The Story of MET
Hijacked by cancer, a critical player in embryo growth and wound healing becomes a driver of metastasis
Arthur Jones’s tumors looked like a straightforward case of kidney cancer.
In the early 1990s, the 68-year-old father of three was referred to the National Cancer Institute for experimental treatment options. His cancer, swelling in both kidneys, was advanced, but it might have gone unstudied if Jones had not noted something unusual about his family. His father, brother, nephew, and two uncles, he reported, all suffered from similar kidney tumors. It was a revelation that would turn Jones from a standard case into patient zero of a never-before-described cancer.
A team of kidney cancer specialists requested permission to survey other members of the Jones family, and fifteen were exhaustively examined at the National Institutes of Health in Bethesda, Maryland. What the research team found was indeed surprising: across three generations, nine of the 15 Joneses exhibited the same peculiar tumors in both kidneys. Geneticists checked the family for chromosome 3 abnormalities, the origin of other known hereditary kidney cancers, but were puzzled to find nothing out of the ordinary.
To rule out environmental factors as the cause of the tumors, the research team had to locate more families with the disorder. By 1995, they reported nine additional families in which 29 men and 12 women exhibited similar tumors. Hereditary papillary renal cell carcinoma (HPRCC), as they called it, was a newly described cancer with a genetic basis.
The cancer remains exceptionally rare. The gene that caused it, however, turned out to be a familiar player to cancer biologists. In 1998, a global group of investigators finally pinpointed the cause of Mr. Jones’ tumors: abnormalities in a gene called MET. The scientists identified a mutation in MET – just a single substitution in the gene’s vast code – that predisposed family members who carried it to the rare variant of kidney cancer.
MET’s association with cancer was first discovered in the mid-1980s, when dramatic strides in the understanding of cancer’s molecular basis had recently cracked open a field frustrated by decades of stagnancy. The realization that changes in human genes – rather than material from viruses or other foreign agents – gave rise to cancerous cells spurred a whirlwind of research. Scientists raced to identify and catalog all the genes that could be linked to human cancers.
George Vande Woude, a Rutgers-trained cancer biologist, arrived at the National Cancer Institute in Frederick, Maryland at the start of this scientific push. Within a year, his research team put forth MET as their own contribution to the growing list of normal genes that could, when damaged, become cancer-causing “oncogenes.”
The name was an apt abbreviation of metastasis, the process by which cancer spreads from its original site to other parts of the body. Damaged versions of MET, as Vande Woude’s team discovered over the subsequent decade, are intimately tied to invasion and metastasis in many cancers.
To understand why, it helps to know what the gene controls in normal, healthy cells. MET is one of an estimated 1,000 protein-encoding genes located on chromosome 7. Like all chromosomes, humans possess two copies of 7 – one from each parent. Abnormal changes in many of the genes on chromosome 7, including MET, have been linked to cancer.
The MET gene provides the genetic script that is used to produce a protein called c-MET, also known as hepatocyte growth factor receptor (HGFR). C-MET’s job is to “turn on” different processes in the cell by adding a phosphate group to other proteins. Each time c-MET tags a specific protein with a phosphate group, the event triggers a cascade of molecular chatter. Protein A receives a message to turn on protein B, which triggers protein B to turn on protein C, and so on, eventually resulting in a change in a cell’s behavior. The flow of this information across the cell is referred to as a signaling pathway.
MET and its protein product c-MET are responsible for activating a crucial array of activities that
are tightly regulated in normal cells. In the womb, c-MET helps cells migrate long distances across growing embryos and stick to the sites where they’ll develop into limbs, organs, and the tongue. You might also thank c-MET the next time you suffer a cut or scrape – in adults, its expression plays an essential role in wound repair and the protection of organs such as the liver and skin, where it regulates the regeneration of new cells. When scientists removed the gene from mice, they found that MET-less embryos died before birth, their livers undersized and their limbs undeveloped.
The MET gene is likewise necessary to human survival. Given its involvement in so many important cellular functions, it comes as little surprise that small changes to the genetic code of MET and the expression of c-MET can have grave consequences.
MET mutations have been linked to a remarkable range of cancers spanning the breadth of the human body, from the brain to the lungs to the colon – places where the protein is not ordinarily present. Yet the relationship between the MET gene and these cancers is rarely as clear as in the case of hereditary papillary renal cell carcinoma. Frenzied c-MET activity appears to be a hallmark of advanced cancers; researchers have described cancer cells and tumors that are “addicted” to c-MET, dependent on excess production of the protein for their growth. But experts are still parsing the difference between cases in which MET plays an active, causal role in the development of cancer and those in which the gene is a suspicious but incidental bystander.
In the meantime, clinical researchers are charging forward with drug development to target c-MET and its signaling pathway. Several means of attack have been identified, the most promising of which include anti-MET antibodies and small molecule c-MET inhibitors. Monoclonal antibodies, engineered in the lab, mimic naturally occurring human antibodies that bind to and neutralize
foreign molecules in the body, such as cancer cells. Small molecule inhibitors work similarly by binding, in this case, to the portion of c-MET that trails outside a cell, thereby blocking the dysfunctional signaling pathway from being activated. If your cancer exhibits a MET mutation, talk to your doctor about whether one of these approaches might be right for you.
Tests of these therapeutic drugs are still in their early stages. Across the globe, however, hundreds of clinical trials targeting malfunctioning c-MET are underway, investigating an extensive matrix of cancer variants and drug combinations. As medicine grows ever more personalized and clinical findings accumulate, scientists step closer to unraveling the complex role of MET in human cancers.