Perlecan regulation of sonic hedgehog signaling: from drosophila to humans

Abstract

Prostate cancer is the second leading cause of death from cancer in men in the United States. Most men will die of the advanced, metastatic form of the disease. Thus, treatment strategies targeting the metastatic form of the disease are especially needed. Emerging research on metastatic cancer highlights the importance of the microenvironment in cancer progression and metastasis, with an emphasis on deregulated developmental signaling in cancer progression. Research in model organisms has shown that developmental signaling pathways are regulated by various components of the extracellular matrix, including heparan sulfate proteoglycans. In the model system Drosophila, the heparan sulfate proteoglycan Trol is needed for Hhdependent proliferation in quiescent neural stem cells. In collaboration with others, I have shown that the human homolog of Trol, PERLECAN, regulates SONIC HEDGEHOG-dependent proliferation in advanced prostate cancer by two different mechanisms. This makes PERLECAN a potential drug target and biomarker for prostate cancer screening and treatment. My results also validate the discoveries made in Drosophila in the context of human disease. With this validation, I propose and describe the Drosophila Ejaculatory Bulb (EjB) as model for prostate cancer and prostate aging.