TY - JOUR
T1 - Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer
AU - Abelson, Sagi
AU - Shamai, Yeela
AU - Berger, Liron
AU - Shouval, Roni
AU - Skorecki, Karl
AU - Tzukerman, Maty
PY - 2012/3
Y1 - 2012/3
N2 - 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 CD441 aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD442 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.
AB - 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 CD441 aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD442 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.
KW - Cancer stem cell niche
KW - Cancer stem cells
KW - Human embryonic stem cells
KW - Niche-dependent self-renewal capacity
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=84857485231&partnerID=8YFLogxK
U2 - 10.1002/stem.1029
DO - 10.1002/stem.1029
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C2 - 22267284
AN - SCOPUS:84857485231
SN - 1066-5099
VL - 30
SP - 415
EP - 424
JO - Stem Cells
JF - Stem Cells
IS - 3
ER -