Cancer stem cells (CSCs) have been identified in hematopoietic and solid tumors. However, their precursors—namely, precancerous stem cells (pCSCs) —have not been characterized. Here we experimentally define the pCSCs that have the potential for both benign and malignant differentiation, depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer, they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice. The progress of the pCSCs to cancers is associated with the up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, the pCSCs are regulated by the PIWI/AGO family gene called piwil2. Our results provide clear evidence that a single clone of pCSCs has the potential for both benign and malignant differentiation, depending on the environmental cues. We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers.

BACKGROUNDThe objectives of the current study were to determine the outcome of children who were treated with chemotherapy and radiotherapy on the Children's Cancer Group (CCG) high‐grade glioma protocol (CCG‐945) who were diagnosed with low‐grade gliomas on post hoc central pathologic review and to identify clinical and biologic features associated with prognosis.METHODSBetween 1985 and 1991, 250 children with institutionally classified high‐grade gliomas were enrolled on CCG‐945. Patients older than 24 months with intracranial lesions were assigned randomly to receive either lomustine, vincristine, and prednisone (control regimen) or the 8‐drugs‐in‐1‐day regimen (experimental regimen); younger patients and those with primary spinal cord tumors were assigned nonrandomly to the experimental regimen. Central independent review by 5 neuropathologists led to a reclassification of low‐grade glioma in 70 patients, who were the focus of the current study.RESULTSThe study involved 42 males and 28 females (median age, 7.7 years) with a median follow‐up of 10.4 years. At 5 years, the progression‐free survival (PFS) rate was 63% ± 6%, and the overall survival (OS) rate was 79% ± 5%, compared with a PFS rate of 19% ± 3% (P < 0.0001) and an OS rate of 22% ± 3% (P < 0.0001) in the remainder of the cohort. Significantly poorer 5‐year PFS was seen in children younger than 24 months, those with fibrillary astrocytoma, and those with posterior fossa tumors. Patients demonstrated a modest improvement in PFS but no improvement in OS compared with children with low‐grade gliomas who were treated with contemporary chemotherapy‐alone approaches.CONCLUSIONSThe current report calls attention to the importance of central pathologic review in large multiinstitutional trials of children with gliomas and suggests that aggressive front‐line combined chemoradiotherapy does not confer a survival advantage in this highly selected population of patients. Cancer 2003;98:1243–52. © 2003 American Cancer Society.DOI 10.1002/cncr.11637

Diagnosis of these tumors is challenging, with only 35% of institutional diagnoses confirmed for AMG and 25% for AO, and survival among children with these tumors is poor, despite intensive therapy. This suggests reliable diagnostic markers and new therapeutic approaches are needed.

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