This class of small RNA molecules could be the diagnostic marker that cancer researchers and biotech companies have been looking for.

Mason Inman

MicroRNAs may be only short snippets of nucleic acid, but since their discovery more than a decade ago, biologists—many of them in Boston—have uncovered the important roles these molecules play in orchestrating some of the most basic processes in cells, such as cell division and differentiation. So it’s not surprising that these gene-regulating molecules are turning out to be central to the development of cancer. “The interplay between microRNAs and cancer is enormous,” says Carl Novina, a microRNA researcher at the Dana-Farber Cancer Institute.

Several Boston-area groups are leaders in figuring out which of the more than 500 microRNAs identified so far are linked to the disease. They are also beginning to spot patterns of microRNA expression associated with particular types of cancers. The first pay-off may be improved cancer diagnostics. “Perhaps [cancers] may be detected at an earlier stage,” Novina says.

Researchers have struggled to find cancer “biomarkers”—key molecules that are early, accurate indicators of the presence and even the type of cancer and can be measured in patient samples. The research is still in the early stages, but so far, microRNAs, because they are so intimately involved in the cancer disease process, are emerging as good candidates for such biomarkers. “MicroRNAs seem to have very stable expression levels,” whether in cancer or normal tissue, making them potentially reliable markers, says Jun Lu, a microRNA researcher at the Broad Institute.

RNA roundup

Researchers estimate that microRNAs regulate the activity of at least a third of human genes, often by keeping a variety of core cell processes in check. They do this by binding to, and sometimes cleaving, messenger RNA, which dampens or even stops the translation of messenger RNA into protein. Many types of cancer cells produce lower levels of microRNA. This, in essence, takes the foot off the brakes for some of these key cell processes, leading to cancer.

Todd Golub of the Broad Institute and collaborators were among the first to demonstrate the potential of microRNA as a cancer diagnostic tool. In a 2005 paper, they measured the levels of 217 microRNAs—all that were known at the time of the study—in tumor samples taken from cancer patients. Based on the samples’ microRNA expression profiles, they were able to distinguish between different types of cancer, such as breast, liver, or stomach—something that has proven difficult when measuring levels of messenger RNA.

”MicroRNAs certainly seem better [than messenger RNA],” says Lu, a member of Golub’s lab and lead author of the 2005 study. These patterns of microRNA expression might help researchers identify where in the body a tumor originated, Lu says, a step that could be crucial to finding better treatment options.

Studies like this and others that delve into the role of particular microRNAs in specific forms of cancer are coming together to generate better diagnostics, says Lu. Basic research on cancer and the search for cancer biomarkers have, until now, been largely separate endeavors. “Now we’re seeing a trend of merging these back together,” Lu says. This means that work looking for biomarkers could also lead to the development of therapies that affect microRNA levels, he adds.

Biotech moves ahead

MicroRNAs aren’t ready for use as a diagnostic tool, many researchers say. “To my mind, it is premature to talk about the potential of microRNAs to be useful as diagnostics,” says Robert Weinberg of the Whitehead Institute, whose lab recently linked a particular microRNA to breast cancer metastasis.

But the field is moving fast, he adds. “Within a year there are likely to be a number of observations that correlate certain types of tumors and prognoses with the expression of certain microRNAs. Such observations may only be correlative, but they should prove useful for rendering prognoses.”

Still, a number of companies are already developing microRNA-based diagnostics for cancer. For example, U.S. Genomics, based in Woburn, MA, announced last year a collaboration with the Lahey Clinic, a teaching hospital for Tufts University School of Medicine, to develop more-accurate prognoses for bladder and prostate cancer. The company is also working with Rosetta Genomics, based in Israel, to develop a microRNA-based test for the early detection of lung cancer.