Doctor of Philosophy (PhD)
Michael A. Hollingsworth
As the fourth leading cause of cancer-related deaths, pancreatic cancer is one of the most lethal forms of cancers in the United States. Lymphatic vessel invasion and subsequent metastasis to the lymph nodes are early and significant events observed during pancreatic cancer progression and are used to determine patient prognosis and therapy selection. Although clinicians and researchers recognize the importance of lymph node involvement for patient prognosis and therapy selection, the biological mechanisms that govern lymphatic invasion and metastasis and the contributions of the pancreatic tumor microenvironment to these processes remain poorly understood. In this dissertation, we characterize the interactions of lymphatic endothelial cells with pancreatic tumor cells and pancreatic fibroblasts, showing that while both cell types accelerate lymphangiogenesis, pancreatic fibroblasts are the major recruiters of lymphatic endothelial cells. Additionally, we evaluated pancreatic tumor cell invasion of lymphatics and demonstrated that adhesion protein E-selectin regulates pancreatic tumor adhesion to and transendothelial migration across a lymphatic endothelium. Blockade of E-selectin using a novel glycomimetic inhibitor, GMI-1271, significantly impaired these processes if pancreatic tumor cells expressed the proper E-selectin ligands. E-selectin blockade in vivo significantly impaired pancreatic tumor metastasis to a number of organs sites including the lymph nodes. This impairment of metastasis through the lymphatic vasculature by GMI-1271 was not due to changes in lymphatic vessel density, but rather tumor cell interactions with the lymphatic endothelium.
Chemokine receptor CXCR4 and its ligand CXCL12 have also been implicated in facilitating pancreatic tumor progression and metastasis. Using a novel small molecule inhibitor of both CXCR4 and E-selectin, we demonstrated that CXCR4 blockade significantly impairs pancreatic tumor cell adhesion and transendothelial migration across a lymphatic endothelium independent of tumor cell expression of E-selectin ligands. In vivo blockade of both CXCR4 and E-selectin moderately impaired pancreatic tumor metastasis. However, this inhibition of metastasis through GMI-1359 administration did not prolong animal survival even when administered in combination with chemotherapy and immunotherapy. Examination of pancreatic tumor microenvironment following GMI-1359 treatment revealed significant changes to the cell cellular composition: drastically reduced desmoplasia and lymphatic vascular densities. Further studies are ongoing to evaluate GMI-1359 efficacy in combination with immunotherapy in spontaneous mouse models of pancreatic cancer. Altogether, our data demonstrates that lymphatic biology and function is affected by both pancreatic tumor cells and pancreatic fibroblasts, and that factors expressed by the lymphatic endothelium ((E-selectin and CXCR4) may be targetable for the treatment of pancreatic cancer.
Steele, Maria M., "Pancreatic Cancer Invasion of the Lymphatic Vasculature and Contributions of the Tumor Microenvironment: Roles for E-selectin and CXCR4" (2016). Theses & Dissertations. 166.