The association between circulating levels of serum or plasma insulin-like growth factor I (IGF-I) and cancer risk has been postulated for some time. Recent control-matched epidemiological studies have strengthened this association. These studies demonstrate that relatively high plasma IGF-I and low IGF binding protein-3 (IGFBP-3) levels are associated with greater risk of breast cancer in pre-menopausal women,1 prostate cancer in men,2 colorectal cancer in men and women,3 and lung cancer in men and women.4 Additional in vitro and in vivo studies reflecting a link between IGF and cancer can be found in references 5-8.
The IGF system is an integral part of growth regulation by the body. Abnormalities in all levels of the IGF system have been implicated in carcinogenesis and cellular transformation.8 The ligands of the IGF family, IGF-I and IGF-II, share 50% structural homology to insulin. IGFs act as mitogenic stimulators of cell proliferation as well as suppressors of cellular apoptotic pathways. Under the control of growth hormone (GH), the liver is the primary site of IGF production. IGF-I levels are also influenced by nutrition and developmental stages. Autocrine and paracrine tissue production of IGFs may also contribute to the levels of IGF available for growth regulation.
IGFs act through a family of cell surface receptors, including the insulin receptor, the type 1 IGF receptor (IGF-1R) and the type 2 IGF receptor (IGF-2R). IGF-1R is a tyrosine kinase that binds IGF-I with high affinity and binds IGF-II and insulin with much lower affinity. IGF-2R is the cation-independent mannose-6-phosphate receptor that binds IGF-II with high affinity and may act to remove IGF-II from the extracellular environment.9,10 Free IGF is regulated by a family of six IGF binding proteins (IGFBPs) that undergo proteolysis thus decreasing their affinity to IGF and in the process, releasing bound IGF. IGFBP proteases include serine proteases such as PSA, cathepsins and matrix metalloproteinases (MMPs). Under some conditions, IGFBPs act to potentiate IGF activity.11 The majority of IGF in serum is bound to IGFBP-3 in a ternary complex with acid-labile subunit (ALS). IGFBPs act as transporters of IGF prolonging the life of IGF within the body. IGFBPs may also have IGF-independent activities on cells. Although IGFBP-3 is a potent inhibitor of IGF activity, it also has IGF-independent anti-proliferative effects by facilitating apoptosis.12,13
IGF-1R overexpression can transform cells and appears necessary for transformation by other agents.14,15 Studies involving mutation of the IGF receptor, antibodies to the IGF receptor,16 IGF peptide analogs, knock-out techniques17 and IGF receptor anti-sense expression vectors18 all support the connection between the IGF receptor and transformation of normal cells. Many tumor cells respond to IGF by increasing growth and many cancer cells have been shown to secrete high levels of IGF-I and IGF-II to sustain autocrine growth.5 Laboratory observations have led to animal studies and the association of IGF to enhanced tumor cell formation. High levels of IGFBPs may play a role in protection from tumorigenesis.13 In the review by Khandwala et al.,5 the evidence of the effects of the IGF family on tumorigenesis and neoplastic growth is organized by types of neoplasms and encompass research performed on over 20 classifications of cancers.
Since IGF secretion is primarily under the control of GH, analogs of somatostatin19 and antagonists of GH-releasing hormone20 have been tested to see if blocking GH will affect IGF levels. Pegvisomant is a GH receptor antagonist that decreases IGF levels.5 Antibodies that block the IGF-1R and analogs of IGF that bind to the IGF-1R without inducing signal transduction have been shown to decrease the activity of IGF.16 Although these drugs have been studied primarily in animal models, small clinical trials have also been performed with limited success.
The IGF family plays an important role in the neoplastic process. Pre-diagnostic IGF measurements (particularly, IGF-I levels) may be of use as predictors of risk in several types of cancer. The study by Chan et al.2 demonstrated a four-fold increase in the risk of prostate cancer for men expressing IGF-I in the highest quartile (when controlled for IGFBP-3). Plasma IGF-I levels were assessed in 152 men over an average of seven years prior to prostate cancer diagnosis. Hankinson et al.1 showed a seven-fold increase in the risk for development of breast cancer in premenopausal women 50 years or younger that expressed serum levels of IGF-I at the high end of normal (when adjusted for IGFBP-3 levels). No correlation was noted between IGF-I levels and breast cancer risk in postmenopausal women. In a case-controlled study nested within the Physicians’ Health Study, baseline IGF-I, IGF-II and IGFBP-3 levels were measured on 193 subjects who were later diagnosed with colorectal cancer.3 Compared to matched control subjects, those with IGF-I levels in the highest quintile (when controlled for IGFBP-3) demonstrated a relative increased risk factor of 2.5 for colorectal cancer.3 After controlling for IGF-I levels, subjects with the highest IGFBP-3 expression levels were assigned lower risk. IGF-II levels were not associated with colorectal cancer risk.
IGF measurements may be particularly useful when combined with other markers such as positive family history, dense mammary tissue, and elevated PSA levels. A study of newly diagnosed lung cancer patients and matched control subjects evaluated the combined effects of latent genetic instability (as measured by mutagen sensitivity) and lung cancer risk (as measured by assaying IGF-I, IGF-II and IGFBP-3 levels).4 High levels of IGF-I and increased mutagen sensitivity increased the odds ratio of lung cancer over ten-fold. The association of high IGF-I and low IGFBP-3 levels with cancer risk does not prove that the IGF family causes the initial neoplastic process. The increasing evidence linking members of the IGF family with various cancers, however, emphasizes the need for more study in this particular area.