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October 30, 2006
Winship Cancer Institute study looks at tumor-suppressor gene

by vincent dollard

Researchers at Emory Winship Cancer Institute have conducted the first comprehensive study of the role an important tumor-suppressor gene plays in cancer development.

The gene, p53, is known as a major tumor suppressor. Research has shown that it has frequently mutated in human cancer.

In this study, researchers identified secreted proteins from tumor cells in response to p53. The findings suggest p53 plays a role in the control of the tumor cell’s ability to communicate with the normal cells surrounding it. The results of the study, “Proteomic identification of the p53-regulated tumor cell secretome,” appeared in the Oct. 9 online edition of Oncogene, a leading cancer research journal.

“Cancer formation is traditionally thought of as a cell-autonomous process driven by mutations in genes that increase cell proliferation and survival, where a tumor is composed primarily of transformed cells,” said Erwin Van Meir, professor of neurosurgery and hematology/oncology and lead author of the study. “But increasing evidence suggests that the tumor microenvironment also contributes to [cancer] and that tumor-stroma—a tumor’s surrounding tissue—interactions play a major role in tumor development, maintenance and progression.

“A tumor is more like a casserole of chili than a bowl of white rice, where all the components in the mix interact.” he added, “We need to better understand these tumor-stroma interactions to develop more effective cancer therapies.”

Little is know about cell transformation and how transformation affects cell interactions. The researchers examined cell transformation and how transformation affects a cell’s secreted proteins, which then communicate with other cells.

Focusing on p53 was a natural starting point as p53 directly controls the synthesis of numerous proteins. The gene is best known for its role in maintaining genomic integrity and cell survival in response to DNA damage. Yet some studies suggest that p53 could influence a tumor’s microenvironment by suppressing the growth of new blood vessels from pre-existing vessels as well as the spreading of the tumor.

To identify p53-regulated secreted proteins, the researchers used a cell line derived from a malignant human tumor. The researchers found a total of 111 secreted proteins, 39 that showed enhanced secretion and 21 that showed inhibited secretion in response to p53 expression. None of the proteins, however, were found to be transcriptional targets, which suggests that p53 may have an indirect role in intracellular protein trafficking and secreted-protein stability, Van Meir said. “These secreted targets will be helpful in better understanding how p53 may modulate interactions of tumor cells with their environment and establishes p53 loss in tumors as a major trigger of changes in tumor-stroma interactions. A better understanding of these phenomena will improve our ability to devise new therapies for cancer.”

The study was funded by the American Brain Tumor Association, the Pediatric Brain Tumor Foundation of the United States, the National Institutes of Health and the National Science Foundation. The team of researchers included Winship Cancer Institute and Emory School of Medicine’s Van Meir, Fatima Khwaja, Paul Svoboda, Matthew Reed, Jan Pohl and Beata Pyrzynska.

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