Growth hormone (GH) is currently used for a multitude
of conditions. Two major questions were addressed in this
talk. Since we treat many short patients with GH for non-GHD
(GH deficiency) conditions, one question is whether pharmacologic
use of GH and Insulin-like Growth Factor-I (IGF-I) treatment
have the potential long-term risks for cancer and longevity.
Since IGFs, via IGF-I receptor (IGF-IR), potentiate tumorigenesis
in many cancers and there are anti-IGF therapies, the other
question is what the potential endocrine consequence IGF-IR
disruptors have.
IGFs are critical factors for carcinogenesis. There is
evidence that when the IGF-I/IGFBP-3 (IGF binding protein
3) ratio increases, cancer risk is also increased especially
in prostate, breast, colon, and lung. Many tumors overexpress
IGF-II, which is normally imprinted (11p15) and transcribed
from the paternal allele. Loss of imprinting leads to
Wilm's tumor and rhabdomyosarcoma. This phenomenon is
also seen in Beckwith-Wiedemann Syndrome (overgrowth,
increased incidence of Wilm's tumor, and rhabdomyosarcoma).
Many tumors are also known to overexpress IGF-IR. In contrast,
lack of IGF-IR attenuates malignant transformation by
oncogenes (activated ras, SV40 T antigen) in vitro. Therefore,
disrupting IGF signaling may be effective in the treating
cancer. In cancer cells, it is most important to inhibit
the PI-3K-AKT-TOR pathway downstream of IGF-IR.
Neuroblastoma (NB) is a common pediatric malignancy that
metastasizes to the liver, bone, and other organs. Current
treatment allows for less than 50% chance of survival
in patients with metastases. IGFs stimulate NB growth,
survival, and motility. They are expressed by NB cells
and the tissues they invade. Aggressive NB cells also
express IGF-IR. Thus, therapies that disrupt the effects
of IGFs on NB tumorigenesis may slow disease progression.
Nordihydroguaiaretic acid (NDGA) is a naturally occurring
compound found in creosote, has anti-tumor properties
against a number of malignancies, has been shown to inhibit
the phosphorylation and activation of the IGF-IR in breast
cancer cells, and is currently in Phase I trials for prostate
cancer. In NB cells, NDGA inhibits IGF-I-mediated activation
of the IGF-IR and disrupts activation of ERK and Akt signaling
pathways induced by IGF-I. NDGA inhibits growth of NB
cells and induces apoptosis at higher doses, causing IGF-I-resistant
activation of caspase-3 and a large increase in the fraction
of sub-G0 cells. In addition, NDGA inhibits the growth
of xenografted human neuroblastoma tumors in nude mice.
These results indicate that NDGA may be useful in the
treatment of NB. However, blocking IGF-I signaling may
cause short stature. Moreover, NDGA is not specific for
IGF-IR and shows cross-reactivity with the insulin-receptor,
which may result in insulin-resistance.
Decreasing GH and IGF-I increases life expectancy. IGF-IR
+/- mice have an increased life expectancy of 33% in females
and 16% in males. These mice also show greater resistance
to oxidative stress. Moreover, there is convincing evidence
that in several other experimental organisms decreased
IGF-I signaling results in increased lifespan. This is
in contrast with what is seen in the cell culture systems
whereby reduced IGF-IR activation increases the likelihood
of cell death.
In conclusion, IGFs regulate proliferation, differentiation,
and survival in many tissues. Since they are also linked
to neoplasia and influence lifespan, we must pay scrupulous
attention to these points when using GH and IGF-I in pharmacologic
doses. Disruptors of IGF signaling have potential benefit
for treating a wide variety of malignancies, but have
potential endocrine toxicities with long-term use such
as growth impairment, increased GH secretion, insulin
resistance, and hyperglycemia.
