HOUSTON—Colon cancer researchers are studying a variety of cell surface molecules and receptors as potential targets for new treatments aimed particularly at preventing or treating metastatic disease. Lee Ellis, MD, professor of surgery and cancer biology at the University of Texas M. D. Anderson Cancer Center in Houston, discussed his group’s current work in three new areas: angiopoietins as a target for blocking tumor angiogenesis, integrins, and the insulin growth factor-1 (IGF-1) system.
Tie-2 is a tyrosine kinase receptor expressed almost exclusively on endothelial cells. Dr. Ellis said that angiopoietins 1 and 2, which bind to the Tie-2 receptor, are expressed differently in normal vs cancerous tissues and may represent a useful target for treating tumor metastases.
"In vitro studies show that angiopoietin-1 (Ang-1) is an agonist. It binds to Tie-2 and initiates signaling to stabilize endothelial cells. Angiopoietin-2 (Ang-2) binds to Tie-2 with equal affinity but induces no intracellular signaling. It is thought to be an antagonist to Ang-1. It destabilizes endothelial cells, which is necessary for the initiation of angiogenesis. Ang-2 allows the endothelial cell to separate from the basement membrane, which then releases it to respond to proliferative factors such as vascular endothelial growth factor (VEGF)," Dr. Ellis said.
Maintaining Balance
When the M. D. Anderson researchers examined more than 20 human primary colon cancer samples and 5 human liver metastases, they found that tumor tissue did not express Ang-1 but did express high levels of Ang-2. Normal mucosa expressed both Ang-1 and Ang-2. "The balance seems to be what is important, as is usual in maintaining homeostasis," Dr. Ellis said.
Ang-1 and Ang-2 are made both in blood vessel tissue and outside of blood vessels. Colonocytes in nonmalignant epithelium expressed both Ang-1 and Ang-2. Malignant colonocytes expressed only Ang-2.
Dr. Ellis’s group created an in-vivo model of this situation by transfecting Ang-1 or Ang-2 into human colon cancer cell lines. Overexpression of Ang-2 greatly increased tumor growth. Overexpression of Ang-1 produced relative tumor dormancy. Ang-1 overexpression also decreased vessel counts, while Ang-2 expression increased vessel counts.
