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IGFs and human cancer: implications regarding the risk of growth hormone therapy
Abstract:
Perturbations of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases such as prostate specific antigen (PSA), and cathepsin D have been identified in prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have been found to be negatively correlated to the risk of cancer. Interestingly, IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an IGF-independent mechanism. Recent case-control studies have found an approximately 10% increase in the serum levels of IGF-I in patients with prostate, breast and lung cancers, which are among the most frequently diagnosed cancers. While the studies indicate an association between serum IGF-I levels and cancer risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for autocrine tissue IGF-I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in serum. However, the role of GH in controlling prostate, breast and lung growth and carcinogenesis remains unclear from animal studies. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with prostate, breast or lung cancers, although colon cancer mortality may be increased. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of cancer, interpreting the risk associated with therapies such as GH replacement must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their cancer risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH recipients should become standard of care.
Insights
Insulin-like growth factor (IGF) axis alterations are linked to cancer risk. While serum IGF-I may indicate cancer, its causal role and the impact of growth hormone (GH) therapy require further study for patient monitoring.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Perturbations in the insulin-like growth factor (IGF) axis, including autocrine IGF production, IGF binding proteins (IGFBPs), and proteases like prostate specific antigen (PSA), are implicated in prostate, lung, and breast cancers.
- Serum IGFBP-3 levels show a negative correlation with cancer risk, and IGFBP-3 inhibits IGF action and promotes apoptosis independently of IGF.
- Elevated serum IGF-I levels (approximately 10%) are associated with prostate, breast, and lung cancers, but causality remains unproven, suggesting IGF-I may be a marker for autocrine production.
Purpose of the Study:
- To investigate the association between the insulin-like growth factor (IGF) axis and cancer development.
- To evaluate the potential role of serum IGF-I as a causal factor in cancer pathogenesis.
- To clarify the impact of growth hormone (GH) therapy on cancer risk, considering its effects on IGF-I and IGFBP-3 levels.
Main Methods:
- Review of existing case-control studies and literature on IGF axis perturbations in cancer.
- Analysis of the correlation between serum IGF-I, IGFBP-3 levels, and cancer risk.
- Examination of data regarding the effects of growth hormone (GH) therapy on IGF-I and IGFBP-3 and its association with cancer incidence.
Main Results:
- Serum IGFBP-3 levels are negatively correlated with cancer risk.
- Serum IGF-I levels are approximately 10% higher in patients with prostate, breast, and lung cancers, but a causal link is not established.
- Increased GH levels in acromegaly are linked to benign prostatic hyperplasia but not directly to prostate, breast, or lung cancers.
Conclusions:
- Serum IGF-I may serve as a marker for autocrine tissue IGF-I production rather than a direct causal factor in cancer.
- The role of GH in cancer development is unclear; GH therapy normalizes subnormal IGF-I in deficient patients, suggesting minimal increased cancer risk.
- Routine monitoring of IGF-I levels in GH recipients is recommended as standard care pending further research.