New mode of growth factor signaling
Mutations that increase the expression or activity of the epidermal growth factor receptor (EGFR) are associated with several cancer types. Seven different growth factors, also called ligands, bind to EGFR and have three recognized modes of signaling – autocrine, paracrine and juxtacrine.
Robert Coffey, M.D., and colleagues have identified a new mode of EGFR ligand signaling via exosomes – small (30-90nm) membrane-bound vesicles – and have dubbed this new mode of growth factor signaling extracrine (exosomal targeted receptor activation). They show that human breast and colorectal cancer cells release exosomes containing full-length, signaling-competent EGFR ligands. Exosomes containing the ligand amphiregulin increased invasiveness of breast cancer cells 4-fold over exosomes containing two other EGFR ligands (TGF-α and HB-EGF).
The findings, published in Current Biology, suggest that this new mode of EGFR ligand signaling could have important implications for cancer invasion, metastasis and the tendency of cancer cells to cause changes to normal cells that surround them (cancer field effect).
— Melissa Marino
Protecting brainpower during radiation
Cranial irradiation to treat brain cancers often has long-term negative neurocognitive effects, including lowered IQ, learning difficulties and memory loss, especially in the pediatric population.
Fen Xia, M.D., Ph.D., and colleagues have reported that these effects may be due to radiation-induced damage to the hippocampus, the brain region responsible for learning and memory. They previously demonstrated that inhibition of the protein GSK3β (glycogen synthase kinase 3β) reduces radiation-induced hippocampal neuron cell death and protects neurocognitive function in mice treated with cranial irradiation.
The team has now discovered that inhibition of GSK3β – with specific inhibitors or using genetic manipulations – accelerates the repair of radiation-induced DNA damage (double strand breaks) in normal hippocampal neurons, but not in malignant glioma cells. The findings, reported in the May issue of Neuro-Oncology, link GSK3β to DNA repair pathways and suggest novel targets for the development of neuroprotective drugs to use during whole brain irradiation. In particular, the research suggests that GSK3β inhibitors may have neuroprotective effects.
— Leigh MacMillan
Stomach bugs impact nutrient levels
Infection with the stomach-dwelling bacterium Helicobacter pylori is a strong risk factor for gastric cancer. Because diet may also play a role in the disease, Meira Epplein, Ph.D., and colleagues examined the association between H. pylori infection and circulating levels of micronutrients in the Southern Community Cohort Study, a primarily low-income population from the southeastern United States. The researchers previously found a high prevalence of H. pylori infection in this cohort.
They report in the June issue of Cancer Prevention Research that micronutrient levels, particularly of beta-carotene, folate and retinol, were lower in H. pylori-positive individuals (and even lower in participants infected with more virulent strains) compared to H. pylori-negative individuals. Dietary intakes, assessed by questionnaire, were similar among all participants, suggesting that H. pylori infection impairs nutrient absorption.
The findings support efforts to improve nutritional status and reduce gastric cancer incidence in high-risk populations by treating H. pylori infections.
— Leigh MacMillan
NetWalker finds protein damage clues
Reactive molecules generated in the body – by toxic drugs, environmental chemicals and even the body’s own natural processes – can attack and chemically modify proteins to produce protein “adducts” which may play a role in human diseases. But just how these adducts are involved in toxicity and cellular responses to oxidant damage is unclear.
To facilitate such studies, Bing Zhang, Ph.D., and colleagues have developed a systems approach called NetWalker that integrates data on protein adduction, gene expression, protein-DNA interactions and protein-protein interactions.
Their study – featured on the cover of the July Molecular Biosystems – demonstrates how this approach can predict which protein adducts may act as stress sensors and mechanisms through which they regulate gene expression. Testing this approach with the reactive molecule HNE, they identified several protein “sensors” of HNE and the signaling networks to which they belong. The findings provide novel insights into oxidant stress, which has been implicated in complex human diseases such as cancer, atherosclerosis and neurodegenerative diseases.
— Melissa Marino
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