Scientists pinpoint cellular antecedent for peripheral nerve sheath tumors

Etiology is still terra incognita for many cancers, but a recent statement by the UT Southwestern Medical Center (Dallas) suggests that plexiform neurofibromas, the parent neoplasm for many peripheral nerve sheath tumors, may be descended from Schwann cell precursors located in embryonic nerve roots. The scientists at UT Southwestern made use of genetic labeling for cell fate tracing to make the connection, but these researchers have been on the trail of nerve sheath tumors for some time. The statement explains that UT's Lu Le published the results of a study last year demonstrating that inhibition of a protein called BRD4 caused peripheral nerve sheath tumors to shrink in a mouse model, and UT Southwestern scientists are said to be collaborating with a pharmaceutical company to bring a BRD4-inhibiting drug into clinical trials. Le remarked that this latest study "points to the importance of stem cells and their immediate progenitors in the initiation of tumors, consistent with the notion that these neoplasms originate in a subset of primitive precursors and that most cells in an organ do not generate tumors." The study appeared Oct. 30 in the online edition of Cancer Cell under the title "Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma."

Epidemiology of neurofibromatosis

An Article Review in the Incidence and Prevalence Database, IPD, reported on an annual nationwide survey of neurofibromatosis 1 (NF1) patients by the Japanese Neurocutaneous Syndrome Research Group (JNCSRG). The number of NF1 patients was determined to be around 40,000 in Japan. Detailed information on 1711 patients was obtained, of whom 1593 cases were ascertained as being suitable for further analysis. Age at diagnosis: The average age of NF1 patients was 27.9 years (28.0 for males and 27.8 for females). More than 20% of patients were between 0 and 5 years old and nearly 40% were less than 20 years of age. Patient age at diagnosis was thus averaged as 24.5 years (24.6 in males and 24.5 in females). The age at diagnosis varied, but more than 20% of patients were diagnosed from their birth to 5 years of age. Half of the NF1 patients were diagnosed before reaching the age of 20 years. Almost all of them visited a medical facility and were diagnosed in their early years. Clinical features: Cutaneous neurofibroma developed at the average age of 15.8 years, which is equivalent with "at or around puberty." Diffuse plexiform neurofibroma (pachydermatocele) was associated with 19.3% of patients with their average age at its development being 13 years. Thoraco-vertebral deformity occurred in 18.4% of patients at an average age of 15.4 years. Bone deformity of extremities developed in 7.2% of patients at 9.8 years. Bone fracture and pseudoarthrosis were associated with 5.0% of patients averaging 15.6 years. Nearly 6 years was required for the advancement from bone deformity to fracture and pseudoarthrosis. Spinal cord tumor and brain tumor developed in 7.9% and 12.3% of patients, respectively, and neurological symptoms and signs were seen in 18.2% of NF1 patients. Epilepsy was also seen in 8.9%. These neurological associations were much higher in incidence than was expected. Lisch nodules were present in 21.8% but not as high in association rate, though it was probable in many cases that ophthalmological examination had not been performed or even that attention had not been paid to these. Malignant peripheral nerve sheath tumor developed in 2.5% of patients at the age of 33.4 years. Age of death: The overall average age at death from both NF1 and NF2 was 43 years for both sexes (see Article Review: "Epidemiology of Neurofibromatosis 1 in Japan." as cited in the IPD).

Northwestern scientists devise a 'nanoflare' for cancer detection

There is no shortage of ingeniousness in the world of cancer research, and a recent statement by Northwestern University (Evanston, Illinois) described a "nanoflare" for detection of cancer cells in the blood stream. The statement makes note of the fact that metastasis "is bad news for cancer patients," adding that a nanoflare is "designed to recognize a specific genetic code snippet associated with a cancer." The flare's core nanoparticle is 13 nanometers in diameter, and is designed to enter cells and produce a fluorescent signal if the genetic target is present. Shad Thaxton of Northwestern University said the NanoFlare is "effective in the complex matrix of human blood" and "is a great technical advance. We can find small numbers of cancer cells in blood, which really is like searching for a needle in a haystack," Thaxton said. Once they identified the cancer cells, the researchers were able to separate them from normal cells. This ability to isolate, culture and grow the cancer cells will allow researchers to zero in on the cancer cells that matter to the health of the patient. Most circulating tumor cells may not metastasize, and analysis of the cancer cells could identify those that will, the statement indicates. Thaxton and his colleagues report their findings Nov. 17 in the Proceedings of the National Academy of Sciences (PNAS), under the title, "NanoFlares for the detection, isolation, and culture of live tumor cells from human blood."

Cirmtuzumab shows therapeutic effect in study of ovarian cancer

Makers of companion diagnostics take note: A relatively novel monoclonal antibody that is in trial for chronic lymphocytic leukemia (CLL) might prove effective as a treatment for ovarian cancer as well, according to a recent statement by the University of California San Diego (UCSD; San Diego). The UCSD statement claims that cirmtuzumab may prove effective in "other cancers as well," in an article appearing in the Nov. 17 online early edition of the Proceedings of the National Academy of Sciences (PNAS). The statement reminds the reader that cirmtuzumab targets the protein dubbed ROR1, which plays an important role in the development of embryonic cells, but which is also "exploited by cancer cells to promote tumor growth and metastasis." Normal adult cells do not typically express ROR1, thus making it useful as biomarker of "cancer cells in general and cancer stem cells in particular," and the researchers believe this protein could be a good target for anticarcinogenics due to its role in tumor growth and metastasis. The scientists discovered that ovarian cancer stem cells express ROR1, and high levels of expression are said to be associated with more aggressive disease states and more frequent recurrence. The researchers tested the notion in transgenic mice that were stripped of their immune systems, after which some of the mice were infused with low doses of cirmtuzumab. The therapy is said to have "induce[d] senescence in cancer stem cells, degrading their ability to grow and metastasize," and UCSD's Thomas Kipp said, "it seems like ROR1 may be required to keep cancer stem cells healthy."

UT Southwestern discloses more than 3,000 new mutations

UT Southwestern Medical Center (Dallas) announced Nov. 17 that its use of next generation gene sequencing technologies has led to the identification of more than 3,000 new mutations involved in a range of cancers, a list that includes kidney cancers, but the statement claims that the findings may "help explain the diversity of cancer behaviors."

James Brugarolas, an associate professor of internal medicine and the director of UT Southwestern's kidney cancer program, said the studies, conducted as part of a collaboration with Genentech (South San Francisco, California), allowed the researchers to identify "novel therapeutic targets and suggest that predisposition to kidney cancer across species may be explained, at least in part, by the location of tumor suppressor genes with respect to one another in the genome." The epidemiology of kidney cancer includes a worldwide incidence of 250,000, and the lifetime risk of diagnosis in the U.S. is 1.6%. Most kidney tumors are renal cell carcinomas, which when metastatic remain largely incurable. Researchers at UT Southwestern's kidney cancer program had previously identified the BAP1 gene as a critical to kidney cancer formation, but this latest effort spells out the process by which BAP1 interacts with VHL to push a normal cell over the edge into a cancerous state. The newest findings suggest that the transformation begins with a mutation in one of the two copies of VHL, which is the most frequently mutated gene in the most common form of kidney cancer, clear cell type, which accounts for about 75% of kidney cancers. The VHL mutation is followed by a loss of the corresponding chromosome arm containing the second copy of VHL, as well as several other genes including PBRM1 and BAP1. This step eliminates the remaining copy of VHL and along with it, one of the two copies of PBRM1 and BAP1, two important genes that protect the kidney from cancer development. The subsequent mutation of the remaining copy of BAP1 leads to aggressive tumors, whereas mutation of the remaining copy of PBRM1 induces less aggressive tumors, according to Payal Kapur, an investigator in both studies. This model also explains why humans born with a mutation in VHL have a high likelihood of developing kidney cancer during their life time. In these individuals, all kidney cells are already deficient for one VHL copy and a single deletion eliminates the second copy, along with a copy of BAP1 and PBRM1. In contrast, in other animals, these three genes are located on different chromosomes and thus more mutational events are required for their inactivation than in humans. Consistent with this notion, when UT Southwestern researchers mutated VHL and BAP1 together, kidney cancer resulted in animals. These findings are described in the Proceedings of the National Academy of Sciences.

In a second collaborative study with Genentech published in Nature Genetics, investigators implicated several genes for the first time in non-clear cell kidney cancer, a less common type that accounts for about 25% of kidney cancers. Researchers identified a gene signature that can help differentiate subtypes of non-clear cell tumors to better define their behavior. Specifically, the researchers characterized alterations from 167 human primary non-clear cell renal cell carcinomas, identifying 16 significantly mutated genes in non-clear cell kidney cancer that may pave the way for the development of novel therapies. The research team also identified a five-gene set that enabled molecular classifications of tumor subtypes, along with a potential therapeutic role for BIRC7 inhibitors for future study.

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