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Bissell and her colleagues were undeterred. The group, now part of the NCI TMEN, pursued its interest in how tissue context contributes to tumorigenesis.
Focusing on the mammary gland as an experimental system, Bissell and colleagues developed a three-dimensional cell culture model. In this culture system, normal breast epithelial cells form growth-arrested multi-cellular structures that resemble mammary
lobules in vivo, but breast carcinoma cells fail to "mature" into such structures and instead continuously grow in a disorganized fashion.
Blocking a single cell surface molecule, an integrin, on the surface of the tumor cells caused these cells to undergo a "striking morphological reversion," Bissell wrote, "becoming visually indistinguishable from the acinus-like structures formed by the nonmalignant cells." The findings, published in 1997, made other investigators take notice.
"For a lot of us, that was a very dramatic demonstration that you can override the genetics with the microenvironment," Matrisian says.
Matrisian was no stranger to thinking about the tumor microenvironment. Her own laboratory was exploring the roles of enzymes called matrix metalloproteinases (MMPs), molecular "scissors" that cut up proteins in the extracellular matrix. MMPs are now known to be present at high levels in tumors and inflammation, but not in
normal tissues, and to participate throughout the processes of tumor progression, from initiation to metastasis.
At the request of the NCI's Tumor Biology and Metastasis Branch, Matrisian co-organized a 2001 workshop on epithelial-stromal interactions and tumor progression. More than 90 percent of human cancers – the "carcinomas" – originate in epithelial cells. The 2001 meeting was the first of a series of workshops and then NCI-sponsored think-tanks from which a common theme emerged, recalls NCI's Mohla. "We kept coming back to the idea that if we knew more about the stromal cells, we would benefit more."
From the recommendations of the small group meetings, the division of Cancer Biology developed the concept of the Tumor Microenvironment Network. Matrisian is the principal investigator for Vanderbilt's program, called the VUTMEN. The overall network has broad goals, Mohla says, that emphasize understanding the host characteristics in normal tissues and studying human cancers.
Cancer's bad influence
The tumor microenvironment is awash in "conversations" between tumor cells and the cells that surround them. Cancer cells produce a variety of growth factors that "activate" the stroma to secrete additional growth factors and proteases, promote the growth of new blood vessels (angiogenesis), and induce an inflammatory-like response. These changes make the stroma supportive of cancer progression. Tumor cells also produce enzymes including MMPs that contribute to a pro-migratory, pro-invasive microenvironment.
The activating effects of the tumor on surrounding fibroblasts were first demonstrated by Gerald Cunha, Ph.D., and colleagues at the University of California, San Francisco. Cunha's group, including Simon Hayward, Ph.D., now associate professor of Urologic Surgery and Cancer Biology at Vanderbilt and one of the VUTMEN project leaders, developed an in vivo "recombination model" to study interactions between human prostate epithelial cells and fibroblasts. In short, they combined the two types of cells, mixed them together with collagen – a structural Jello-like substance – and put the mixture under the kidney capsule in mice, an environment whose ample blood supply is able to support cell growth.
Combining normal prostate fibroblasts with normal or "immortalized" (able to grow continuously in culture) prostate epithelial cells did not generate cancer. But combining fibroblasts from prostate
cancer – "carcinoma-associated fibroblasts" – with the immortalized epithelial cells generated malignant tumors. The studies showed that cancer changed the fibroblasts and made them capable of promoting tumorigenesis of nonmalignant cells, Hayward explains.
How do the fibroblasts promote tumorigenesis? What are the molecules that convey this particular message? Hayward and Neil Bhowmick, Ph.D., assistant professor of Urologic Surgery and Cancer Biology, are using the prostate tissue recombination model to probe these questions in one of the VUTMEN projects.
"We have the tools now to put specific genes into a tissue, or inhibit specific genes in a tissue, so we can really mix and match and see the effects of those manipulations," Hayward says. "Ultimately we're looking for the really key molecular pathways that are involved in the stroma acting to promote tumor progression, and which ones of those need to be taken out to prevent that progression."
In the case of prostate cancer, specifically, knowing the pathways that push progression will open up possibilities for moving the window of "active surveillance," Hayward says, so that the patient's cancer doesn't progress in his lifetime.
"Obviously we want to identify the disease early on and stop it progressing any further," Hayward says, "and if we have to intervene, we need to know the critical timepoint markers for intervention."
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