How MicroRNAs Drive Tumor Progression

UCSF researchers have identified collections of tiny molecules known as microRNAs that affect distinct processes critical for the progression of cancer. The findings, they say, expand researchers' understanding of the important regulatory function of microRNAs in tumor biology and point to new directions for future study and potential treatments.

The researchers refer to these microRNA collections as signatures, and their study results are reported in the September 15 issue of Genes & Development. The study, available online at http://genesdev.cshlp.org/, was led by the laboratory of Douglas Hanahan, PhD, an American Cancer Society Research Professor in the Department of Biochemistry and Biophysics at UCSF.

Approximately five percent of all known human genes encode, or produce, microRNAs, yet scientists are only now - nearly a decade after their discovery - beginning to unlock the mystery of their functions.

MicroRNAs are snippets of single-stranded RNAs that prevent a gene's code from being translated from messenger RNA into proteins, which are essential for cell growth and development. Produced in the nucleus and released into the cytoplasm, they home in on messenger RNAs that possess a stretch that is complementary to their genetic sequence. When they locate them, they latch on, preventing the messenger RNA from being processed by the protein-making machines known as ribosomes. As such, microRNAs are able to ratchet down a cell's production of a given protein.

Over the last several years, several groups have identified hundreds of microRNAs that are deregulated between normal tissue and tumors, however researchers only understand what a handful of these powerful regulators are doing to drive tumor formation.

"Virtually all cancers acquire approximately six distinct capabilities en route to tumor formation," said lead author Peter Olson, PhD, a postdoctoral fellow in the Diabetes Center and Helen Diller Family Comprehensive Cancer Center at UCSF. "When a cancer researcher observes a gene or microRNA go awry, it can be challenging to understand how that microRNA impacts tumorigenesis."

To home in on the question, the authors turned to a mouse model of pancreatic neuroendocrine tumors in which lesions go through discrete stages before culminating in invasive and metastatic carcinomas. In the three-year microRNA study, they found that cells in the mouse model developed and functioned normally but started to replicate uncontrollably at five weeks. Several weeks later, some pancreatic islets had become angiogenic (forming new blood vessels) - a step in the journey from a dormant state to a malignant state - though had not yet formed a tumor. By 10 weeks, a subset of angiogenic lesions had progressed to the tumor stage, and by week 16, a small percentage of mice had developed liver metastasis.

"This represents the spectrum of stages that we think are important for all tumors, including human disease," said Olson.

By measuring the expression level of all known microRNA in pre-tumor stages, tumors and metastases, the authors were able to associate deregulated microRNAs with processes such as hyperproliferation, angiogenesis and metastasis.

Focusing on the metastatic signature, researchers found - in one of the most striking observations of the project - that tumors bore a startlingly divergent microRNA expression pattern compared to primary tumors. Moreover, a subset of primary tumors showed more similarity to metastases than to other primary tumors.

"If you can identify tumors that have an increased propensity to metastasize, then it would have a very important clinical application," said Olson. "A lively debate in metastatic research has centered around whether primary tumor cells must suffer an additional mutation that endows that cell with a metastatic capability, or whether certain mutational combinations that are responsible for primary tumor formation also significantly increase the propensity of that cell to metastasize. These data provide evidence for the latter.''

Olson conducted the research in the Hanahan laboratory. Hanahan is a member of the UCSF Helen Diller Family Comprehensive Cancer Center. He also is a professor at the UCSF Diabetes Center.

Also collaborating on the project were Anny Shai and Matthew G. Chun of the UCSF Diabetes Center and the UCSF Helen Diller Family Comprehensive Cancer Center, and Yucheng Wang and Eric K. Nakakura of the UCSF Helen Diller Family Comprehensive Cancer Center. Other co-authors include Jun Lu, Hao Zhang, and Todd R. Golub of the Broad Institute of MIT and Harvard, and Steven K. Libutti who is with the Tumor Angiogenesis Section, Surgery Branch, of the National Cancer Institute.

The research was supported in part by the National Cancer Institute, the American Cancer Society and the National Science Foundation.

Source:
Elizabeth Fernandez
University of California - San Francisco

New Way Deadly Food-borne Bacteria Spread Discovered By University Of Central Florida Professor

University of Central Florida Microbiology Professor Keith Ireton has uncovered a previously unknown mechanism that plays an important role in the spread of a deadly food-borne bacterium.

Listeria monocytogenes is a bacterium that can cause pregnant women to lose their fetuses and trigger fatal cases of meningitis in the elderly or people with compromised immune systems. The bacterium has been linked to outbreaks traced to food processing plants in the U.S. and Canada.

In 2002, a multi-state outbreak of listeriosis - the serious disease caused by Listeria - resulted in 46 confirmed cases, seven deaths and three stillbirths or miscarriages. Those cases in eight states were linked to people eating contaminated sliced turkey deli meat. From January to August 1985, there was another outbreak with 142 cases of listeriosis.

Scientists have long known that Listeria spreads from one human cell to another. Bacteria growing in one cell move fast enough to create a finger-like structure that protrudes from the cell and pushes into an adjacent cell. The bacteria then infect the adjacent cell.

Ireton and his team have discovered a previously unknown second process that aids in the spread of bacteria to healthy cells. The process, which gradually overwhelms the second cell's ability to defend itself from infection, is featured in this week's edition of the science journal Nature Cell Biology.

The plasma membrane, or outer layer, of healthy human cells normally exhibits tension. Such tension might be expected to prevent Listeria from spreading to adjacent uninfected cells. However, Ireton's lab found that a Listeria protein called InlC appears to relieve tension at the plasma membrane in infected cells, making it easier for moving bacteria to deform the membrane and then spread into adjacent, healthy cells.

Ireton's laboratory also reports that the way InlC relieves tension is by blocking the function of a human protein called Tuba. The normal role of Tuba in uninfected human cells appears to be to help generate tension at the plasma membrane. The Listeria protein InlC inactivates Tuba, reducing that tension and enabling bacteria to spread to nearby cells.

"The idea that a pathogenic bacterium can spread by controlling membrane tension in the human cell has not been previously described in the scientific literature," Ireton said. "Our discovery could have relevance for bacterial pathogens that cause Shigellosis or Rocky Mountain spotted fever, as these bacteria resemble Listeria in their ability to move inside the host cell and spread."

More research is needed, but Ireton says that discovering this mechanism could aid in future therapies and perhaps open a window into understanding how certain bacterial pathogens cause disease.

Others who worked on Ireton's team include Tina Rajabian and Scott D. Gray-Owen at the University of Toronto, Balramakrishna Gavicherla at UCF and Martin Heisig, Stefanie Müller-Altrock and Werner Goebel at the University of Würzburg in Germany.

Ireton joined UCF's Burnett School of Biomedical Sciences, housed in the College of Medicine, in 2006. He earned his Ph.D. at the Massachusetts Institute of Technology and completed post-doctoral work at the Pasteur Institute in France, a private institute dedicated to the treatment of diseases through biomedical research, education and public health. He conducted research and taught at the University of Toronto for several years before arriving at UCF.

Source:
Zenaida Gonzalez Kotala
University of Central Florida