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Focusing on a key growth factor
The VUTMEN has as its unifying theme a focus on transforming growth factor-beta (TGF-beta), a protein that is near and dear to its co-discoverer, Harold Moses, M.D., the Hortense B. Ingram Professor of Molecular Oncology and director emeritus of the Vanderbilt-Ingram Cancer Center.
TGF-beta is a "molecular Jekyll and Hyde" in cancer, Moses says; it can both suppress and promote cancer growth. It functions in normal cells as a tumor suppressor, and its loss is critical to tumorigenesis.
"If you look at the whole signaling pathway, most cancers have some aberration in one of the molecules necessary for TGF-beta growth inhibition," says Moses, who is leading another of the
VUTMEN projects.
Once a carcinoma is present, TGF-beta switches personalities and promotes cancer progression. TGF-beta levels go up in the tumor microenvironment, and it acts to inhibit immune surveillance – mechanisms that fight against the cancer – and to promote the angiogenesis necessary to build tumor blood supply lines.
In their quest to understand the complex nature of TGF-beta
signaling in the tumor microenvironment, Moses and colleagues including Bhowmick generated mouse models in which the TGF-beta receptor (type 2) was eliminated only in certain types of cells. When they eliminated the receptor in fibroblasts, the mice developed prostate and forestomach cancers and died by eight weeks of age.
"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 findings suggested that TGF-beta normally acts in the stromal cells to suppress the development of cancer in the neighboring epithelial cells. So, not only can the microenvironment put pressure on existing cancer cells to "behave," it can directly contribute to tumor initiation.
Moses' VUTMEN team will extend their studies of the tissue-specific TGF-beta receptor knockouts – they are generating mice in which they can eliminate the receptor in an acute way, rather than from the beginning of its expression during development. The group also will explore TGF-beta signaling using breast tissue recombination models.
To probe the "conundrum" that both blocking and enhancing TGF-beta signaling promote cancer progression, Moses and colleagues are studying bone marrow-derived cells they call Myeloid Immune Suppressor Cells (MISCs). The investigators propose that blocking TGF-beta signaling enhances the expression of chemokines – signaling factors that influence immune system cells – which then recruit MISCs to the tumor. The MISCs, in turn, pump out more TGF-beta, other tumor-promoting factors, and MMPs to remodel the extracellular matrix.
"I'm pretty convinced that in many model systems, in many human cancers, the immature bone marrow-derived cells play a key role," Moses says. "So if we can figure out which chemokines and which chemokine receptors are involved in recruiting those cells ... those molecules might offer good targets."
TGF-beta signaling is also a target of interest for cancer therapy, and small molecule inhibitors are already in clinical trials, Moses says, adding that caution is warranted given that inhibition of TGF-beta signaling in the stroma can promote carcinoma development.
The vicious cycle in bone
Another VUTMEN project, led by Gregory Mundy, M.D., will focus on a third microenvironment: bone. Both breast cancer – Moses' focus – and prostate cancer – Hayward's focus – metastasize preferentially to bone.
"When patients with breast or prostate cancer die, it's most often because the cancer has spread to bone, and in fact the bulk of the tumor burden is likely to be in bone," says Mundy, Oates Professor of Medicine and Pharmacology and director of the Vanderbilt Center for Bone Biology.
Bone offers fertile "soil" for breast and prostate cancer metastases, and Mundy and colleagues propose that TGF-beta is one key nutrient.
TGF-beta is stored in the bone matrix and released in its activated form when bone tissue turns over. It is likely important in normal bone remodeling and normal injury repair, Mundy says.
When tumor cells metastasize to bone, Mundy's group proposes that a "vicious cycle" begins to spin: the tumor cells stimulate bone resorption (bone-dissolving activity of osteoclast cells), active TGF-beta is released, and tumor cells behave aggressively to promote
bone resorption.
The investigators are teasing apart the mechanisms by which TGF-beta causes this aggressive tumor cell behavior. In one model, they inject human breast cancer cells into the heart of immunodeficient mice, which develop bone metastases. The investigators examine those metastases – the tumor burden and the bone lesions, taking advantage of small animal imaging technologies available through
the Vanderbilt University Institute of Imaging Science.
"When we follow these tumors, we're always looking at the effects on bone in parallel with the effects on the tumor," Mundy says. "That's going to be really important for patients, because if we can block this vicious cycle, we'll have effects not only on reducing the bone lesions, but also on relieving tumor burden.
"I think we're really just beginning to scratch the surface of understanding how important the microenvironment is in terms of how tumors behave." 
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