Laboratory research: Zinc-sensitive MRI contrast agent distinguishes healthy prostate tissue from cancerous tissue

A novel MRI technique that detects low levels of zinc ion can help distinguish healthy prostate tissue from cancerous tissue, radiologists at the UT Southwestern Medical Center have determined. Laboratory research reported in the Proceedings of the National Academy of Sciences provide offers the potential of a new diagnostic imaging method to detect early stage prostate cancer and/or to monitor therapies used to treat the disease.

Typically MRI exams do not reliably distinguish between zinc levels in healthy, malignant and benign hyperplastic prostate tissue. The discovery of the technique using laboratory mice could eventually prove useful as a biomarker to track the progression of prostate cancer, according to researchers at the Advanced Imaging Research Center of the Harold C. Simmons Comprehensive Cancer Center in Dallas, TX.

Divalent zinc [Zn(II)] is the second most abundant metal in the human body. The prostate exhibits the highest amount of Zn(II) in mammals. Scientists have hypothesized that the high concentration of Zn(II) in prostatic fluid is necessary for optimal male fertility because of its antimicrobial effects and its role in supporting sperm motility. Prior published studies have snown that there is an approximately sixfold decrease in Zn(II) content in prostate cancer tissue versus healthy prostate and benign prostate hyperplasia tissues.

T2-weighted MRI and multiparametric MRI are widely used to characterize prostatic tissue that could potentially have malignant lesions. Senior author A. Dean Sherry, MD, UT Southwestern professor of radiology and director of the Advanced Imaging Research Center, and colleagues advise that it is challenging to identify and characterize cancers in transition zones compared with the peripheral zones, and that lack of consensus regarding MRI protocols presents a substantial barrier for establishing standardized apparent diffusion coefficient (ADC) cutoff values as a biomarker for prostate cancer evaluations.

The researchers developed a method to detect healthy prostate tissue by using a gadolinium-based contrast agent that shows an increase in r₁ relativity in the presence of Zn(II) by forming a ternary complex with human serum albumin. They discovered that glucose serves as a secretagogue to initiate Zn(II)release from epithelial prostate cells in fasted mice. They subsequently used this protocol to differentiate malignant prostate cells from healthy cells in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. When the glucose stimulated the release of the zinc ions from inside epithelial cells, they could be tracked on MRI. The prostate cancer tissue secreted lower levels of zinc ions, offering an opportunity to distinguish between malignant and healthy tissue. The research team was able to successfully detect small malignant lesions as early as 11 weeks.

“The potential for translating this method to human clinical imaging is very good, and will be useful for diagnostic purposes,” said Dr. Sherry. “The method may prove useful for monitoring therapies used to treat prostate cancer.” The authors wrote that by capitalizing on the sixfold decrease in zinc content in normal human prostate versus prostate cancer tissues, “the present experiments illustrate that glucose-stimulated Zn(II) release from secretory prostate cells may provide a new and more specific diagnostic method to differentiate the noncancerous prostatic tissue from prostate cancer”.

Co-author Neil Rofsky, MD, chairman of radiology and director of translation research at the Advanced Imaging Research Center, added, “Prostate cancer often has no early symptoms, so identifying potential new diagnostic methods that might catch the cancer at an earlier stage or allows us to track how it is progressing is an important opportunity.”

The researchers reported that detection of Zn(II) release from the prostate by contrast enhanced MRI in response to glucose was unexpected. They wrote, “Although it is well known that zn(II) is secreted from prostate cells into the seminal fluid, it was surprising to find that Zn(II) secretion in the mouse prostate was, much like the pancreas, also stimulated by glucose. The imaging data suggests that Zn(II) is secreted into the interstitial space surrounding prostate cells where it comes into direct contact with Gd-CP027 and albumin.”

REFERENCE

1. Jordan MVC, Lo S-T, Chen S, et al. Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate. Proc Natl Acad Sci U S A. doi. 10.1073/pnas.1609450113.