Extracellular Proliferating Cell Nuclear Antigen as a Marker and Therapeutic Target for Cancer Stem Cells.
Cancer is the second leading cause of death in the United States, making it a major public health issue. Due to increased efficiency in detecting and treating cancer, primary tumors account for only 10% of cancer mortalities. Today, the majority of cancer related deaths are due to metastasis and relapse after therapy, which current cancer treatments fail to prevent. Recently, cancer stem cells (CSCs) have emerged as being responsible for metastasis and relapse. CSCs are cancerous cells with stem cell characteristics including self renewal and the ability to evade chemotherapy and elimination by the immune system. A part of the innate immune system, Natural Killer (NK) cells provide the first line of defense against cancerous cells. NK cells kill cancerous cells through release of cytotoxic granules, a process regulated by activating and inhibitory receptors at the NK cell surface recognizing specific surface molecules on a tumor. Of the NK cell receptors, signaling via NKp44 is pivotal in determining the fate of tumor cells because it possesses both activating and inhibitory functions and is only expressed on activated NK cells. In this study, expression of Proliferating Cell Nuclear Antigen (PCNA), an inhibitory ligand of NKp44, is identified on the surface of a Diffuse B Cell Lymphoma, Prostate, and Breast cancer cell lines in novel association with Human Leukocyte Antigen Class I molecules. By blocking interactions between NKp44 and the PCNA/HLA I complex, NK cell mediated cytotoxicity and IFN-γ secretion is enhanced. Finally, prostate and breast cancer cells expressing PCNA at the cell surface express several molecular signatures of cancer stem cells which increase the ability of these cells to survive the metastatic process.