The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets

EMBO Molecular Medicine

Naomi Pode-Shakked⁶  Rachel Shukrun⁶  Michal Mark-Danieli⁶  Peter Tsvetkov⁷  Sarit Bahar⁶  Sara Pri-Chen⁶  Ronald S. Goldstein⁹  Eithan Rom-Gross²  Yoram Mor⁴  Edward Fridman⁴  Karen Meir³  Amos Simon⁵  Marcus Magister¹  Naftali Kaminski¹  Victor S. Goldmacher⁸  Orit Harari-Steinberg⁶ 

[1] University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;Department of Pediatric Surgery, Hadassah Medical Center, Hebrew University, Jerusalem, Israel;Department of Pathology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel;Sackler School of Medicine, Tel Aviv University, Israel;Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat-Gan, Israel;Pediatric Stem Cell Research Institute, Edmond and LiliSafra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel;Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;ImmunoGen, Inc., Waltham, MA, USA;Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Givaat-Shmuel, Israel

关键词: cancer initiating cells;    cancer stem cells;    kidney stem cells;    renal progenitor cells;    targeted therapy;   

DOI  :  10.1002/emmm.201201516

来源: Wiley

【 摘 要 】

Abstract

There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated – NCAM1 expressing – “blastema” phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets.

→See accompanying article http://dx.doi.org/10.1002/emmm.201202173

【 授权许可】

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Copyright © 2013 EMBO Molecular Medicine

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