Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Shijie Sheng

Abstract

This dissertation highlights several novel findings. Maspin has been consistently detected in the conditioned media of maspin-expressing cells of normal and tumor breast, prostate and lung origin. Furthermore, extracellular maspin has been demonstrated to have anti-tumor effects. Interestingly, maspin has been reported as cargo of the exosomes, which highlights one of the secretion mechanisms of maspin. Maspin secretion as an exosomal molecule was verified by electron microscopy, atomic force microscopy, light scattering dynamic analysis and immunoblot analysis.

The data showed that exosomes derived from the non-malignant cell lines have two distinct populations that do no overlap in their size distributions. Based on the size distribution and the electron microscopy analysis, it is likely that exosomes derived from the non-malignant cells are aggregated exosomes. In contrast, tumor cell-derived exosomes comprised a population of broader size distribution.

To understand how secreted maspin may contribute to tumor suppression, it is critical to understand how maspin is regulated at the step of protein trafficking. The data showed that maspin is secreted by dual mechanisms, as free and exosomal protein, respectively. These two mechanisms seem to be independent. While tumor cells are capable of secreting maspin as a free molecule, albeit at a lower level as compared to that by normal epithelial cells, they do not secrete exosomal maspin.

Loss of maspin in exosomes from derived non-malignant cells conferred a stimulatory effect on the motility of fibroblasts, suggesting a biological function of exosomal maspin in suppressing the stromal reactivity in the tumor microenvironment. These novel findings highlight a new role for exosomal maspin as a tumor suppressor.

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