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The transformation
In normal cells, TGF-ß’s “Dr. Jekyll” personality dominates, restricting cell growth, differentiation and cell death. This is key
to keeping normal developmental processes and the body’s repair mechanisms in check.
But sometime during the early stages of cancer, TGF-ß signaling is lost – typically because of a mutation in some component
of the system (e.g., TGF-ß receptors, or the downstream “second messengers” that carry the TGF-ß signal to the cell’s nucleus). These changes coincide with TGF-ß’s transformation into its tumor-promoting alter ego.
“The current dogma is that early in tumor formation and the initiation of cancers, TGF-ß remains tumor suppressive. Then later it changes to Mr. Hyde to promote tumor growth and metastasis,” Moses explains.
The triggers for this personality switch are unclear. But recently, Moses and colleagues found an important role for a type of bone marrow-derived immune cells, called myeloid immune suppressor cells (MISCs), in this switch.
Moses and Vanderbilt-Ingram colleague Li Yang, Ph.D., deleted the gene encoding a TGF-ß receptor in a mouse model of breast cancer, disrupting TGF-ß signaling in the breast cancer cells.
The tumors of these mice contained a significantly higher number of MISCs than tumors from mice with a functional TGF-ß receptor. This increased recruitment of MISCs to the tumor was sparked by the increased production of certain chemokines – signaling chemicals that influence immune cell behavior – by the tumor cells. The studies suggested that TGF-ß signaling normally suppresses important chemokines.
“So if you lose the signaling in cancer cells, the tumor cells produce more chemokines, and this brings in more bone marrow-derived cells, which promotes metastasis,” says Moses. These cells, he suggests, may be “the answer to the TGF-ß paradox.”
Because blocking the interaction between the chemokine and its receptor inhibits the recruitment of MISCs, these immune cells or the chemokine signaling involved might represent useful therapeutic targets for inhibiting metastasis.
Beware of neighbors
The importance of these cells in cancer progression highlights another new research direction for the Moses lab: the tumor microenvironment, or stroma.
The stroma is a supportive meshwork of proteins and polymers and the cells that secrete these components, called fibroblasts. Moses’ lab is now working to understand the interactions between the stroma and tumors.
“We’ve become interested in the tumor microenvironment because TGF-ß signaling is a major regulator of what goes on in the microenvironment of cancer,” he says.
In a mouse model, Moses’ group has shown that disrupting TGF-ß signaling selectively in fibroblasts can initiate carcinomas – cancers that arise from epithelial cells that line body cavities – in the prostate and forestomach (an organ similar to the esophagus
in humans).
“To my knowledge, this is the first demonstration of the development of a carcinoma with the initiating genetic lesion in stromal cells,” Moses says.
The importance of this previously overlooked factor – the biological “stuff” that surrounds the tumor cells – is changing the way cancer researchers think about treating cancer.
“For many decades we have focused on just treating cancer cells, expecting that the host (stromal) cells are just bystanders,” Moses says. “We now know that is not the case, that invasive
cancer is like an organ.”
This “organ” called cancer is not only composed of cancer cells, but the fibroblasts and the bone-marrow derived (immune) cells that help the cancer invade and grow, Moses explained. And TGF-ß appears to have an important role in how this “organ” interacts with its microenvironment.
TGF-ß’s ability to both promote and suppress tumor growth makes this signaling pathway an attractive – but risky – therapeutic target. Inhibiting TGF-ß signaling at the wrong time or in the wrong cells might actually promote the cancer’s spread.
Still plugging away at the complex system, Moses sees the TGF-ß field as full of potential and opportunity. For one, the TGF-ß “superfamily” is incredibly complex, containing nearly 40 ligands, 12 receptors, and dozens of downstream signaling intermediates. Also, the range of biological functions that involve
TGF-ß continues to grow broader.
This complexity has helped keep TGF-ß research going strong for three decades.
“It’s never been easy,” he says. “It’s always been a difficult pathway to study. But when many other areas have received decreased interest and funding, TGF-ß continues to become more and more complicated.”
That leaves a lot of work yet to do. But Moses is undeterred. After stepping down as the Cancer Center’s founding director in 2004, Moses returned with renewed energy to peeling away the layers that conceal TGF-ß’s many identities and functions.
Now focused on understanding how TGF-ß enhances invasion and metastasis, he hopes that the discoveries his team makes will lead to new therapeutic targets for preventing or limiting metastasis.
And while proud of his accomplishments in establishing and leading the Cancer Center, Moses can’t get away from his calling, his inner detective.
“I’ve done a lot in terms of administration, but my real love has always been my research program.” 
Moses is also the Hortense B. Ingram Professor of Molecular Oncology; professor of Cancer Biology; professor of Pathology; and professor of Medicine.
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