TSC: Full-Body Peril
But whatever their path, the fact that LAM cells may also appear in a lung transplanted to replace the failing, LAM-infected organ suggests the cells are indeed metastasizing, says Henske, whose research has found that genetic mutations in AML and LAM cells are identical. And, in another link to cancer, both kinds of TSC cells produce many of the same proteins that melanoma cells do. Unlike cancer, however, LAM can suddenly stop progressing, especially after menopause. (Estrogen appears to help these cells migrate.)
All of these ailments, from epilepsy and autism to kidney and lung problems, seem to stem from mutations in two genes, TSC1 and TSC2, that scientists discovered during the 1990s. But it wasn’t until years later that researchers unraveled the process through which tuberin and hamartin—the proteins synthesized by TSC1 and TSC2, respectively—cause the runaway cell growth that gives rise to TSC tubers and tumors.
When they work properly, tuberin and hamartin team up to provide an essential cell function. “A cell makes decisions through signaling pathways, a logical network of proteins that bind to other proteins to send the cell instructions to grow, divide or die,” says Lewis C. Cantley, professor of systems biology at Beth Israel Deaconess Medical Center in Boston. The job of tuberin and hamartin is to act as a brake when a cell is in trouble—if, for example, it’s running out of nutrients or oxygen. “The TSC proteins suspend the growth of the cell, which would die if it kept trying to grow,” Cantley says. “It’s an ancient mechanism—even yeasts have it—and it allows the cell to do everything it can to repair itself.”
In 2002, Cantley was trying to learn how another protein, Akt—which operates in the same cellular pathway as tuberin and hamartin and has been linked to several human cancers—transforms a cell to make it cancerous. When a cell wants to divide and grow, growth factors that bind to the cell’s outer surface activate Akt, which then passes a signal to tuberin and hamartin to suspend their braking function. With those proteins turned off, the growth signal from Akt proceeds along the pathway to turn on another protein, Rheb, which activates still another, mTOR. This final, pivotal protein then signals the cell to take up more nutrients, produce more proteins, and grow and divide.
When either TSC1 or TSC2 is defective, it interferes with the braking mechanism and keeps mTOR switched on all the time, letting cells divide uncontrollably and leading to the development of TSC’s tubers and tumors. The mTOR pathway exists in every cell of the body and serves as a master switch to regulate normal cell growth, development and survival. In the brain, for example, mTOR controls the synthesis of proteins needed to form synapses and strengthen synaptic connections, important in learning and memory. Problems with the pathway also seem to be involved in diabetes, cardiovascular disease, Alzheimer’s disease, cancer and obesity.
But the discovery of mTOR’s role in TSC wasn’t the protein’s first appearance in medical research. Years earlier, researchers had found that it plays a critical role in modulating the function of the immune system, particularly in lymphocytes, a type of white blood cell that attacks viruses, bacteria and other foreign bodies. Lymphocyte function needs to be suppressed in people who’ve had kidney transplants, to prevent lymphocytes from attacking and rejecting the new organs, and it turned out that a drug, rapamycin, developed for immunosuppression, worked by inhibiting mTOR. (The drug came first, and the protein is actually named for it—mTOR is an acronym for mammalian target of rapamycin.)
Because rapamycin can head off the unrestrained cell growth caused by problems with TSC proteins, researchers immediately saw it as a potential therapy, and several clinical trials quickly got under way. The first, begun in 2002 at Cincinnati Children’s Hospital, examined rapamycin’s effect on AMLs and LAM in the kidneys and lungs of 25 TSC patients. The results, published in 2008, showed that kidney tumors shrank significantly during the year of therapy, though most returned to their original size when patients stopped taking the drug. For the 11 trial participants who had LAM, rapamycin improved their lung function, an effect that persisted for some even after the trial ended.