טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAbelson Sagi
SubjectStudy and Analysis of In Vitro and In Vivo Heterogeneity in
Ovarian Cancer Cell Populations
DepartmentDepartment of Medicine
Supervisors Professor Karl Skorecki
Dr. Maty Zukerman
Full Thesis textFull thesis text - English Version


Abstract

Diminished successes of chemotherapy treatment, recurrent disease and tumor resistance to anticancer therapy have all been attributed to intra-tumoral differences among sub-population of cancer cells, and to the existence of cancer stem cells with the capacity for self-renewal. In our laboratory, it has been shown that the use of an experimental platform comprising human embryonic stem cell (hESC)-derived cellular microenvironment in immune-compromised mice enables functional distinction of heterogeneous tumor cells; including cells that do not grow into a tumor in the conventional platform of a direct tumor xenograft. We used six clonally expanded sub-populations derived from ovarian clear cell carcinoma of a single tumor, to demonstrate striking intra-tumoral heterogeneity that has a component which is inherent to subpopulation and hence durable and a component which is dynamically dependent on the tumor microenvironment. Each of six clonally expanded sub-populations displays a different level of both morphologic and tumorigenic differentiation, and properties of self-renewal, often attributed to cancer stem cells. We have shown that the human embryonic stem cell (hESC)-derived cellular microenvironment exposes the functional distinction of heterogeneous cancer stem cell ?sub-populations ? and learned that ovarian cancer cells display microenvironment-dependent plasticity with the ability to differentiate and then restore the capacity for self-renewal ? . We delineate the distinct gene expression profile and epigenetic landscape of two such sub-populations representing the extremes of phenotypic heterogeneity in terms of niche dependent-self-renewal and tumorigenic differentiation and present a suite of robust differences in the genes and pathways that underlie this intra-tumoral phenotypic heterogeneity. Importantly, we demonstrated that a single ovarian tumor may contain multiple sub-populations of cancer cell which exhibits major differences in theirs sensitivity to different drug compounds. This research presents a view into the vast extent of cancer cell heterogeneity in solid tumors and indicates the urgent need for the development of clinically relevant characterization procedures for the different sub-population which exist within a single tumor and for the use of multimodal anti-cancer therapeutic strategies to eliminate both the heterogeneous cancer stem cells and their differentiated derivatives.