The study, led by scientists at Memorial Sloan-Kettering Cancer Center (MSKCC), appears in the January 10, 2008, issue of Nature.

MicroRNAs are known to inhibit the activity of entire sets of genes associated with cancer metastasis ??“ a process that leads to the majority of cancer-related deaths. The new work explains how the loss of certain microRNAs allows cancer cells to migrate through organ tissue and to grow more rapidly.

The researchers examined human breast cancer cells with strong metastatic ability and found that the cells had lost large numbers of three different microRNA molecules. Conversely, when researchers put those molecules back into human breast cancer tumors in mice, the tumors lost their ability to spread.

In addition, the researchers looked at breast cancer patients and discovered that those with tumors that had lost these molecules were much more likely to suffer from cancer metastasis to the lung and bone.

???The identification of molecules that inhibit a cell's metastatic potential may help guide clinical decision-making in the future by enabling oncologists to more accurately identify patients at highest risk for metastatic relapse,??? said the study's lead author Sohail Tavazoie, MD, PhD, a postdoctoral fellow in the Oncology-Hematology Fellowship program at MSKCC.

In further analyzing one of these microRNAs, called miR-335, investigators found that miR-335 works by suppressing certain genes that are associated with human metastasis, particularly SOX4, which acts as a transcription factor (meaning that it regulates a group of genes responsible for cell development and migration), and tenascin-C, which functions outside the cell in what is called the extracellular matrix and is implicated in cell migration.

???We now have a better understanding of the role this molecular pathway plays as a suppressor of breast cancer's ability to spread to the lung and bone, and we have identified the genes involved in that process. These findings may enhance our ability to come up with more effective drugs to prevent or treat cancer metastasis,??? said Joan Massagu?©, PhD, Chair of the Cancer Biology and Genetics Program at MSKCC, a Howard Hughes Medical Institute Investigator, and the study's senior author.

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Both TSC and LAM are associated with gene mutations that result in inappropriate activation of mTOR (mammalian target of rapamycin), an enzyme that helps control the growth and proliferation of all cells. Researchers suspect that sirolimus works by inhibiting mTOR signaling. Several new studies are currently underway, including a Phase III double-blind, randomized trial to examine the effect of sirolimus on lung function in patients with LAM.

Side effects observed in the proof of concept study included mouth ulcers, diarrhea, upper respiratory infections and joint pain. Support was provided by The LAM Foundation, the Tuberous Sclerosis Alliance (with funding from the Kettering Fund), Wyeth, the National Cancer Institute and the National Institutes of Health.

In a Jan. 10 letter to the editor published in NEJM, University of Cincinnati College of Medicine investigators reported the serum VEGF-D may be a clinically useful diagnostic test for LAM. Vascular endothelial growth factor (VEGF) is a major angiogenic growth factor produced by malignant cells. Previous research reported elevated levels of VEGF-D, but not VEGF-A or VEGF-C in patients with LAM.

Investigators found VEGF-D levels were elevated up to 30-fold in LAM patients, but were normal in patients with lymphangiomatosis, PLCH, and emphysema, suggesting the serum may distinguish LAM from S-other cystic and chylous lung diseases.

Following validation in a larger, longitudinal study, the test could be used to test for LAM in women who present with characteristic symptoms of LAM, such as a collapsed lung (pneumothorax) and/or lung cysts. Women who have tuberous sclerosis complex (TSC) may also be tested, as 40-50 percent of women with LAM develop TSC kidney tumors.

???Beyond its use as a potential clinical diagnostic for LAM, VEGF-D may prove useful as a potential biomarker for the development of LAM treatments,??? said Lisa Young, M.D., Pulmonary, Critical Care & Sleep Medicine at the UC College of Medicine, and study co-author. ???It may prove useful in testing outcome measures similar to the way we used kidney tumor volume as a measurement in the sirolimus study.???

Researchers say that if validated as a biomarker, the serum test may improve the ability to conduct trials more quickly. Furthermore, identification of a biomarker for LAM may have treatment implications for other diseases with similar pathways that affect millions of Americans, including breast cancer, diabetes, obesity and even autism.

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