Circuits of IGF-1R and Niche Signaling (Hypoxia/Inflammation) in Stem Cell Transformation and Its Clinical Implication of Molecular Target Therapy (Model of Germline Stem Cells)

Recent advances in cancer research demonstrate that stem cells-like ability in cancer cells contributes the proliferation and various differentiated cell types in tumors. These cancer stem cells (CSCs) may be refractory to current therapies. Thus, the therapeutic targeting on the CSCs would provide the most promising strategies for curing the cancer diseases. Recently, CSCs have been hypothesized to be originated from its stem cells, such as glioma and intestinal CSCs. However, little understanding of the possible transformation signaling leads to a poor therapeutic targeting in cancer treatment. The serum-containing culture system generally used in stem cells maintenance in vitro may dramatically hinder the finding of potential regulation signaling. In this aspect, we have recently established a serum-free testicular co-culture system to generate pluripotent mouse germline stem cells in vitro. By utilizing such an ex-vivo-like cell platform, we uncovered the role of IGF-1R signaling in maintenance of the pluripotent ability of germline stem cells. Further studies by examining the human pluripotent germ cell tumors, e.g. seminomas and embryonal carcinomas, we interestingly found the high expression of IGF-1/IGF-1R/phospho-IGF-1R (pluripotency regulator), HIF-1/HIF-2(hypoxia), and MCP-1/CD68 (inflammatory) in tissues. These observations strongly suggested an important role of niche stress in transformation of stem cell into CSCs. As the stem cells and their related tumors are often tightly affected by their niche environments, we hypothesized a cross-talking of IGF-1R signaling with the niche stress, e.g. hypoxia and inflammation, may drive the transformation of germline stem cells into CSCs. The finding in this proposal would provide a knowledgeable research values as well as the potential clinical molecular therapeutic targets in cancer diseases. Three specific aims were addressed as listed: Aim 1: To characterize the effect of niche stress, e.g. hypoxia and inflammation, on tumorigenic transformation of pluripotent germline stem cells into CSCs Aim 2: To characterize the circuits of IGF-1R signaling and hypoxia/inflammation in transformation of mouse germline stem cells into CSCs Aim 3: To characterize the clinical impacts of niche factors (hypoxia and inflammation) and IGF-1R signaling on human pluripotent testicular tumors (using human NCCIT and NT2 cell model and primary seminomas cells) (human model)