Oct. 5, 1999 UC San Francisco researchers have identified a new variable in the process that causes cells to become cancerous, and the finding, described as "very exciting" by one of the senior authors, could ultimately provide a new marker for cancer diagnosis and prognosis, and a new target for therapy.
The discovery centers on fibroblasts, cells that help form the supportive base surrounding epithelial cells - which line the glands, ducts and surfaces of organs, such as the breast, colon and stomach, and are the cells from which most cancers arise.
Using cells derived from human prostates, the researchers discovered that epithelial cells that are "initiated", or mid way down the genetically destabilizing road towards cancer, engage in a molecular dialogue with surrounding fibroblasts that is critical to their development into full-fledged cancer.
When the fibroblasts, so-called carcinoma-associated fibroblasts (CAFs) -- which look the same as normal fibroblasts, but are not -- were grown next to "initiated" human prostate epithelial cells, they "dramatically stimulated the progression" of the cells toward a cancerous state.
But when CAFs were absent, the "initiated" prostate epithelial cells, which have acquired some, but not all, of the genetic mutations that undermine a cell's regulatory control, did not progress further toward cancer.
"The finding represents an important new insight into the complex process by which a cell becomes cancerous", said one of the senior authors of the study, Gerald R. Cunha, PhD, UCSF professor of urology and anatomy and a member of the UCSF Cancer Center. "We consider this finding an important first step in a new field of cancer research."
Cunha made the seminal observations on the phenomenon.
"Our data indicates that the multi-step progression of cancer development involves genetic alterations in the epithelium as well as contributions from the surrounding supportive tissue, which includes fibroblasts," said the other senior author of the study, Thea D. Tlsty, PhD, UCSF professor of pathology and a member of the UCSF Cancer Center. "Both components are necessary for this process -- neither component alone is sufficient to induce tumor progression."
The human prostate epithelial cells were examined in mice and cell culture.
While the study focused on prostate cells, the finding should apply to the broad range of cancers that arise in epithelial cells, including those of the breast, stomach and colon, said co-author Simon W. Hayward, PhD, UCSF assistant adjunct professor of urology and anatomy and a member of the UCSF Cancer Center. "This finding is fundamental to cancer processes in general. It potentially opens a whole new field for cancer diagnosis, prognosis and treatment."
The finding is reported in the Oct. 1 issue of Cancer Research.
Scientists have long known that epithelial cells and fibroblasts exchange molecular signals that are critical for tissue formation during embryonic development, wound healing and numerous other physiological functions.
And more recently, researchers (including Mina Bissell, of Lawrence Berkeley Laboratory) have detected hints of changes in the biochemical behavior of fibroblasts found near "initiated" epithelial cells. But scientists have not known what role, if any, these so-called carcinoma-associated fibroblasts play in the development or progression of epithelial cells into cancerous cells.
In the UCSF study, the researchers teased out the functional role of CAFs. When normal fibroblasts were placed next to initiated prostate epithelial cells in cell culture or in mice with tissue grafts, there was no impact on the epithelial cells. When CAFs were placed next to normal prostate cells, there was an indication of abnormal signaling, as the epithelial cells began to replicate in a disregulated manner, but the impact was not sufficient to stimulate tumor formation.
But when CAFs were grown next to initiated prostate epithelial cells, the epithelial cells made a "dramatic" progression in the process towards cancer, the researchers reported, as measured by excessive epithelial cell proliferation, lack of normally programmed cell death, the structure of the tissue and acquisition of the ability to invade other tissues.
"Grafts of CAFS and the initiated prostate epithelial cells formed tumors in mice," said co-author Hayward.
The finding suggests that CAFs play a crucial role in stimulating an already initiated epithelial cell towards a full-blown cancerous state.
Discovering the signals that underlie the CAF-epithelial cell interaction could enable researchers to develop a drug that would interrupt the molecular dialogue, said co-author Gary D. Grossfeld, MD, UCSF assistant professor of urology and a member of the UCSF Cancer Center.
Moreover, while the researchers don't know when fibroblasts are converted to CAFs, nor what prompts their conversion (though they suspect the directive comes from signals issued by the initiated epithelial cells), discovering CAFs in human tissue could prove an effective marker for the diagnosis and prognosis of cancers.
Research may show that people with hereditary cancer are born with abnormal fibroblasts, in which case these abnormal cells could serve as a marker for diagnosing cancer, said co-author Aria F. Olumi, MD, UCSF, a former UCSF urologic fellow. Alternatively, the development of CAFs could prove to be a marker for a certain stage in the progression of a cell toward cancer, or the degree of a particular cancer's deadliness.
The technique used to examine the interaction between epithelial and fibroblast cells was developed by senior author Cunha during two decades of study.
The close interaction of basic scientists and clinicians in this study exemplifies the collaborations taking place in the recently established UCSF Cancer Center, which is organized by tissue site, the researchers said.
The other co-author of the study was Peter R. Carroll, MD, UCSF professor and chairman of the Department of Urology and member of the UCSF Cancer Center.
The UCSF study was funded by CAPCure, the American Foundation of Urologic Diseases, Pfizer Pharmaceuticals Groups and the National Institutes of Health.
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