title: Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer.
abstract: Resistance to anticancer therapy has been attributed to interindividual differences in gene expression pathways among tumors, and to the existence within tumors of cancer stem cells with self-renewal capacity. In previous studies, we have demonstrated that the human embryonic stem cell (hESC)-derived cellular microenvironment in immunocompromised mice enables functional distinction of heterogeneous tumor cells, including cells that do not grow into a tumor in conventional direct tumor xenograft platform. In the current study, we use clonally expanded subpopulations derived from ovarian clear cell carcinoma of a single tumor, to demonstrate striking intratumoral phenotypic heterogeneity that is dynamically dependent on the tumor growth microenvironment. Each of six clonally expanded subpopulations displays a different level of morphologic and tumorigenic differentiation, wherein growth in the hESC-derived microenvironment favors growth of CD44+ aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD44- aldehyde dehydrogenase negative derivatives. Strikingly, these derivative cells display microenvironment-dependent plasticity with the capacity to restore self-renewal and CD44 expression. Such intratumoral heterogeneity and plasticity at the level of the key properties of self-renewal and tumorigenic differentiation suggests that a paradigm shift is needed in the approach to anticancer therapy, with the aim of turning malignant growth into a chronic manageable disorder, based on continual monitoring of these tumor growth properties. The hESC-based in vivo model renders intratumoral heterogeneity in the self-renewal and tumorigenic differentiation amenable to biological analysis as well as anticancer therapy testing.
authors.affiliation: Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Abelson
authors.forename: Yeela
authors.initials: Y
authors.lastname: Shamai
authors.forename: Liron
authors.initials: L
authors.lastname: Berger
authors.forename: Roni
authors.initials: R
authors.lastname: Shouval
authors.forename: Karl
authors.initials: K
authors.lastname: Skorecki
authors.forename: Maty
authors.initials: M
authors.lastname: Tzukerman
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D055153:Stem Cell Niche; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D018960:Hyaluronan Receptors