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Researchers at the Los Angeles Children's Hospital were able to determine the exact stage of development of the human retina, when cells can grow unchecked and form masses resembling cancer. The discovery could pave the way for future interventions in retinoblastoma (RB), a retinal tumor that affects children under five.
The study is a continuation of research funded by a grant from the National Cancer Institute and was published online Sept. 13 in the prestigious journal. PNAS, Proceedings of the National Academy of Sciences.
The survey represents the first of its kind in identifying the phase of retinal development in humans when specific cells, called precursors of cones, can become cancerous.
"Understanding this stage of development and what's wrong can help us find ways to intervene and possibly prevent retinoblastoma," said David Cobrinik, MD, of Vision's Children & # 39; s Hospital Center. Los Angeles.
Although rare, retinoblastoma is the most common malignant tumor of the eye in children and can lead to devastating vision loss. ACIS is considered a world leader in the research and treatment of the disease, which can be fatal if it is not diagnosed quickly.
At a previous breakthrough in 2014 that led to this study, CHLA researchers identified precursor cells of the cone as the origin cell of retinoblastoma. Cone cells, present in the retina, are responsible for color vision.
Following the 2014 discovery with the current study, the team found that at some point in their maturation, precursor cells of human cones could enter the cell cycle – this is a series of events leading to their division. The cells then begin to proliferate and form pre-malignant lesions that can develop into fast-growing retinoblastoma-like masses. The precursors of maturing cones enter the cell cycle in response to the inactivation of the tumor suppressor gene RB1 and the loss of the functional RB protein, which regulates cell growth and prevents the division of precursor cells into the cell. cone.
"We suspect that mature cone precursors are wired to become cancer cells in response to the loss of RB protein," said Cobrinik, a researcher at the CHLA's Saban Research Institute. Associate Professor of Ophthalmology School of Medicine at the University of Southern California.
In another key finding, the researchers compared the development process of the human eye to a traditional mouse model. Lead author and postdoctoral researcher, Hardeep Singh, PhD, found that stage-specific proliferation and retinoblastoma formation occurred in RB-deficient human cone precursors, but not in mouse precursors. Animal models have failed to replicate the genetic, cellular, and developmental characteristics of human retinal cells. This discovery challenges the accuracy of some models of retinoblastoma in animals.
Another way to study the condition could involve induced pluripotent stem cells, Cobrinik said. These can be generated directly from adult cells and are another subject of investigation in his laboratory.
Retinoblastoma was one of the first tumors to have identified its genetic cause. About 30 years ago, mutations of the tumor suppressor gene RB1 were identified at CHLA and in other institutions. Since then, much has been learned about how RB1 mutations initiate retinoblastoma tumors.
"Given the current state of genomic analyzes," Cobrinik said, "we can hope to be able to test for mutations in RB1 as well as other genes associated with the disease and provide preventative interventions."
SOURCE: Los Angeles Children's Hospital
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