Analysis of Angiogenic Pathways in Metastatic Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Tumor size is limited in the early stages of breast cancer because, unlike normal tissues, there is no blood supply. In order to grow beyond 1-2 mm in size, tumor cells stimulate the development of blood vessels that infiltrate the tumor, in a process called angiogenesis. This provides the tumor with a nutrient source, and the means by which metastatic tumor cells enter the circulation and invade the rest of the body. Data from animal models shows that inhibition of angiogenesis can significantly reduce the growth and spread of breast cancer. The blood vessels that infiltrate the tumor are comprised of normal endothelial cells. These cells make an attractive target for therapeutics, since they have not undergone the malignant genetic changes characteristic of breast cancer and are less likely to develop drug resistance. In order to identify therapeutic targets at the molecular level, we must understand the differences between the tumor and the normal vasculature in the rest of the body.
 
 
 
 
 
 
 
 During angiogenesis, endothelial cells display many changes compared with the inactive endothelial cells of established vessels, which can potentially be targeted for anti-angiogenic therapy. It is desirable, however, to target tumor angiogenesis without disrupting angiogenesis that occurs in normal tissues. We propose that tumor angiogenesis may be different to normal angiogenesis, and characterizing such differences at the molecular level could provide new targets for developing anti-angiogenic treatments. Another aspect of angiogenesis that has not been examined is that of possible differences between the blood supply to the primary tumor in the breast and at different metastatic sites, such as the lung, liver, and bone. It is important that treatment be appropriate for the distant metastatic sites, as these cannot be surgically removed and are the source of failure in current chemotherapy approaches. If tumor angiogenesis is different in each host organ, then we may require a panel of drugs for anti-angiogenic therapy.
 
 
 
 
 
 
 
 The experimental approach in this project is to use "gene chips" to compare the complex gene expression profiles of angiogenic endothelial cells in normal tissues, breast tumors and breast cancer metastases from different organs. We will model metastatic breast cancer by transplanting human breast cancer cells into mouse mammary tissue, where they grow into a tumor that metastasizes to multiple organs. After removing the tumors from each organ, we will microdissect endothelial cells from tumor blood vessels, and subject them to gene chip analysis. Gene chips provide a simultaneous read-out of thousands of genes, and indicate which genes are expressed in greater or lesser abundance in a given cell or tissue. The aim is to compare the unique "molecular fingerprint" of angiogenic endothelial cells from tumors at each organ site. Our goal is to identify differences in the molecular fingerprints of endothelial cells involved in angiogenesis in tumors compared with normal tissues, and between secondary tumors associated with different organs. Obtaining the "angiogenic signature" for each type of breast tumor will potentially lead to the development of more effective strategies for blocking tumor angiogenesis.