Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation

PLOS ONE, Mar 2007

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.

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Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation

et al (2007) Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation. PLoS ONE 2(3): e293. doi:10.1371/journal.pone.0000293 Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation Li Chen 0 1 Rulong Shen 0 1 Yin Ye 0 1 Xin-An Pu 0 1 Xingluo Liu 0 1 Wenrui Duan 0 1 Jing Wen 0 1 Jason Zimmerer 0 1 Ying Wang 0 1 Yan Liu 0 1 Larry C. Lasky 0 1 Nyla A. Heerema 0 1 Danilo Perrotti 0 1 Keiko Ozato 0 1 Satomi Kuramochi-Miyagawa 0 1 Toru Nakano 0 1 Allen J. Yates 0 1 William E. Carson III 0 1 Haifan Lin 0 1 Sanford H. Barsky 0 1 Jian-Xin Gao Jian-Xin.Gao@osumc 0 1 0 Funding: The work is supported from the Grants of Start-up funding, Department of Pathology, Ohio State University (OSU) (JXG); Strategy Initiative Grant (SIG) 2005/2006, OSU (JXG); American Cancer Society grant IRG-112367 (JXG); Immunology Program Award 2007 (OSU) (JXG); Davis/Bremer Medical Research Grant, OSU (RS); Strategy Initiative Grant (SIG) 2006, OSU (SHB); National Cancer Institute CA095512 (D.P.); the United States Army, Chronic Myelogenous Leukemia (CML) Research Program DAMD17-03-1-0184 (D.P.); and National Institute of Child and Human Development HD42012 (H.L.) 1 Academic Editor: Dong-Yan Jin, University of Hong Kong , China 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. - INTRODUCTION A variety of cancers can arise from reversible premalignant stages of hyperplasia and dysplasia, which might progress to primary and invasive tumors. Recent evidence indicates that the process is initiated by the cancer stem cells (CSCs) [13]. While CSCs have been identified in the hematopoietic and solid cancers [49], the mechanisms underlying CSC derivation are largely unknown. CSCs may originate from a stem or progenitor cell through a precancerous stage, during which stem cells are hierarchically disturbed in their genetic program of self-renewal by environmental insults [1,6,10], whereas the progenitor cells may acquire the properties of stem cells [11]. Thus, whether or not pCSCs exist and how they develop into cancer cells are critical issues for cancer stem cell biology. While investigating tumor incidence in mice with the targeted mutation of p53 and stat-1 genes [12,13], we found that a mouse developed dendritic cell (DC)-like leukemia, which was characterized by massive infiltration of CD11c+CD8a+ DCs in spleen, lymph nodes, and liver [14]. After cloning DC-like lines from the spleen of this leukemic mouse [14], 3 of 25 clones (designated as 2C4, 3B5C and 3B6C) expressed neither hematopoietic and lineage (Lin) markers nor hematopoietic stem cell (HSC) markers (CD452c-kit2Sca-12Lin2). These cells have the potential for both benign and malignant differentiation, and their fate appears to be determined by environmental cues. Since they have the properties of both normal stem cells and CSCs, we use the term pCSCs to recognize their hybrid-like characteristics. The progression of pCSCs to cancer cells is associated with up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, their expansion is regulated by a PIWI/AGO gene piwil2 (alias mili in mouse and hili in human) [15,16]. These findings will help us develop a novel strategy for the early detection, prevention, and treatment of cancers. RESULTS 1. pCSCs exhibit stem-like cell phenotype Although cancer stem-like cells can be detected in the existing tumor cell lines [17], no clonal CSC lines have been established. We previously reported that we cloned DC-like cell lines from the spleen of a leukemic mouse [14]. Here, we found that 3 of the 25 clones (2C4, 3B5C and 3B6C) failed to express hematopoietic panmarker CD45 and lineage (Lin) markers CD3e, CD4, CD8, B220, Ter-119, CD11b and Gr-1 (Fig. 1a), while the remaining clones, such as 3B11, exhibited monocytic and B cell phenotypes, expressing CD45, CD11b, B220, and CD19 (Fig. 1b). Further analysis of the stem cell-related markers revealed a unique phenotype CD342, CD38 (...truncated)


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Li Chen, Rulong Shen, Yin Ye, Xin-An Pu, Xingluo Liu, Wenrui Duan, Jing Wen, Jason Zimmerer, Ying Wang, Yan Liu, Larry C. Lasky, Nyla A. Heerema, Danilo Perrotti, Keiko Ozato, Satomi Kuramochi-Miyagawa, Toru Nakano, Allen J. Yates, William E. Carson III, Haifan Lin, Sanford H. Barsky, Jian-Xin Gao. Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation, PLOS ONE, 2007, 3, DOI: 10.1371/journal.pone.0000293