The process of new blood vessel formation, or angiogenesis, is regulated by a balance between pro-angiogenic and anti-angiogenic factors. Tumor cells interact with their host environment (e.g. soft tissue, lung, liver) and must create a positive angiogenic balance in order to promote the ingrowth of new blood vessels. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two of the most important pro-angiogenic factors for tumor growth, yet expression of these factors can be quite variable in tumors growing in different sites. For example, human colon carcinoma cells growing in the liver express less VEGF than the same cells growing in subcutaneous tissue. In addition, renal carcinoma cells implanted under the renal capsule of mice demonstrate a 10-20 fold higher level of basic fibroblast growth factor (bFGF) than when implanted into subcutaneous tissue.

Our laboratory is currently investigating whether the primary angiogenic factors driving tumor angiogenesis for soft tissue sarcomas vary according to the site in which the tumor or metastasis is growing. Soft tissue sarcomas represent a model cancer to study angiogenesis in different organ environments as well as the possible variable effects of anti-angiogenic therapies. These tumors arise from tissues usually of mesenchymal origin throughout the body and metastasize most frequently to the lung and liver. Corresponding mouse models of soft tissue sarcoma growth in primary and metastatic locations have been well characterized. After collecting some interesting preliminary data, our laboratory has received a National Cancer Institute K12 grant to investigate tumor angiogenesis in different organ environments with three specific aims:

• To characterize human soft tissue sarcoma angiogenesis in different host organ environments by analyzing circulating levels of angiogenic factors in soft tissue sarcoma patients and by analyzing DNA microarrays of soft tissue sarcomas.
• To characterize the effect of VEGF and bFGF inhibition in mouse models of soft tissue sarcomas in different host organ environments.
• To develop clinical trials of anti-angiogenic agents for soft tissue sarcomas.
  

We are also investigating angiogenesis in colorectal cancer metastases to the liver and lung.   Our recently completed clinical trial of patients with colorectal cancer liver metastases demonstrated that these patients had widely elevated levels of circulating angiogenic factors including VEGF, bFGF, hepatocyte growth factor (HGF), and epidermal growth factor (EGF).  Levels of these factors were able to predict the risk of recurrence following surgical resection of these liver metastases.  Currently, we are examining the efficacy of endogenous anti-angiogenic proteins (thrombospondin 1, tumstatin, and endostatin) in inhibiting the growth of colorectal cancer metastases in the liver and lung.  Investigations in mouse models of liver and lung metastases have shown significant differences in the efficacy of these anti-angiogenic proteins in inhibiting metastatic tumor growth based on the site of metastasis.  These findings may have implications on the use of these agents in clinical trials of patients with metastatic colorectal cancer.

Sam S. Yoon, MD
2006