New pathway found for regulation of tumour-induced angiogenesis
People who inherit mutations affecting p14 ARF develop melanoma-astrocytoma syndrome
- Date : 06 Mar 2012
- Topic : Melanoma
Researchers at Winship Cancer Institute of Emory University have identified a new function for a gene that normally prevents the development of cancer. Scientists had known that this gene, which encodes a protein p14 ARF, works inside the cell to control proliferation and division. A team of researchers led by Erwin Van Meir, PhD, a professor of neurosurgery, haematology, and medical oncology, discovered that p14 ARF also regulates tumour-induced angiogenesis.
The findings, published in the Journal of Clinical Investigation, provide insight into how cancers form and progress, communicate with surrounding vascular cells and could guide the development of new therapies to fight tumours whose growth is driven by loss of p14 ARF.
Pinning down the new function for p14 ARF was a several-year detective investigation for Abdessamad Zerrouqi, PhD, research associate, the first author of the paper. The gene was a slippery target because growing cells in culture tend to lose or silence it. p14 ARF is not turned on in most tissues, but is activated in response to aberrant growth signals.
Gene encoding p14 ARF is mutated or silenced in many types of cancers
The gene encoding p14 ARF is mutated or silenced in many types of cancers, including most gliomas, the most common brain cancer in adults. People who inherit mutations affecting this gene develop melanoma-astrocytoma syndrome, with increased occurrence of both types of tumours.
ARF stands for "alternate reading frame" because the DNA sequence overlaps with another protein that is read out of step in comparison to ARF. Previous research had linked the function of p14 ARF to another gene, p53, which is also frequently mutated in cancers. p53 is known as "guardian of the genome" because it shuts down cell division in response to DNA damage.
Several clues pointed to a separate function for p14 ARF
p14 ARF is often lost when astrocytoma progresses to glioblastoma. These tumours are bigger, more infiltrative and more vascularized. Yet p53 is usually lost at an early stage, before this transition takes place. This suggested that p14 ARF has a function that is independent of p53.
Researchers could show that restoring p14 ARF in cells from a tumour that had lost it interfered with the tumour's ability to stimulate blood vessel growth. p14 ARF induces brain cancer cells to secrete a protein called TIMP3, which inhibits vascular cell migration.
The findings are applicable to brain cancers as well as several other cancer types. TIMP3 itself has been found to be silenced in brain, kidney, colon, breast and lung cancers, suggesting that it is an obstacle to their growth.
The research was supported by the USA National Institutes of Health, the Paediatric Brain Tumour Foundation of the USA, the American Brain Tumour Association, and the Southeastern Brain Tumour Foundation.
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