The ‘Growth’ Of A Cancer Discovery

H aim Werner, a professor in the department of human molecular genetics and biochemistry at the Tel Aviv University’s Sackler School of Medicine, is conducting research aimed at understanding the role of insulin-like growth factors (IGFs) in cancer development.

During a recent visit here, Werner, 59, met with donors of the Israel Cancer Research Fund, which on three occasions in recent years has awarded him grants for his research. The last grant was to investigate the link between obesity, diabetes and cancer. Since its inception in 1975, ICRF has awarded 1,863 grants totaling more than $43 million to Israeli cancer researchers.

For many years Werner has had a collaboration with Professor Zvi Laron of the Schneider Children’s Medical Center in Petah-Tikva. Laron is the founding father of pediatric endocrinology in Israel and a world leader in growth disorders in children. Their joint research is aimed at understanding why people afflicted with a rare type of dwarfism (now called Laron syndrome, LS) do not get cancer.

JW: Please tell us about the growth hormone — IGF-1 axis?

Haim Werner: Growth hormone (GH) is secreted from the hypophysis, a gland located in the base of the brain. GH travels in the bloodstream and binds to GH-receptors in the liver, causing the liver to produce IGF-1. IGF-1, in turn, is released into the blood and reaches its target organs, including the bones, leading to elongation and longitudinal growth. This hormonal axis is very active during puberty and is responsible for the growth spurt seen in adolescence. However, high levels of IGF-1 later in life may increase the risk of developing certain types of tumors, in particular breast and prostate cancers. In other words, (high) IGF-1 is considered a risk factor for certain types of adult cancers.

Would you please describe what we know about the Laron syndrome.

LS is a rare type of dwarfism first identified by Professor Laron in two siblings of Yemenite origin in the mid-1950s. The disease is inherited in a recessive manner. One of the first observations was a surprising and, initially, difficult to explain high level of circulating GH — despite the sibling’s short stature. After many years of research, Laron and his team identified the molecular defect responsible for the disease: a mutant or non-functional GH-receptor. As a result, LS patients are unable to produce IGF-1 and have severe growth impairment, as well as additional metabolic defects. LS patients can be treated with synthetic IGF-1, which is now clinically available and might help patients grow a few more inches.

I understand those with the syndrome are believed to be cancer-free.

Last year Laron and his co-workers published an epidemiological study of 230 LS patients up to the age of 85 in which they reported no cases of cancer in any of them. On the other hand, their family members had rates of cancer similar to the general population – 5 to 15 percent. Given that IGF-1 is a mitogenic hormone — that is a hormone that induces cell proliferation and growth — we believe the fact that LS patients had undetectable levels of IGF-1 in their blood protects them from malignancy and cancerous tumor development. There may be additional factors that also contribute to the apparent protection of LS patients from cancer development.

Is this a particularly Jewish disease?

Not really. LS is a rare condition. The total number of LS patients worldwide is unknown, although it is estimated that it may reach several hundred patients. The Israeli cohort of 65 patients includes Jewish patients of oriental origin — such as Yemen and Iraq — as well as non-Jewish patients, including Palestinians and Druze. Cases have been also reported in other countries in the Mediterranean basin, including Turkey, Italy, Iran, etc., and Far-Eastern countries. Of interest, a cohort of about 100 LS patients has been described in a remote village in Ecuador named Loja. Historians believe that these people are descendents of Converso Jews who fled from the Spanish Inquisition in the 16th-17th centuries and found shelter in this isolated area. Similarly, no cancer cases were reported in those Ecuadorian LS patients.

I understand you are now starting experiments using cells derived from Laron syndrome patients.

We have at Tel Aviv University a unique collection of cells derived from different populations of Israelis, including people with LS and other conditions. We are now applying some of the modern post-genomic technologies in order to identify the factors that may confer upon LS patients protection from cancer. Despite the fact that the incidence of LS is very low, I believe that we might learn lessons from this disease with broad impact in biology and medicine. As usually happens, the importance of these types of ‘experiments of nature’ is extremely high.