Abstract
Purpose: The molecular, cellular and animal studies have established that overexpressed proline-directed protein kinase FA (PDPK FA) is essential for the development of tumorigenesis, invasion, and metastasis of human cancer cells. However, the role of PDPK FA in tumor microenvironment remains largely unknown and needs to be further established. Our purpose of this thesis was to analyze the association of PDPK FA expression with the modulation of the interaction of tumor and stroma and relation to survival of gastrointestinal (GI) cancer patients. Patients and Methods: PDPK FA expression in the resected tumors of 142 gastric cancer and 43 colorectal cancer patients was analyzed by immunohistochemistry. Expression pattern of highly condensed nuclear PDPK FA exhibited in tumor and stromal cells were used as the major parameter for positive PDPK FA expression. Survival analysis was used to analyze the data. Results: First, we demonstrated that overexpressed nuclear PDPK FA was associated with the downregulation of E-cadherin, and therefore might promote the process of epithelial-mesenchymal transition (EMT). Second, PDPK FA expression with HSPC and/or MSC in tumor-stroma hierarchically associated with equal or more than one hotspot of CD68 macrophages and/or vimentin mesenchymal cells (P<0.001), and therefore had co-evolution with mesenchymal tumor cells through OPN (P<0.001), IL-6 (P<0.001), TGF-β1, VEGF, and TF networks. Under this circumstance, GI cancer patients who had tumor-stroma co-evolution of PDPK FA tend to be poor outcome (P<0.001). Conclusion: In consistence with its multisubstrate/multifunctional PDPK nature essential for the development of highly malignant phenotypes, the present human study indicates that PDPK FA is a new signal transducing molecule for prediction of GI cancer patient outcome. Furthermore, it elucidates the probable mechanism that PDPK FA has the role in tumor-stroma interaction. Together with the previous molecular, cellular, animal, and clinical studies, this thesis establishes PDPK FA as a new and common promising target for the strategic development of reliable and accessible therapeutic modalities for more efficacious treatment in GI cancer.