Chidren's Hospital Los Angeles. US: Retinoblastoma is a childhood retinal tumor usually affecting children
one to two years of age. Although rare, it is the most common malignant
tumor of the eye in children. Left untreated, retinoblastoma can be
fatal or result in blindness. It has also played a special role in
understanding cancer, because retinoblastomas have been found to develop
in response to the mutation of a single gene – the RB1
gene—demonstrating that some cells are only a step away from developing
into a life-threatening malignancy.
David E. Cobrinik, MD, PhD, of The Vision Center at Children’s Hospital Los Angeles (CHLA),
together with colleagues at Memorial Sloan-Kettering Cancer Center, has
answered the long-standing question of why mutations to the RB1 gene
primarily cause tumors of the retina and not of other cell types. His
study –which could reveal new cellular signaling pathways relevant to
retinal development, cancer development, and ultimately, the development
of novel therapies – is published in this week’s early on line issue of
the journal Nature.
“These findings significantly advance our understanding of cancer,
not only because they solve the RB riddle, but also because they more
generally imply that cancers can develop through the collaboration
between a cancer-causing mutation – in this case, inactivation of the
RB1 gene – and cell type-specific circuitry,” said Cobrinik, who also an
investigator with The Saban Research Institute of CHLA and associate
professor of Ophthalmology at USC Eye Institute, Keck School of Medicine
at the University of Southern California.
The RB1 gene encodes a tumor suppressor protein, referred to as Rb,
which prevents excessive cell growth by inhibiting cell cycle
progression until a cell is ready to divide. If both alleles of the RB1
gene are mutated early in life, the Rb protein is inactivated,
resulting in development of retinoblastoma cancers. (While the Rb
protein regulates proliferation in many cell types, only cells in the
retina routinely form cancers when the function of the RB1 gene is
lost.)
Cobrinik and colleagues discovered that retinoblastomas
originate in cone photoreceptor precursors, and their study explains why
retinoblastomas originate in these precursor cells. Cone cells, or
cones, are one of the two types of photoreceptor cells in the retina,
and are responsible for color vision. A cone precursor is an immature
cone cell which is not yet fully differentiated.
The study
indicates that cone precursors prominently express key, cancer-related
proteins that enable proliferation and suppress apoptosis, or programmed
cell death. Meanwhile, the role of the Rb protein is to hold back such
proliferation—which means that the loss of Rb alone is sufficient to
allow unchecked cell proliferation, causing retinoblastomas to form.
“We
showed that the cone precursors’ normal developmental program
collaborates with RB1 mutations to deregulate cell growth,” Cobrinik
explained. “In other words, loss of the RB1 gene results in abnormal
proliferation because the cone precursor cells lack a self-monitoring
‘surveillance system’ – which would normally cause aberrantly
proliferating cells to undergo apoptosis. Instead, cells are able to
divide uncontrollably and eventually become cancerous.”
Additional
contributors include first author Xiaoliang L. Xu, Lu Wang, David H.
Abramson and Suresh C. Jhanwar, Memorial Sloan-Kettering Cancer Center,
New York; Hardeep P. Singh and Dong-Lai Qi, The Saban Research Institute
of Children’s Hospital Los Angeles; and Bradford K. Poulos, Albert
Einstein College of Medicine. Funding for the study was provided in part
by NIH grant R01CA137124.
Researchers at Children’s Hospital
Los Angeles were among the first to isolate and clone the RB1 gene. The
Vision Center at CHLA is one of the largest clinical programs in the
U.S. for the treatment of retinoblastoma, was one of the first sites in
the nation to offer gene testing for all retinoblastoma patients, and
the first to offer a prenatal diagnosis for the disease. In June of this
year, a team of physicians and scientists here announced development of
a retinoblastoma next generation (RB1 NextGen) sequencing panel. CHLA
became the first place to offer this whole-gene sequencing to patients
and family members who may also have inherited the gene mutation,
placing them at high risk.