Study Shows How Normal Cells Fuel Tumor Growth
MICHAEL OSTROWSKI, PhD,
(right), OSUCCC – James
Co-leader of the Molecular Biology and Cancer Genetics Program
GUSTAVO LEONE, PhD,
OSUCCC – James Associate Director for Basic Research
Researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) have discovered how normal cells within tumors can fuel tumor growth.
Their study examined what happens when normal cells called fibroblasts in mouse mammary tumors lose the Pten tumor-suppressor gene. The findings:
• Suggest new strategies for controlling tumor growth by developing drugs that disrupt communication between tumor cells and normal cells;
• Provide insight into mechanisms that control the co-evolution of cancer cells and surrounding normal cells in tumors;
• Demonstrate how the Pten gene normally suppresses cancer development.
"Our study is the first to define a specific pathway in tumor fibroblasts that reprograms gene activity and the behavior of multiple cell types in the tumor microenvironment, including tumor cells themselves," says co-principal investigator Michael Ostrowski, PhD, co-leader of the Molecular Biology and Cancer Genetics Program at the OSUCCC – James.
The findings increase basic knowledge about how tumors grow and spread, and they have translational implications for the treatment of breast-cancer patients, Ostrowski says.
The researchers found that Pten regulates a molecule called microRNA-320 (miR-320), and that loss of Pten leads to a dramatic drop in levels of that molecule in a tumor fibroblast. With little miR-320 around, levels of a protein called ETS2 rise in the fibroblast, activating genes that cause the fibroblast to secrete more than 50 factors that stimulate proliferation and invasiveness of nearby cancer cells.
"The cancer field has long focused solely on targeting tumor cells for therapy," says co-principal investigator Gustavo Leone, PhD, associate director for basic research at the OSUCCC – James. "Our work suggests that modulation of a few key molecules such as miR-320 in noncancer cells in the tumor microenvironment might be sufficient to impede the most malignant properties of tumor cells."
Published in the Journal Nature Cell Biology
Oral HPV Infection More Common in Men Than Women
MAURA GILLISON, MD, PhD,
medical oncologist and head and neck cancer specialist
Research at the OSUCCC – James shows that men are three times more likely to have an oral human papillomavirus (HPV) infection than women – findings that help explain why HPV-related oral cancers are three times more common in men than women.
Maura Gillison, MD, PhD, a medical oncologist who is a head and neck cancer specialist and member of the OSUCCC – James Viral Oncology and Cancer Control programs, led the study, which sought to determine the prevalence of oral HPV infection in the United States and to understand factors associated with infection and oropharyngeal cancer. Her team analyzed mouth-rinse samples for HPV DNA and examined data collected from 5,579 men and women who participated in the 2009-2010 National Health and Nutrition Examination Survey.
"This study of oral HPV infection is the first step toward developing potential oropharyngeal cancer-prevention strategies," Gillison says. "This is important because HPV-positive oropharyngeal cancer is poised to overtake cervical cancer as the leading type of HPV-caused cancer in the United States, and we have no means to prevent or detect these cancers early."
The researchers estimate that 7 percent of Americans between ages 14 and 69 have an oral HPV infection, with 10.1 percent of men infected versus 3.6 percent of women.
Other key findings include:
• About 1 percent of the U.S. population is infected with HPV 16 – the type of HPV most often responsible for cervical cancer – and HPV 16 infection is five times more common in men than in women.
• Oral HPV infection is uncommon among those with no history of sexual contact compared with those with a history of sexual contact of any type (0.9 percent versus 7.5 percent, respectively).
• Oral HPV infection was independently associated with age, gender, number of sexual partners and current number of cigarettes smoked per day.
Read a Frontiers feature about Maura Gillison and her research.
Published in the Journal of the American Medical Association.
Mobile DNA Elements Can Disrupt Gene Expression
DAVID SYMER, MD, PhD,
a member of the Viral Oncology Program at the OSUCCC – James
The many short pieces of mobile DNA that exist in the genome can contribute to significant biological differences between lineages of mice, a study at the OSUCCC – James has shown.
These movable pieces are called transposons or "jumping genes" because they can migrate from one chromosomal location to another. Unlike viruses, they are not infectious and do not move from cell to cell. They have accumulated over time in the genomes of mice and humans and now constitute about half of genomic DNA in both.
For this study, researchers mapped the genomic locations of transposons called endogenous retroviruses (ERVs) in diverse mouse strains and compared those strains to learn how ERVs might influence gene expression. They found that ERVs can significantly disrupt expression by prematurely halting gene transcription, even when the ERV is more than 12,000 base pairs away in the same chromosome. They also found that the disruptive influence is affected by the gender of the parent who supplied the ERV.
"These findings add an interesting new angle to our understanding of fundamental mechanisms of natural variation and human biology, and possibly cancer and other diseases," says principal investigator David Symer, MD, PhD, a member of the Viral Oncology Program at the OSUCCC – James.
A mouse gene containing an ERV inherited from the father often produced only an incomplete, truncated form of messenger RNA (mRNA); if the ERV came from the mother, not only the truncated transcript but also nearly normal levels of the full-length mRNA were produced from the gene.
"We believe this is an unusual, interesting example of a wellknown phenomenon called DNA imprinting," Symer says. "We are now conducting experiments to understand how premature termination of gene expression can be triggered by the transposons, and also how the parent-of-origin effect occurs."
Published in the Journal of Genome Research.
Finding Could Yield New Liver Cancer Therapy
THOMAS SCHMITTGEN, PhD,
a member of the OSUCCC – James
Experimental Therapeutics Program
Hepatocellular carcinoma, or liver cancer, kills an estimated 549,000 people annually worldwide. Recent findings by researchers at the OSUCCC – James and the Mayo Clinic show that it is possible to target and block a microRNA that is important in the disease, perhaps offering a new therapy for the malignancy.
The animal study focused on microRNA-221 (miR-221), a molecule that is consistently present at abnormally high levels in liver cancer.
To control the problem molecule, researchers designed a second molecule as a mirror image of the first. The mirror molecule, called an antisense oligonucleotide, selectively bound to and blocked the action of miR-221 in human liver cancer that was transplanted in mice. The treatment significantly prolonged the animals' lives and promoted the activity of important tumor-suppressor genes.
"Liver cancer generally has a poor prognosis, so we badly need new treatment strategies," says principal investigator Thomas Schmittgen, PhD, a member of the OSUCCC – James Experimental Therapeutics Program.
Schmittgen and colleagues injected liver cancer cells labeled with the luminescent lightningbug protein known as luciferase into the livers of mice, then used bioluminescence imaging to monitor tumor growth. When the tumors reached an appropriate size, one group of animals received the anti-miR molecule while the other group received a control molecule.
After treatment with the antisense oligonucleotide, half of the treated animals were alive at 10 weeks versus none of the controls. Also, the antisense oligonucleotide significantly reduced levels of miR- 221 in both tumor and normal liver samples. And treatment with the antisense oligonucleotide caused a three-fold increase in the activity of three tumor-suppressor genes that are blocked by miR-221 in liver cancer.
"Overall, this study provides proof-of-principle for further development of microRNAtargeted therapies for hepatocellular carcinomas," Schmittgen says.
Published in the journal Cancer Research.
Mutation Signals High Recurrence Risk in Older AML Patients
CLARA D. BLOOMFIELD, MD,
Distinguished University Professor and OSUCCC – James cancer scholar and senior adviser
Older patients with acute myeloid leukemia (AML) and normal-looking chromosomes in their cancer cells have a higher risk of recurrence if they have mutations in the ASXL1 gene, according to a study by OSUCCC – James researchers.
The study is the first to investigate the influence of these mutations on prognosis in patients with cytogenetically normal AML (CN-AML) and in conjunction with other prognostic gene mutations. It also reports the first gene-expression signature for CN-AML with mutated ASXL1
"Our findings could lead to more effective targeted therapies and improved cure rates for these patients," says principal investigator Clara D. Bloomfield, MD, a Distinguished University Professor who also serves as cancer scholar and senior adviser to the OSUCCC – James.
Bloomfield and colleagues found that patients age 60 and older with CN-AML and ASXL1 mutations had significantly shorter survival than patients with the normal gene – only 5 percent of patients with the mutation were alive after three years, compared with 23 percent of patients without the mutation. Complete remission rates were also significantly lower, at 53 percent for patients with versus 71 percent for patients without the mutation.
The findings were presented at the 53rd Annual Meeting of the American Society of Hematology. The study's first author, Klaus Metzeler, MD, a research fellow at the OSUCCC – James, received an "Abstract Achievement Award" for this novel and clinically relevant work.
"Mutations in the ASXL1 gene appear to be an important marker of poor prognosis in older AML patients," says Bloomfield, Metzeler's mentor. "Importantly, their negative impact was greatest in patients who, based on established genetic markers, would be expected to have favorable outcomes.
"ASXL1 mutations therefore identify a previously unknown high-risk subgroup in older AML patients," she adds. "These patients don't do well with current standard therapy and may be candidates for treatment with novel drugs in a clinical trial."
Published in the journal Blood.
BEYOND THE THYMUS
Tonsils Make T-Cells Too
MICHAEL A. CALIGIURI, MD,
director of the OSUCCC and CEO of The James
T lymphocytes (T cells) have been thought to develop only in the thymus, but a study led by OSUCCC – James researchers suggests they can also develop in human tonsils. This finding could improve the understanding of T-cell cancers and autoimmune diseases, as well as how stem-cell transplantation is done.
The study identified T cells at five stages of development in the tonsils. These stages, revealed by molecular signposts on the cells, were very similar to the stages of T-cell development in the thymus, although some differences were found. The study also discovered that the cells develop in areas near the fibrous scaffold of the tonsil.
"We've known for a long time that a functional thymus is necessary to develop a complete repertoire of T cells, but whether a T-cell factory existed outside the thymus was controversial," says principal investigator Michael A. Caligiuri, MD, director of the OSUCCC and CEO of The James. "I believe our study answers that question. It is the first to describe a comprehensive, stepwise model for T-cell development outside the thymus."
It also raises other questions. Caligiuri says it is still unclear whether T cells that develop in the tonsils also mature there or leave to mature elsewhere.
"The complete implications of this phenomenon for human health and disease are not entirely known," adds first author Susan McClory, a graduate fellow in Caligiuri's laboratory. "It could be important in the development of T-cell cancers and autoimmune diseases, or it might suggest a location for T-cell development when thymus function is poor. We hope to explore these possibilities."
"Our work suggests that the tonsils serve as a T-cell factory, along with the thymus," Caligiuri says. "Next we need to learn what proportion of T cells is derived from the tonsils compared with the thymus."
The findings are reported in the Journal of Medical Genetics.