The Contributions of Extracellular Hsp90 to the Tumor Microenvironment.
Wong, Daniel.
2019
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Cancer is the second
leading cause of death worldwide. The morbidity and mortality caused by this disease is
primarily a result of metastasis, the spread of tumor cells throughout the body.
Currently, there are no anti-cancer therapies available that block metastasis.
Metastasis begins in the tumor microenvironment (TME), which consists of tumor cells,
host cells, extracellular matrix (ECM), ... read moreand secreted signaling molecules. Heat shock
protein 90 (Hsp90) is a chaperone protein necessary for essential cellular processes.
Many anti-cancer therapies have targeted Hsp90, but have resulted in failed clinical
trials due to severe side effect profiles. When secreted from cells on microvesicles
celled exosomes, extracellular Hsp90 (eHsp90) activates ECM-modifying proteins and
facilitates intercellular signaling that contribute to metastasis. This work addresses
an unmet need in cancer research by elucidating the role of eHsp90 as one of the
fundamental molecules of metastasis. My hypothesis is that the function of eHsp90 is
distinct from its intracellular roles, and its contributions to the TME facilitate
metastatic phenotypes. I tested this hypothesis by examining the effects of eHsp90
inhibition using a membrane-impermeant inhibitor in comparison to multiple control
conditions including non-treatment, mock treatment, and general Hsp90 inhibition. I
looked at the effects on cell viability and migration, on the population and size
distribution of exosomes derived from these cells, and on the microRNA content of these
exosomes. These data show that eHsp90 can be inhibited independent of intracellular
Hsp90 and the inhibition of eHsp90 specifically, reduces the magnitude of early
metastatic phenotypes. Extracellular Hsp90 inhibition is as effective as general Hsp90
inhibition while being less toxic to cells at the same concentration. eHsp90 inhibition
also changes the exosome population and microRNA cargo. The extracellular abundance of
one species of microRNA, miR-297, increases with eHsp90 inhibition and is significant
because its targets include proteins that support angiogenesis, a common feature of
metastasis. My results suggest that eHsp90 could be a promising, highly specific target
for anti-cancer therapy. Restricting Hsp90 inhibition to the extracellular space would
block the pro-metastatic activity of the protein while avoiding interference with its
critical intracellular functions, thereby reducing unwanted cytotoxic side
effects.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Daniel Jay.
Committee: Brent Cochran, Guo-fu Hu, and Daniel Bolon.
Keywords: Cellular biology, Physiology, and Biochemistry.read less - ID:
- bk128q19b
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