Studies on Adipose Stem Cells and Ovarian Cancer Stem Cells : 지방줄기세포 및 난소암줄기세포에 관한 연구

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농업생명과학대학 농생명공학부
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서울대학교 대학원
ovarian canceradipose stem cellscancer stem cellstumor microenvironmentchemoresistancePGC-1a
학위논문 (박사)-- 서울대학교 대학원 : 농생명공학부(바이오모듈레이션전공), 2015. 8. 송용상.
The problems in ovarian cancer therapy are that ovarian cancer is diagnosed at an advanced stage and resistant to chemotherapy, leading to poor prognosis. Adipose stem cells (ASCs) and cancer stem cells (CSCs) can be driving forces acting on ovarian cancer progression and chemoresistance, respectively. The present study focused on the interaction between ASCs and ovarian cancer, and the role of 2) CSCs in ovarian cancer. First, ASCs regulate obesity, defined as abnormal or excessive fat accumulation, through the proliferation and adipogenic differentiation, and contribute tumor microenvironment supporting cancer cells. Although several epidemiologic studies have suggested evidence for the relationship between obesity and ovarian cancer, experimental evidence is still lack to verify it. Here, we suggested that ASCs affect ovarian cancer progression via paracrine factors. Among adipokines containing in the conditioned medium of ASCs, interleukin-6 (IL-6) strongly expressed and facilitated the migration and proliferation of ovarian cancer cells (SKOV3 and patient-derived cancer cells). IL-6 derived from ASCs activated the JAK2/STAT3 signaling pathway of ovarian cancer cells, leading to enhanced cancer progression. Taken together, ASCs as a part of tumor microenvironment facilitate the migration and proliferation of ovarian cancer cells via secretion of the paracrine factor. This result provides experimental evidence for the relationship between obesity and ovarian cancer. Second, existence of CSCs with self-renewal and clonal initiating potential confers chemoresistance to ovarian cancer through the multiple way, such as drug efflux, detoxification (drug metabolism), and dormancy. Sphere formation induced enrichment of CSCs with high ALDH activity. CSCs exhibited expression of ABC transporter proteins (MDR1/ABCB1 and ABCG2), and were resistant to cisplatin compared to parental cells (attached-cultured cells). Oxidative stress caused by sphere formation induced PGC-1α expression (a key regulator of mitochondrial biogenesis and metabolism), resulting in the enhanced chemoresistance of sphere forming cells. When oxidative stress was exogenously exerted to parental cells, PGC-1α expression was observed. Overexpression of PGC-1α in parental cells led to the same response with sphere forming cells. Silencing of PGC-1α in sphere forming cells reduced the resistance to cisplatin. Collectively, PGC-1α induced by oxidative stress mediates chemoresistance in ovarian cancer. We first reported a new function of PGC-1α for the intermediate mechanism in chemoresistance. Therefore, targeting the microenvironmental effects of ASCs and chemoresistant properties of CSCs could elicit a better response to therapy and prognosis in ovarian cancer.
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College of Agriculture and Life Sciences (농업생명과학대학)Dept. of Agricultural Biotechnology (농생명공학부)Theses (Ph.D. / Sc.D._농생명공학부)
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