Pathway to colon cancer progression
Identifying the molecular pathways that lead normal colon cells to become cancer cell could provide much needed biomarkers and therapeutic targets. Previously, Punita Dhawan, Ph.D., and colleagues showed that claudin-1 – a protein member of “tight junctions” that help bind cells together into an organized tissue structure – was greatly increased and mislocalized in colorectal cancer.
In a recent report in Gastroenterology, they describe the cellular pathway by which claudin-1 influences the transition of normal colon cells into cancerous ones. They show that increased claudin-1 expression in colon cancer cells is associated with loss of expression of the epithelial cell marker E-cadherin, whose reduced expression is correlated with poor prognosis and survival in colon cancer patients. Cell experiments showed that claudin-1 modulates expression of another protein, ZEB-1, which in turn affects E-cadherin expression. This chain of events then leads to cellular changes associated with invasion and progression in colon cancer cells.
The results suggest that ZEB-1, E-cadherin and claudin-1 could serve as biomarkers to indicate invasiveness and prognosis in colorectal cancer.
The research was supported by grants from the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Disorders.
— Melissa Marino
Lung resections not always “futile”The gold standard for definitive diagnosis of a lung nodule is surgical removal (resection). However, between 10 percent and 30 percent of suspicious nodules are benign. Because thoracic operations are highly invasive and pose significant risks, these operations have been labeled “unnecessary” or “futile.”
Eric Grogan, M.D., M.P.H., and colleagues report that, even when surgical resection results in a benign diagnosis, the operation still provides significant benefits by providing a new diagnosis and/or change in treatment course. Out of 278 lung operations for known or suspected lung cancer performed by surgeons at Vanderbilt, 23 percent of cases had benign disease. Resection led to definitive diagnosis or treatment changes in 85 percent of cases. Despite the highly invasive procedure, in-hospital complications were rare and no deaths occurred.
The findings, reported in the October Journal of Thoracic Oncology, suggest that despite the invasive nature, operative resections for suspicious lung lesions often offer benefits to patients and carry minimal risk of complications or surgery-associated mortality.
The research was supported by grants from the National Cancer Institute and the National Center for Research Resources.
— Melissa Marino
Move out, cholesterol
In atherosclerosis, sticky plaques composed of white blood cells called macrophages build up inside artery walls. The disease progresses when fatty materials such as cholesterol accumulate inside the macrophages, leading to foam cell formation. Current treatments use drugs to lower cholesterol levels in the body; an alternate strategy is to increase the flow of cholesterol out of the macrophages – to prevent them from becoming foam cells.Charles Hong, M.D., Ph.D., and colleagues at Emory University now demonstrate the feasibility of this alternative treatment approach in an animal model. They report in Arteriosclerosis, Thrombosis, and Vascular Biology that a drug that inhibits the BMP signaling pathway increases cholesterol efflux from macrophages and reduces foam cell formation and atherosclerosis in mice. The BMP inhibitor reduces iron levels in macrophages by suppressing a hormone called hepcidin, and administration of hepcidin reverses the drug’s effects. The findings suggest that drugs that inhibit BMP signaling could become future treatments for atherosclerosis.
This research was supported by the Carlyle Fraser Heart Center, CVPath Inc., and the National Heart, Lung and Blood Institute.
— Leigh MacMillan
Drug target for deadly heart infection
The binding of bacteria to human platelets is important for the development of infective endocarditis, a life-threatening infection of the heart. Streptococcus gordonii, a leading cause of endocarditis, uses a protein called GspB to attach to a receptor on human platelets, but little is known about the molecular details of this interaction.
Tasia Pyburn, Tina Iverson, Ph.D., and colleagues determined the crystal structure of the region of GspB that binds to platelet receptors. Using their structural map, the investigators predicted how to disrupt the interaction. They made mutations in GspB that prevented S. gordonii from binding to platelets and reduced endocardial infections in a rat model.
The studies, reported in PLoS Pathogens, provide the first structural information detailing the molecular interactions between a GspB-type of bacterial binding protein and its host receptor. The findings suggest that this interaction may be a drug target in streptococci that could be used to prevent endocardial infections without increasing antibiotic resistance.
This research was supported by grants from the American Heart Association, the Vanderbilt Institute of Chemical Biology, the Vanderbilt Institute for Clinical and Translational Research, the National Institute of General Medical Sciences and the National Institute of Allergy and Infectious Diseases.
— Leigh MacMillan
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