A protein used by embryo cells during early development, and recently found in many different types of cancer, apparently serves as a switch regulating the spread of cancer, known as metastasis, report researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center in the June 15, 2013 issue of the journal Cancer Research.
Metastasis is responsible for 90 percent of cancer-related deaths. More than 575,000 Americans die of cancer each year, the second leading cause of death in the United States after cardiovascular disease.
This image shows metastasized human breast cancer cells (magnified 400 times, stained brown) in lymph nodes. Credit: Image courtesy of National Cancer Institute
The scientists, led by principal investigator Thomas Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research at UC San Diego, discovered an association between the protein, called Receptor-tyrosine-kinase-like Orphan Receptor 1 or ROR1, and the epithelial-mesenchymal transition (EMT), a process that occurs during embryogenesis when cells migrate and then grow into new organs during early development.
In research published in 2012, Kipps and colleagues reported for the first time that ROR1 is expressed during embryogenesis and by many different types of cancers, but not by normal post-partum tissues. They also discovered that silencing the protein impaired the growth and survival of human breast cancer cells.
In their latest work, the scientists found that high-level expression of ROR1 in breast cancer cells correlates to higher rates of relapse and metastasis in patients with breast adenocarcinoma, a type of cancer that originates in glandular tissue. Conversely, silencing expression of ROR1 reverses EMT and inhibits the metastatic spread of breast cancer cells in animal models. Moreover, the researchers found that treatment with a monoclonal antibody targeting ROR1 also could inhibit the growth and spread of highly metastatic tumors that express ROR1.
"We might think of ROR1 as an oncogene," said study co-author Bing Cui, PhD, a postdoctoral fellow in Kipps' lab. "This means ROR1 has some tumor initiation functions. However, ROR1 also appears to allow transformed cells to invade other tissues and to promote tumor expansion in both the primary tumor site and in distant organs."
Because ROR1 is expressed only in cancer cells, Kipps' team says it presents a singular, selective target for anti-cancer therapies that would leave normal cells unaffected. It's not yet clear how the monoclonal antibody approach, tested thus far only in culture and animal models, impacts primary tumors, said Cui, but it does offer promise for inhibiting the spread of cancer. The researchers are developing a humanized monoclonal antibody for potential clinical studies in patients with cancers that express ROR1.
Funding for this research came, in part, from the National Institutes of Health (grant PO1-CA081534), the California Institute of Regenerative Medicine and the Blood Cancer Research Fund, UC San Diego Foundation.
Multipotent stromal cells have long been a hot topic in medical research. Scientists at the University of Bonn have now found a way to specifically mark these stem cells. This makes it possible to analyze their distribution pattern and their function in living organisms. The study, which included researchers from Oxford University, Tsukuba University and the Karolinska Institute Stockholm, is now being published in the journal “Cell Stem Cell”.
In the histology lab (from left): Dr. Martin Breitbach and Dr. Kenichi Kimura at the Institute of Physiology I of the University of Bonn.
“In all these development and disease processes however, there are still many unanswered questions”, explains Dr. Martin Breitbach from the Institute of Physiology I at the University of Bonn. “Which is why we looked for a way to mark multipotent stromal cells in the living organism.”
To this end, the scientists searched for genetic information that is read frequently in the cells of interest, but is rather inactive in other cell types. They found what they were looking for in the so-called CD73 gene.
Identifying previously uncharacterized gene’s role is the key first step in disease understanding and therapy development
University of Michigan researchers have discovered a new cause of congenital myopathy: a mutation in a previously uncharacterized gene, according to research published this month in the American Journal of Human Genetics.
About 50% of congenital myopathy cases currently do not have a known genetic basis, presenting a clear barrier to understanding disease and developing therapy, says James Dowling, M.D., Ph.D., the paper’s co-senior author and assistant professor of Pediatric Neurology at the University of Michigan’s C.S. Mott Children’s Hospital. Finding a new myopathy gene opens the possibility of providing a genetic explanation for disease in these individuals where no genetic cause is currently known.
In addition, “the identification of a new myopathy gene is an essential first step towards understanding why this disease occurs and how we combat its effects.” says Dowling, who worked with Margit Burmeister, Ph.D. and her team from the University of Michigan’s Molecular and Behavioral Neuroscience Institute to study the new myopathy gene (CCDC78).
Dowling says the gene, which has not been studied previously, is an important potential regulator of muscle function and, in particular, part of an important muscle structure called the triad.
“Many myopathies and dystrophies have abnormal triad structure/function, so finding a new gene product involved in its regulation will help researchers better understand the triad and its relationship to muscle disease,” Dowling says.
Congenital myopathies are clinically and genetically heterogeneous diseases that typically become evident in childhood with hypotonia and weakness. They are associated with impaired mobility, progressive scoliosis, chronic respiratory failure and often early death.
The researchers performed linkage analysis followed by whole exome capture and next generation sequencing in a family with congenital myopathy. They then validated the gene mutation and provided insights into the disease pathomechanisms using the zebrafish model system.
Dowling says the researchers’ next step is to further model the disease using zebrafish, in the hopes that this knowledge can be translated into therapy development.
“The study provides the first descriptions of the zebrafish model, and gives insight into how we will use it,” says Dowling, who also is director of the Pediatric Neuromuscular Disorders Clinic at C.S. Mott Children’s Hospital.
“Once we develop and characterize a model of the disease, we can then use it as a platform for therapy development.”
About the University of Michigan’s C.S. Mott Children’s Hospital: Since 1903, the University of Michigan has led the way in providing comprehensive, specialized health care for children. From leading-edge heart surgery that's performed in the womb to complete emergency care that's there when you need it, families from all over come to the U-M C.S. Mott Children's Hospital for our pediatric expertise.