For many biological processes, the Goldilocks Principle rules. You don't want too much, or too little, of something, you want it just right.
So it is with the body's delicate concentration of growth factors. Too much of a signaling protein called insulin-like growth factor-I (IGF-I) may fan the flames of cancer, while too little of the protein may cause short stature, dementia and osteoporosis, among other problems.
New research from The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine deepens the understanding of how the growth hormone/IGF system is affected by another important actor: p53, the tumor suppressor gene that puts the brakes on cancer. The interplay of the two signaling pathways reinforces questions about the long-term risks of prescribing growth hormone and IGF-I to patients, at the same time that it may suggest a future new avenue for cancer therapy.
The study, which used cell cultures and mice, was published in the October issue of Cancer Biology & Therapy.
"It was already known that the tumor suppressor protein p53, which causes a cell to stop growing or to self-destruct, also acts on genes in the growth hormone/IGF axis to turn down IGF signaling," said pediatric endocrinologist and lead author Adda Grimberg, M.D., of The Children's Hospital of Philadelphia. "In this paper we showed that p53 increases production of insulin-like growth factor binding protein-2, an interaction that was not previously known." That protein, abbreviated as IGFBP-2, binds to IGF-I, and thus makes the growth factor less available to act on the body's tissues.
When the authors used genes to halt IGFBP-2 production by prostate cancer cells in culture, they found that p53 lost its ability to block IGF-I from activating one of its major signaling targets in those cells.
IGF-I is important because, along with naturally produced human growth hormone, it is the major regulator of body growth during childhood. These hormones continue to have important health effects during adulthood, after growth is done.
IGF-I is also of considerable interest to cancer researchers, because of mounting evidence that high levels of the protein contribute to cancer risk. One of the study's co-authors, oncologist Wafik El-Deiry, M.D., Ph.D., of the University of Pennsylvania, is internationally prominent for his studies of the p53 protein. "This work provides a novel and important insight into the regulation of growth by the major tumor suppressor p53," Dr El-Deiry said. He added, "For years we've known that p53 regulates another binding protein, IGBFP-3, to inhibit IGF signaling, but now we know that was the tip of the iceberg, as p53 appears to regulate the IGF axis at multiple nodes. It took collaboration between an endocrinologist and a medical oncologist to break this new ground, which has impact on both fields."
"We have no evidence now that either growth hormone or IGF-I actually causes cancer, but IGF-I may contribute to cancer progression and aggressiveness," said Dr. Grimberg. "IGF-I doesn't ignite the fire; it fuels it." At each stage that cancer progresses, she added, "IGF signaling can stimulate cells to behave more dangerously."
The study may have implications for patients receiving growth hormone or other growth-promoting therapies. Recombinant human growth hormone has been prescribed for the past 21 years for children with deficiency of normal growth hormone, to avoid abnormally short stature. However, in a controversial usage, that growth hormone is also prescribed for some short but healthy children with normal IGF-I levels to increase their height. "Excess levels of growth hormone and IGF-I may have long-term health risks," said Dr. Grimberg. "This study shows the interactions among pathways affecting growth and cancer are more complex than we have previously appreciated."
Better understanding of those complexities may have eventual clinical benefits as well, added Dr. Grimberg. "Understanding the fine-tuning of the growth hormone/IGF system at the cellular level may also lead to novel therapies for cancer. If we can develop drugs to safely inhibit IGF signaling, these may improve the effectiveness of conventional anti-cancer treatments such as chemotherapy and radiation."
The National Institute of Diabetes and Digestive and Kidney Diseases, the Lawson Wilkins Pediatric Endocrine Society Genentech Clinical Scholar Award and the McCabe Fund Pilot Project Award all contributed grant support to this study. Dr. Grimberg's and Dr. El-Deiry's co-authors were Carrie M. Coleman, Zonggao Shi, Timothy F. Burns, Timothy K. MacLachlan and Wenge Wang, all from the University of Pennsylvania School of Medicine.
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