world cancer report - iarc
world cancer report - iarc
world cancer report - iarc
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IGF-1 AND CANCER<br />
Insulin-like growth factors (IGFs) are a<br />
family of peptide hormones which have<br />
been found to reflect excess energy intake<br />
associated with the Western lifestyle and<br />
an increased risk of several hormonallyresponsive<br />
tumours.<br />
IGFs have direct effects on tumour development.<br />
IGF-1 has been found to be<br />
involved in the stimulation of cell proliferation<br />
and differentiation and suppression<br />
of apoptosis in organs such as the<br />
breast, prostate gland, colon and lung<br />
(Yu H et al., J Natl Cancer Inst, 92: 1472-<br />
1489, 2000). IGFs are overexpressed in<br />
certain <strong>cancer</strong>s, and <strong>cancer</strong> cells with a<br />
strong tendency to metastasize have<br />
higher expression of IGFs. Many molecules<br />
known to be involved in <strong>cancer</strong><br />
interact with IGFs, for example, the<br />
tumour suppressor p53, and the products<br />
of the WT1 and PTEN genes, and<br />
also tumour viruses, e.g. HBV. Estrogens<br />
increase the cell-proliferative effects of<br />
IGF-1, induce IGF-1 expression and promote<br />
production of the IGF-1 receptor in<br />
breast <strong>cancer</strong> cells. Conversely, IGF-1<br />
can strongly stimulate expression of the<br />
estrogen receptor in estrogen-receptor<br />
positive breast <strong>cancer</strong> cell lines (Yee D et<br />
al., J Mammary Gland Biol Neoplasia, 5:<br />
107-15, 2000).<br />
endometrial <strong>cancer</strong> risk is increased in<br />
women taking high-estrogen/lowprogestogen<br />
oral contraceptives or estrogen<br />
replacement medication without<br />
progestogens, whereas combination-type<br />
oral contraceptives containing estrogens<br />
plus progestogens protect against<br />
endometrial <strong>cancer</strong>, and hormonal<br />
replacement therapy with estrogens plus<br />
progestogens causes only a weak<br />
increase risk.<br />
Ovarian <strong>cancer</strong><br />
Ovarian <strong>cancer</strong> may develop in two<br />
stages. In the first stage, ovarian surface<br />
epithelium is entrapped into the stroma in<br />
Blood and tissue concentrations of insulin,<br />
IGF-1 and IGF-binding proteins are intimately<br />
linked to energy balance and nutritional<br />
status (Kaaks R et al., Proc Nutr Soc,<br />
60: 91-106, 2001). The primary factor<br />
influencing production of IGFs is growth<br />
hormone, whilst insulin appears to regulate<br />
levels according to nutritional conditions.<br />
Circulating IGFs in the blood are<br />
mainly bound to IGF-binding proteins<br />
(IGFBPs), in particular IGFBP-3, and are<br />
subject to elaborate systems of regulation.<br />
The bioactivity of IGF-1 is increased by<br />
insulin, which both promotes its synthesis<br />
and decreases production of certain IGFbinding<br />
proteins. Prolonged fasting or<br />
insulin-dependent diabetes mellitus (low<br />
plasma insulin levels) decrease the synthesis<br />
of IGF-1, whereas obesity and noninsulin<br />
dependent diabetes mellitus (high<br />
insulin levels) are characterized by<br />
reduced levels of IGFBPs-1 and -2, and<br />
increased levels of IGF-1. Brief periods of<br />
physical exercise in adults appear to<br />
increase levels of IGF-1 and IGFBP-1,<br />
although activities such as marathon running<br />
can decrease levels of IGF-1 for several<br />
days. IGF-1 and insulin are also directly<br />
involved in the regulation of circulating<br />
levels of sex steroids. This is achieved by<br />
the inhibition of synthesis of sex hormonebinding<br />
globulin, as well as stimulation of<br />
the production of sex steroids, especially<br />
androgens.<br />
the form of inclusion cysts, that are<br />
believed to form as a result of repeated<br />
damage and remodelling of the ovarian<br />
epithelial surface induced by regular ovulations<br />
[16]. In the second stage, the<br />
inclusion cysts gradually transform to<br />
tumour cells, under the influence of hormonal<br />
factors. One hormonal factor<br />
strongly implicated is excessive stimulation<br />
by luteinizing hormone [2] which may<br />
act either directly, through the activation<br />
of luteinizing hormone-responsive genes,<br />
or indirectly, through over-stimulation of<br />
ovarian production of androgens. There is<br />
at least one study showing an increased<br />
ovarian <strong>cancer</strong> risk in women with poly-<br />
The role of IGFs may thus help to explain<br />
associations between energy imbalance<br />
and <strong>cancer</strong> risk discovered in epidemiological<br />
studies. Some <strong>cancer</strong>s, including<br />
those of the endometrium and colon,<br />
have been linked to a history of type 2<br />
diabetes, characterized by insulin<br />
resistance and chronic hyperinsulinaemia<br />
(excessive blood levels of<br />
insulin). Increased risk of several <strong>cancer</strong>s,<br />
including those of the breast,<br />
prostate, endometrium and colon, is<br />
associated with excessive energy intake<br />
relative to expenditure (as a result of<br />
low physical activity or a diet rich in fats<br />
and carbohydrates.<br />
Studies to date suggest a link between<br />
raised levels of IGF-1 and increased risk<br />
of breast, colon, prostate and lung <strong>cancer</strong>s<br />
and childhood leukaemia, and a<br />
decreased risk associated with high levels<br />
of another IGF binding protein,<br />
IGFBP-3 (Yu H et al., J Natl Cancer Inst,<br />
92: 1472-1489, 2000).<br />
Further research is necessary to determine<br />
the influences of lifestyle factors<br />
on IGF levels and how these interact<br />
with genetic susceptibility. Such information<br />
could be used in the development<br />
and targeting of intervention programmes<br />
to prevent and control <strong>cancer</strong>.<br />
cystic ovary syndrome, who generally<br />
have increased pituitary luteinizing hormone<br />
secretion. Oral contraceptive use,<br />
pregnancies and lactation all cause a suppression<br />
of pituitary luteinizing hormone<br />
secretion, and are also related to reduced<br />
ovarian androgen production, especially<br />
in women with a tendency to become<br />
hyperandrogenic.<br />
Prostate <strong>cancer</strong><br />
Risk of prostate <strong>cancer</strong> may be increased<br />
in men with high intra-prostatic concentrations<br />
of dihydrotestosterone. Dihydrotestosterone<br />
is formed from testosterone<br />
in the prostate and binds and activates the<br />
Reproductive factors and hormones<br />
79