role of genetic rearrangement of dele-
tion versus localized mutation in the forma-
tion of human cancer has recently been re-
viewed (5). It was concluded that the rate-limit-
ing component in human cancer was not likely
to be chemical mutagens that are detected in
the usual tests for mutagenicity. More likely
candidates were the large-scale changes such
as rearrangements and deletions. These con-
clusions were based primarily upon an evalua-
tion of cancer rates in xeroderma pigmento-
sum patients who are defective in UV-type ex-
cision repair and experience a narrow range
of tumour types and patients with Bloom’s syn-
drome, who exhibit chromosomal instability (5)
and a wide spectrum of tumors. It is, however,
clear that localized lesions in DNA can be
carcinogenic (21). Whether such lesions act
independently or through direct or indirect
induction of major genetic alterations is at
present unknown.
The role of genetic transposition via trans-
posers in cancer has also been suggested;
however, little direct data support this conten-
tion (5). Despite the lack of methods to readily
measure such changes in vertebrates, this
suggestion is interesting since such genetic
alterations are; 1) much more drastic than
localized changes in base sequences; 2) may be
either site-specific or nonsite-specific; 3) may
occur at different frequencies; 4) appear to
affect the stability of neighboring genes; and
5) are virtually irreversible (5). In rapidly
multiplying bacterial cells, conventional muta-
gens do not enhance the frequency of transpo-
sition (62); however, too little is known
concerning the factors that trigger transposi-
tions to eliminate an indirect method by which
mutagens might enhance transposition in
mammalian cells in vivo.
The precise role of chromosomal changes in