New MRI Approach Detects Early Liver Tumors in Mouse Model of Human Disease

Science Highlights
June 9, 2015
Raymond A. MacDougall

Scientists at Georgia State University (GSU) with funding from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have designed an imaging technique to detect early-stage liver tumors, and have proven it successful in mice. Their study in an animal model is an essential step toward creating tools to improve liver tumor detection in human patients—whether primary liver cancer or metastatic tumors that have spread from other organ sites.

Early detection offers the best opportunity for treating and surviving cancer, however, liver cancer often advances undetected and is almost always diagnosed when it has reached late stages. Liver cancer accounts for nearly 25,000 cancer deaths each year in the United States.

In a study published in the May 11, 2015 Proceedings of the National Academy of Sciences, senior author Jenny Yang, Ph.D., professor of biochemistry and biophysics at GSU, and colleagues describe their enhanced imaging technique, which complements magnetic resonance imaging (MRI) with protein-based contrast solutions. Yang also serves as associate director of GSU’s Center for Diagnostics and Therapeutics.

Liver MRI and staining
MRI with protein contrast, left, achieves early detection of liver tumors in mice, a finding confirmed by tissue staining, right. Credit: Xue et al, PNAS.

MRI uses a magnetic field and radio waves to create detailed images of tissues inside the body. In liver imaging, a solution called a contrast medium is injected into the bloodstream to enhance the visibility of the liver tissue. However, current MRI contrast media are not sufficiently sensitive to find small tumors and can be quickly excreted from the liver. Small, early-stage cancers are the most responsive to drug treatments.

“MRI is an effective and safe technique that uses non-ionizing radiation,” said Yang. “It is very high resolution and shows soft tissue detail. Enhancing the MRI contrast offers the most preferred imaging for diagnostic evaluation, follow up treatment, and image guided interventions.”

Dr. Yang’s team has developed the new class of protein-based contrast agents and tested one called ProCA32 that enabled a much earlier detection of liver cancer tumors in mice. Using, the new contrast medium, the researchers could distinguish tumors as small as a grain of sand, or .24 millimeter. The limit for detection of tumors up until now has been about a centimeter in diameter. “This approach has opened up a new avenue to the use of MRI in detecting early liver cancers,” Yang said.

The researchers designed a modification in the chemistry of the ProCA32 MRI contrast agent so detectable metals form a bond with calcium molecules on proteins specific to liver tumor tissue. To test the effectiveness of the novel contrast agent, the team conducted imaging of mice livers to detect the spread of a type of melanoma.

A further chemical modification in the ProCA32 MRI contrast agent improves the ability for the compound to be retained in blood for a longer period of time, permitting a longer window for imaging and tumor detection. The researchers also found that the contrast works in lower doses than available contrast agents, reducing the potential of toxicity. The solution produces both positive and negative contrast images, one confirming the other, boosting the accuracy of detection.

“The authors have shown a very sensitive and specific way of distinguishing the disease process within a healthy liver and have found a characteristic molecular signature that indicates the presence of an early liver tumor,” explained Richard Conroy, Ph.D., director, Division of Applied Science & Technology, NIBIB. “Sensitivity and specificity are key for early detection.”

Dr. Yang and her colleagues anticipate that the new MRI contrast solution and imaging technique will be beneficial for patients in detection of liver cancer and other liver diseases, such as cirrhosis and liver fibroids, and in guiding the treatment of these diseases. They will begin working with radiologists to translate this new technique to one that doctors can use for their patients and are hopeful their solution can meet the high bar of approval for safe use in human patients established by the U.S. Food and Drug Administration.

The study is supported in part by NIBIB grant EB007268, and NIH grants GM62999, CA118113, CA176001, and S10RR023706.

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Xue S, Yang H, Qiao J, Pu F, Jiang J, Hubbard K, Hekmatyar K, Langley J, Salarian M, Long RC, Bryant RG, Hu XP, Grossniklaus HE, Liu ZR, Yang JJ. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6607-12.




Health Terms
Liver Disease