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1. Khotskaya, Yekaterina B. Role of syndecan-1 as key regulator of multiple myeloma pathogenesis.
Degree: PhD, 2009, University of Alabama – Birmingham
Syndecan-1 (CD138), a transmembrane heparan sulfate-bearing proteoglycan, is expressed at high levels on most myeloma cells and is shed into the microenvironment. In patients, high levels of serum syndecan-1 are indicative of poor prognosis and elevation of shed syndecan-1 in animal models dramatically enhances tumor growth, angiogenesis and metastasis. Because syndecan-1 is a key regulator of myeloma pathogenesis, we hypothesized that reduction of syndecan-1 levels expressed by the myeloma cells will block their growth and dissemination. Syndecan-1 knockout and knockdown variants of two human myeloma cell lines, CAG and RPMI-8226, were developed using short hairpin RNA (shRNA) technology. In vitro, knock out of syndecan-1 from the myeloma cell surface resulted in a loss of cell viability via initiation of apoptosis. In contrast, syndecan-1 knockdown cells expressing 14-28% normal syndecan-1 levels were phenotypically similar to the control cells and did not reveal significant growth differences when compared to the control cells in vitro. In contrast, when these knockdown cells were injected into severe combined immunodeficient (SCID) mice in vivo, they formed tumors poorly as compared to cells expressing wild-type levels of syndecan-1. Tumor immunohistology revealed that the VEGF levels were dramatically lower in the knockdown tumors as compared to the controls. Moreover, knockdown of syndecan-1 resulted in grossly underdeveloped vasculature in these tumors. Importantly, most syndecan-1 knockdown cells also failed to grow when injected intravenously into SCID mice, suggesting that post-intravasation steps of the metastatic cascade may be syndecan-1 dependent. Few tumors that arose from knockdown cells in animals injected intravenously formed at extra-osseous sites, further implicating syndecan-1 as a critical molecule for homing of myeloma cells to bone. Taken together, these results indicate that syndecan-1 expression is required for robust myeloma tumor development and growth in vivo via regulation of angiogenesis and metastasis, and that therapies aimed at reducing expression of this proteoglycan may benefit myeloma patients.
1 online resource (xi, 114 p. : ill., digital, PDF file)
Joint Health Sciences
Multiple myeloma syndecan-1 angiogenesis heparan sulfate proteoglycan metastasis
UNRESTRICTEDAdvisors/Committee Members: Sanderson, Ralph D., Lopez, Richard<br>, Welch, Danny R.<br>, Woods, Anne<br>, Zayzafoon, Majd<br>, Zinn, Kurt R..
Subjects/Keywords: Gene Expression Regulation, Neoplastic<; br>; Melanoma – metabolism<; br>; Neoplasm Proteins – biosynthesis<; br>; Neovascularization, Pathologic – metabolism<; br>; Syndecan-1 – biosynthesis
APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager
APA (6th Edition):
Khotskaya, Y. B. (2009). Role of syndecan-1 as key regulator of multiple myeloma pathogenesis. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,766
Chicago Manual of Style (16th Edition):
Khotskaya, Yekaterina B. “Role of syndecan-1 as key regulator of multiple myeloma pathogenesis.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed April 06, 2020. http://contentdm.mhsl.uab.edu/u?/etd,766.
MLA Handbook (7th Edition):
Khotskaya, Yekaterina B. “Role of syndecan-1 as key regulator of multiple myeloma pathogenesis.” 2009. Web. 06 Apr 2020.
Khotskaya YB. Role of syndecan-1 as key regulator of multiple myeloma pathogenesis. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2020 Apr 06]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,766.
Council of Science Editors:
Khotskaya YB. Role of syndecan-1 as key regulator of multiple myeloma pathogenesis. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,766