J. William Harbour, MD Phone: 314/362-3315, Fax: 314/747-5073, E-mail: harbour@vision.wustl.edu, Dr. Harbour has no proprietary
interest in any aspect of this report.
|
Fort Lauderdale, FL—Research in retinoblastoma (RB) and uveal melanoma, two relatively rare ocular cancers, will contribute to all areas of oncology,
not just ocular oncology. Discoveries concerning the mechanisms in those two cancers are shedding light on how other tumors
function and may aid in the development of therapies and means of predicting metastasis, according to J. William Harbour,
MD, who delivered the Cogan Lecture at the annual meeting of the Association for Research in Vision and Ophthalmology.
"These eye cancers, despite their rarity, have an influence well beyond their prevalence. We started with clinical observations
that led to basic science discoveries, biological insights, and exponential cross-fertilization with other fields that have
already led to clinical impact," he said. "In the future we expect more clinical impact. The research that we conduct extends
far beyond ocular oncology to all areas of oncology."
Dr. Harbour, associate professor, and director of the ocular oncology service at Washington University School of Medicine,
St. Louis, is the winner of the 2005 Cogan Award for his significant contributions to the understanding of the molecular regulation
of the cell cycle in ocular tumors. The Cogan Award recognizes a researcher, 40 years or younger at the time of nomination,
who has made important contributions to research in ophthalmology and visual science directly related to disorders of the
human eye or the visual system.
RB gene mutation
Dr. Harbour described recent discoveries in oncology research including the activity of the RB gene mutation, which is present
in many other cancers. Retinoblastoma, while rare, is the most common ocular cancer in children. In the United States, 95%
of children with RB survive, but worldwide, most die.
"Scientifically, the genetics of RB have provided a clue to the revolution in cancer research 20 years ago," Dr. Harbour explained.
"The basic observation was that there were two forms of retinoblastoma. One form develops in only one eye and is not passed
on to children, and the other form develops in both eyes and it is passed on to children."
This discovery accounted for the different inheritance pattern based on the presence of a recessive cancer gene, which was
a revolutionary idea at the time. It resulted in the understanding that the RB gene mutation had different patterns; either
it was partly or completely missing or there were gross rearrangements. A parallel discovery was that the RB gene mutation
also appears in small-cell lung cancer, other lung cancer, and breast cancer.
RB protein
The real revolution started, he pointed out, when investigators began looking at the RB protein. Virtually every cancer studied
has some defect that inactivates the RB protein. The important factors associated with the RB protein are that there are 16
sites where it can be phosphorylated and the "business end" of the molecule has a pocket with two boxes that allows multiple
proteins to bind to it.
"Binding at the molecular level represses gene expression," according to Dr. Harbour.
Further research showed that the RB protein is regulated differently. Uveal melanoma, the most common primary ocular cancer
in adults, and most solid tumors partially inactivate RB and the tumors proliferate slowly with a low rate of apoptosis. Conversely,
retinoblastomas, small-cell lung cancer, and high-grade melanomas delete RB and there is rapid proliferation of the tumor
with a high rate of apoptosis.
"There are at least two tumor suppressor mechanisms by which RB blocks tumor formation," he said. "The primary one is regulation
of the cell cycle. The apoptotic response, we think, is the 'last-ditch' tumor suppressor mechanism when a tumor cell escapes
the primary mechanism before becoming cancerous."
Tumors that partially inactivate RB do so by inactivating p16, a tumor suppressor gene, or by overexpressing cyclin D. This
usually leads to slow proliferation, and the advantage for the tumor cell is that the apoptotic response is not triggered.
"We believe that this is why most melanomas in adults do not grow rapidly like leukemia or RB cells. The melanomas grow slowly
but avoid the apoptotic tendency," Dr. Harbour explained. "In contrast, when RB is inactivated completely or phosphorylation
is affected, there is more rapid proliferation because of the release of a transcription factor (E2F) that results in rapid
tumor growth but with a tendency to apoptosis. This may partially explain what we see in melanoma and most solid tumors."
The high apoptotic rate may be a factor in why RB and small-cell lung cancer may be more sensitive to chemotherapy and radiotherapy,
he noted.
This raised the question of why melanomas can target the RB pathway.
New trustees appointed during ARVO meeting
|
Dr. Harbour and colleagues discovered that the melanocytes are involved. In normal melanocytes from the choroid, E2F can drive
gene expression. In a dividing normal melanoblast, the RB is still partially active and blocks the apoptotic genes from being
expressed. They found the melanocyte differentiation factor binds to p16 promoter and activates p16 expression. "This links melanocyte differentiation to the RB pathway," he said. When p16 is activated, RB becomes dephosphorylated, remodeling
enzymes can be recruited, and they inactivate the cell cycle genes. The cells stop growing and differentiate. Melanocytes
are required in the pathway for differentiation and for cell cycle activity.
"This is important in melanoma because the pathway creates a selective pressure to inactive p16," Dr. Harbour said. "If cells
are driven into melanocyte differentiation, there is occasionally an escape clone that starts to grow rapidly and inactivates
p16 and methylates the p16 promoter, as uveal melanoma does in vivo. When p16 is missing, RB is rephosphorylated and the cells
re-enter the cell cycle. This is one of the earliest events in malignant transformation."
He contrasted this to the events in RB and in other tumors in which RB is inactivated completely. The RB pathway is irrelevant;
there is cell cycle gene activation but activation of apoptotic genes.
Dr. Harbour posed the question of whether apoptosis can be induced in melanoma by driving RB into a hyperphosphorylated state.
He and his colleagues did that by overexpressed cyclins D and E, which resulted in apoptosis of the cancer cells.
Class 1, 2 tumors
About half of patients with uveal melanoma die of metastatic disease and the metastasis likely occurs before uveal melanoma
is diagnosed. However, the disruption of the RB pathway does not predict metastatic death. The disruption of the pathway happens
early in the development of uveal melanoma.
Dr. Harbour investigated gene expression profiling to find out what causes uveal melanoma to metastasize in enucleated eyes
with melanoma. RNA analysis showed that the tumors clustered into class 1 and class 2. The class 2 tumors had a high number
of epitheloid cells, which carry a poor prognosis in melanoma, and in fact in Dr. Harbour's series all deaths occurred in
patients with class 2 tumors. Monosomy 3 was also found to be a high risk factor for metastasis.
"We believe that early in tumor progression, there are relatively subtle changes in the RB pathway and the other pathways
that lead to a class 1 melanoma," he said. "The class 1 melanoma cells can persist for years, cause local ocular destruction,
but never result in patient death. The change to a class 2 melanoma is a huge genetic switch, a malignant progression, during
which the cells undergo an epitheloid reversion.
"RB and uveal melanoma provide unique important insights into molecular angiogenesis and have implications far beyond their
incidence for cancer biology, developmental biology, and other areas of vision research," he concluded. "RB research, I believe,
will continue to have a profound impact on clinical care in both of cancer diagnosis and treatment, and we hope to improve
survival, if we can harness the RB pathway and use it in a controlled way."
We subscribe to the HONcode principles of the Health On the Net Foundation