Date of Graduation
12-2015
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Mikhail G Kolonin, Ph.D
Committee Member
Pamela L. Wenzel, Ph.D
Committee Member
Gary E. Gallick, Ph.D
Committee Member
Jan A. Burger, MD, Ph.D
Committee Member
Qing Ma, Ph.D
Committee Member
Rick A. Wetsel, Ph.D
Abstract
Obesity increases cancer risk and progression as shown by epidemiologic studies. However, the underlying pathophysiology remained unclear. Adipose stromal cells (ASC) are adipose tissue-derived mesenchymal progenitors, abundant in white adipose tissue (WAT). In this study, we show that the ASC pool is expanded in obesity and is associated with promoted tumor growth. Next, by using a chimeric GFP-RFP bone marrow transplant model, we observed higher tumor infiltrating cells with ASC phenotype in obese mice compared to lean. Consistently, systemic circulating ASC frequency is six fold higher in tumor-bearing obese mice compared to lean. The tumor infiltrating cells with ASC phenotype are found to be perivascular, suggesting them being incorporated into vessels as pericytes to support tumor vasculature. We obtained evidence that ASC is mobilized in response to obesity and cancer, however, the mechanisms regulating ASC trafficking are poorly defined. We previously reported that the binding of the matricellular protein SPARC to β1 integrin on ASC surface induces their motility. Here, we demonstrate that absence of SPARC diminishes ASC capacity to mobilize. As adiposity correlates with circulating SPARC and is the major producer of it, we evaluate SPARC level in distinct adipose depots and identify two SPARC proteolytic isoforms: C-SPARC (lacking the N-terminus) and N-SPARC (lacking the C-terminus), generated in the mesenteric white adipose tissue of obese mice. Both isoforms exhibit distinct β1 integrin binding capacity. C-SPARC binds to β1 integrin on ASC, while N-SPARC fails to, but shows to be a potent extracellular matrix (ECM) / integrin interaction blocker and these events are associated with integrin-dependent FAK-ERK signaling and integrin-independent ILK-Akt signaling. We show that both isoforms induce ASC de-adhesion and, acting through different mechanisms, have additive effect in promoting ASC migration.
Keywords
obesity, adipose stromal cells, mobilization, SPARC