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Mr. Hyde
Moses’ interest in cancer biology was born during his early career at Vanderbilt. A 1962 graduate of the Vanderbilt University School of Medicine, Moses had returned to Vanderbilt in 1968 after a three-year research stint at the National Institutes of Health. But the heavy clinical load at Vanderbilt soon prompted Moses to head to the Mayo Clinic in Rochester, Minn., to concentrate on his true passion – research.
In the early 1980s, Moses was investigating how normal cells could be “transformed” into malignant ones. He was specifically searching for factors that could give cells the ability to grow when suspended in a semi-solid agar (a jelly-like substance used for
growing cells in culture).
While most normal cells will not grow in this environment, “transformed” (malignant) cells will, forming tiny tumor-like cell clusters in the agar. This growth, Moses says, “was and still is the best in vitro correlate of tumorigenicity.”
In 1978, researchers at the National Cancer Institute had isolated and partially purified a factor secreted by cells that had been transformed by a cancer-causing virus. The factor bound epidermal growth factor (EGF) receptors – major cell growth regulators. The factor was dubbed “transforming growth factor,” and suggested to have the ability to turn normal cells malignant.
In 1981, Moses’ lab began striking the first chinks in the factor’s identity, showing that this one factor was actually two – that its ability to bind EGF receptors was separate from its ability to turn normal cells cancerous.
“We were slow getting (the results) out because we were very uncertain about it,” Moses says. “But even so, we were the first group to report on a transforming growth factor that does not bind to the EGF receptor.”
Moses’ close competitors at the NCI – led by Michael Sporn, M.D., and Anita Roberts, Ph.D. – weren’t far behind. In September that same year, the NCI group reported similar results, leading to the differentiation of a separate “TGF-α” (the EGF receptor-
binding activity) from “TGF-ß” (the tumor-promoting activity).
Thus the TGF-ß field was born. And the race to uncover its secrets spawned a career-long friendship and collegial competition between Moses and Roberts. Shortly before Roberts died in 2006, she and Moses completed a history of the TGF-ß field – a culmination of the work to which they and others have devoted
their careers.
The early years were productive. Moses’ lab found TGF-ß activity in mouse embryos (an indication of its crucial role in development), and identified receptors through which TGF-ß acts to regulate cell growth and division. Moses also identified an easily accessible and abundant source of the protein in blood platelets, those tiny cells that help blood clot. Platelets, Moses noted, are now the source of much of the TGF-ß on the world market.
Dr. Jekyll
But soon, Moses noticed something unexpected from a supposed tumor-promoting factor. The TGF-ß they had isolated from platelets seemed to be inhibiting the growth and multiplication of certain types of cells in culture.
This unanticipated inhibitory activity was creating confusion in the Roberts lab too. They had also been noticing a growth deficiency in some cancer cells treated with TGF-ß, but assumed that the decreased cell growth was due to impurities in the TGF-ß preparation.
In the spring of 1984, Moses presented his results on this growth inhibition at a national meeting, and Roberts listened as
he presented his data.
“I felt the blood drain from my body, because we were very competitive in those days,” she said in a 2004 video interview.
She hurried out of the auditorium to phone the lab. “I said ‘our experiments aren’t wrong, it’s growth inhibition!” she relayed to
her colleagues back at the NCI.
“So we had found – sort of serendipitously – that it would inhibit growth,” Moses recalled. “It’s the sort of moment you live for. Science can be very frustrating. You can go for months with a lot of frustration and no reward. But a moment like that will carry you for a few years.”
Moses returned to Vanderbilt in 1985. And in 1993, with the new influx of support from the T. J. Martell Foundation, he and his Vanderbilt colleagues were able to create the animal models they needed to study TGF-ß’s in vivo roles.
“(Martell’s) support was critical for us to be able to do the mouse models,” Moses says. His lab was able to create mice with TGF-ß expression altered only in specific sets of cells – a crucial technique for defining the protein’s biological functions.
In one study, his group overexpressed TGF-ß in the mammary glands of mice, showing that this amped-up TGF-ß activity could slow development of mammary tumors.
After years of research showing TGF-ß’s growth inhibitory role in cultured cells, this work provided some of the first solid
evidence of TGF-ß’s tumor-suppressing ability in animals.
These animal studies, “contributed to a large body of data indicating that TGF-ß signaling is tumor suppressive,” Moses says. “It’s likely from what we know now that it is one of the major tumor suppressor pathways.”
Mounting evidence of mutations in TGF-ß, its receptors, and its extended family of signaling molecules suggests that errors in the TGF-ß “superfamily” might be an instigating factor for various cancer types – including colon, breast and pancreatic cancers.
“In fact, for normal cells to become cancer cells, there has to be an impairment of this signaling pathway,” Moses says.
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