The Fas Mechanism As A Novel Target To Treat Lung Metastases Using Metastatic Osteosarcoma Model
Koshkina, Nadezhda V., PhD
Assistant Professor
Div. Surgical Oncology
UT MD Anderson Cancer Center
1515 Holcombe Blvd.,
Houston, TX 77030
USA
Abstract:
Lung cancer and lung metastases are the leading courses of cancer-related deaths and have poor response to therapy. The goal of our studies is to understand mechanisms that may be used by cancer cells to grow in the pulmonary environment. We used osteosarcoma (OS) as a cancer model due to its exclusive metastatic preference to the lungs. Lungs belong to few organs in the body that constitutively express Fas ligand (FasL) which triggers apoptosis in cells after binding with its receptor on the cell surface. When we examined OS lung metastases form patients and animals we found negative-low levels of Fas-positive cells in tumor lesions. This suggests that Fas-positive tumor cells died in the lungs upon binding with FasL there. Indeed, we showed that manipulations with fas gene expression in OS cells significantly changed their metastatic behavior in vivo. We also noticed that Fas expression in OS lung metastases increased after chemotherapy humans, dogs and mice. This indicated that drugs could stimulate Fas receptor expression in Fas-negative tumor cells, which could then bind with FasL in the lungs and thus kill tumor cells. In fact, when we inhibited downstream Fas signaling in pulmonary metastatic cells, treatment effect was significantly impaired. All these findings indicate on the important role of the Fas mechanism in formation of lung metastases and its contributory role in treatment. Currently, we investigate the agents that can activate Fas expression in tumors. Specifically, we found that HDAC inhibitors can increase Fas receptor expression and potentiate its downstream mechanism in OS cells and inhibit their metastases growth in vivo. To maximize drug delivery to the lungs we use aerosol technology.
