Genetic Dissection of the Role of Heparan Sulfate in Mammary Tumor Progression

摘要

There is accumulating evidence that heparan sulfate (HS) controls various growth factor signaling events. There is also evidence that cellular HS production itself exerts strong influences on tumorigenesis, exemplified by the fact that mutations of Ext1, the gene encoding an HS synthesizing enzyme, cause multiple bone tumors. Furthermore, the level of HS degrading activity correlates with the aggressiveness of the tumor. Despite these longstanding observations, much less is known about the mechanisms by which HS influences the malignant behavior of tumors in vivo. Also important is the fact that HS is produced not only by tumor cells themselves but also by stromal cells that constitute the tumor microenvironment. This project will address these key issues by using genetic mouse models. The second year of this project was dedicated to conduct tumorigenesis studies that form the core of the project. Preliminary results suggest that HS indeed affects the progression of mammary tumors. We will continue these experiments during the third year to obtain statistically significant survival data. Analysis of tumors formed in these mice will shed light on the molecular mechanisms by which HS regulates mammary tumor progression.