June 2012
S. John Weroha and Paul Haluska
IGF System and Cancer Risk
Insulin-like growth factor (IGF) plays an important role in tissue growth and development. As such, several studies have demonstrated the association between circulating levels of IGF-1 and -II and cancer risk. In patients with acromegaly, an endocrine disorder which is characterized by a hypersecretion of growth hormone (GH) and consequently higher endogenous IGF, several studies have shown a 2-fold increased risk of gastrointestinal cancers [1–4].
Other studies have shown a modest association between higher circulating IGF-1 and -2 levels and an increased risk for prostate, breast, colorectal, and ovarian cancer [5–11]. However, several other studies do not show a similar increase in cancer risk [12–19]. Exogenous recombinant GH has been proposed as a potential cancer-promoting agent but no convincing link between cancer risk and its use in children or adults have been identified [20, 21].
The role of IGF in cancer risk is multifactorial and taken together, the preponderance of data suggests a slight increased risk of some cancers due to higher activity of the IGF system. Conversely, patients with congenital deficiencies in IGF-1 have a protective effect against developing cancer [22].
Conclusions
The IGF system has been implicated in the oncogenesis of essentially all solid and hematologic malignancies. The central involvement of IGF signaling in tumor cell proliferation, survival, invasion, and metastasis makes it an attractive therapeutic target. Importantly, the IGF signaling pathway has also been directly implicated in resistance to clinically important therapies, including hormonal agents, HER receptor targeting agents, radiation and cytotoxic chemotherapy.
Indeed, several clinical trials are currently evaluating the efficacy of IGF-1R inhibition to either overcome these resistance mechanisms or directly induce anti-proliferative effects on tumors dependent on IGF signaling.
Current strategies include monoclonal antibodies directed at IGF-1R, tyrosine kinase inhibitors with activity against IGF-1R +/− IR and anti-ligand antibodies. The optimal strategy for targeting IGF signaling in patients with cancer is not clear.
The modest benefits reported thus far underscore the need for a better understanding of IGF signaling, which would enable clinicians to identify the subset of patients with the greatest likelihood of attaining benefit from this targeted approach.
