Breast Cancer Tumor-Stroma Interactions in an In Vivo Model
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: A breast cancer tumor is not only composed of tumor cells. There are many other types of cells such as fibroblasts, endothelial cells, and immune cells with which tumor cells intimately interact. Thus, a “tumor” can sometimes contain a majority of normal tissues. It is becoming increasingly clear that these normal cells within and around a tumor are not merely passive bystanders, but rather play an active role in controlling the microenvironment in which the tumor grows. This is true for both the primary tumor and secondary tumors that result from metastatic spread. Breast cancer spreads preferentially to liver, lung, brain, and bone. What is it about these tissues that invite metastatic breast cancer? Unfortunately, the study of the mechanisms governing tissue preference are not very well understood, and to a large extent, this is because it is impossible to “catch metastasis in the act” especially in humans, but even in experimental models. We have devised a method in which we can “seed” cancer cells on various tissues (e.g., “soil”) implanted behind a glass window in a skin-fold of live mice. With this tool, called intravital microscopy (IVM), we can actually watch a tumor develop. For example, when we grow a breast tumor on lung tissue, this is similar to metastasis of breast cancer to the lung. We can actually watch the development of various defining characteristics of the tumor and “catch” it at different stages for thorough molecular analysis.
 
 
 
 
 
 
 
 In this project we will perform microarray (gene expression) analysis of tumor and stroma grown in the IVM model. By using stroma from different tissues, we expect to identify specific genes and gene networks that are differentially induced by the different stroma, possibly revealing differences in the stroma that explain the ability of breast cancer to metastasize to different organs. Next, cells of the immune system, such as macrophages and fibrocytes, undergo epigenetic alterations as they adapt over time to the tumor environment. Using our IVM method we will perform gene expression analysis on cells of the immune system that infiltrate the tumor. By studying gene expression in immune system cells over the time course of tumor development, we expect to be able to identify the major adaptation pathways. Finally, we will use a bioinformatics approach to identify human genes that are homologous to the mouse genes identified in our IVM studies, and explore their expression in human breast cancer tumors.
 
 
 
 
 
 
 
 Direct routes to therapeutic intervention are of immediate importance. However, our understanding of stroma-tumor interaction is in its infancy, and the proposed experiments cannot fail but to expand our knowledge in this potentially clinically important area. We expect some of the genes we discover to explain the propensity of breast cancer to metastasize to some organs more quickly than to others. As such, they serve as potential targets to control breast cancer metastasis.