world cancer report - iarc

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