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Precancerous stem cells have the potential for both benign and malignant differentiation.

Chen L, Shen R, Ye Y, Pu XA, Liu X, Duan W, Wen J, Zimmerer J, Wang Y, Liu Y, Lasky LC, Heerema NA, Perrotti D, Ozato K, Kuramochi-Miyagawa S, Nakano T, Yates AJ, Carson WE, Lin H, Barsky SH, Gao JX - PLoS ONE (2007)

Bottom Line: However, their precursors-namely, precancerous stem cells (pCSCs) -have not been characterized.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America.

ABSTRACT
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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pCSCs developed into various type of tumors in immunodeficient mice.A, Tumor incidence from 3 experiments. Equal numbers of sex matched SCID mice were injected s.c. or i.p. with 5×106 pCSCs. No significant difference in incidence was observed between s.c. and i.p. injected mice. As a control, C57BL/6 mice injected s.c. (n = 10) or i.p. (n = 10) with 2C4 cells did not develop tumors within 5 months of observation (data not shown) “*” indicates that a mouse developed ascites, “**” indicates that the 3B6C cells infiltrated in the liver and spleen (see E). B, Kinetics of tumor growth: the data shown are from experiments 1 & 2 in A. Each color in B corresponds to a specific cell line. C, Comparison of tumorigenesis between pCSCs (2C4) and differentiated cancer cells (3B11); (n = 10/group, each group includes 5 males and 5 females). D, A representative of gross tumors from a mouse injected i.p. with 3B5C clone. E, A histological representative of pCSC-derived tumors from the mice injected i.p. with 2C4 or 3B5C clones. F, A histological representative from the spleen of mice injected i.p. or s.c. with 3B6C clone. Note that megakaryocytes in the spleen of normal SCID mice were replaced by atypical neutrophils or eosinophils. G, Benign differentiation of pCSCs in the liver with metastatic cancers: (a) H & E staining of a liver section with metastatic cancers from a mouse injected i.p. with 2C4 cells (original magnification: ×200). (b) Immunohistochemical staining of the liver section from the same mouse with antibody to neomycin, showing neomycin+ cancer cells (original magnification: ×400). (c) Immunohistochemical staining of pCSC-derived hepatoid cells in the regenerative area of the liver sections from the same mouse (original magnification: ×200). (d) The enlarged micrographs of hepatoid cells demonstrated in (c).
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pone-0000293-g004: pCSCs developed into various type of tumors in immunodeficient mice.A, Tumor incidence from 3 experiments. Equal numbers of sex matched SCID mice were injected s.c. or i.p. with 5×106 pCSCs. No significant difference in incidence was observed between s.c. and i.p. injected mice. As a control, C57BL/6 mice injected s.c. (n = 10) or i.p. (n = 10) with 2C4 cells did not develop tumors within 5 months of observation (data not shown) “*” indicates that a mouse developed ascites, “**” indicates that the 3B6C cells infiltrated in the liver and spleen (see E). B, Kinetics of tumor growth: the data shown are from experiments 1 & 2 in A. Each color in B corresponds to a specific cell line. C, Comparison of tumorigenesis between pCSCs (2C4) and differentiated cancer cells (3B11); (n = 10/group, each group includes 5 males and 5 females). D, A representative of gross tumors from a mouse injected i.p. with 3B5C clone. E, A histological representative of pCSC-derived tumors from the mice injected i.p. with 2C4 or 3B5C clones. F, A histological representative from the spleen of mice injected i.p. or s.c. with 3B6C clone. Note that megakaryocytes in the spleen of normal SCID mice were replaced by atypical neutrophils or eosinophils. G, Benign differentiation of pCSCs in the liver with metastatic cancers: (a) H & E staining of a liver section with metastatic cancers from a mouse injected i.p. with 2C4 cells (original magnification: ×200). (b) Immunohistochemical staining of the liver section from the same mouse with antibody to neomycin, showing neomycin+ cancer cells (original magnification: ×400). (c) Immunohistochemical staining of pCSC-derived hepatoid cells in the regenerative area of the liver sections from the same mouse (original magnification: ×200). (d) The enlarged micrographs of hepatoid cells demonstrated in (c).

Mentions: To test this hypothesis, pCSCs were injected s.c., i.p. or i.v. into severe combined immune deficient (SCID) mice, BM reconstituted, or naive B6 mice; conditions which may provide different levels of immune surveillance (see discussion). The results demonstrated that both the surveillance system and the injection route had an impact on pCSC development in recipients; they developed into either solid or leukemic tumors in immunodeficient mice (Supplementary Table S1). 2C4, 2C4G2 and 3B5C cells, but not 3B6C cells, developed into solid tumors at the site of injection, regardless of i.p. or s.c. inoculation. The latency, incidence, and growth kinetics of tumors were also variable with the experiments (Fig. 4a &b). For example, the tumors were palpable, respectively, at days 10 and 21 post inoculation in the expt 1 and expt 2 (Fig. 4b). In most of the experiments, once tumors were palpable, the tumor growth curves rose steeply, and the mice had to be sacrificed within one wk (Fig. 4b). Consistent with the properties of tumorigenic cancer cells [5], pCSC-derived tumors grew much faster than 3B11 cell-derived tumors (Fig. 4c).


Precancerous stem cells have the potential for both benign and malignant differentiation.

Chen L, Shen R, Ye Y, Pu XA, Liu X, Duan W, Wen J, Zimmerer J, Wang Y, Liu Y, Lasky LC, Heerema NA, Perrotti D, Ozato K, Kuramochi-Miyagawa S, Nakano T, Yates AJ, Carson WE, Lin H, Barsky SH, Gao JX - PLoS ONE (2007)

pCSCs developed into various type of tumors in immunodeficient mice.A, Tumor incidence from 3 experiments. Equal numbers of sex matched SCID mice were injected s.c. or i.p. with 5×106 pCSCs. No significant difference in incidence was observed between s.c. and i.p. injected mice. As a control, C57BL/6 mice injected s.c. (n = 10) or i.p. (n = 10) with 2C4 cells did not develop tumors within 5 months of observation (data not shown) “*” indicates that a mouse developed ascites, “**” indicates that the 3B6C cells infiltrated in the liver and spleen (see E). B, Kinetics of tumor growth: the data shown are from experiments 1 & 2 in A. Each color in B corresponds to a specific cell line. C, Comparison of tumorigenesis between pCSCs (2C4) and differentiated cancer cells (3B11); (n = 10/group, each group includes 5 males and 5 females). D, A representative of gross tumors from a mouse injected i.p. with 3B5C clone. E, A histological representative of pCSC-derived tumors from the mice injected i.p. with 2C4 or 3B5C clones. F, A histological representative from the spleen of mice injected i.p. or s.c. with 3B6C clone. Note that megakaryocytes in the spleen of normal SCID mice were replaced by atypical neutrophils or eosinophils. G, Benign differentiation of pCSCs in the liver with metastatic cancers: (a) H & E staining of a liver section with metastatic cancers from a mouse injected i.p. with 2C4 cells (original magnification: ×200). (b) Immunohistochemical staining of the liver section from the same mouse with antibody to neomycin, showing neomycin+ cancer cells (original magnification: ×400). (c) Immunohistochemical staining of pCSC-derived hepatoid cells in the regenerative area of the liver sections from the same mouse (original magnification: ×200). (d) The enlarged micrographs of hepatoid cells demonstrated in (c).
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pone-0000293-g004: pCSCs developed into various type of tumors in immunodeficient mice.A, Tumor incidence from 3 experiments. Equal numbers of sex matched SCID mice were injected s.c. or i.p. with 5×106 pCSCs. No significant difference in incidence was observed between s.c. and i.p. injected mice. As a control, C57BL/6 mice injected s.c. (n = 10) or i.p. (n = 10) with 2C4 cells did not develop tumors within 5 months of observation (data not shown) “*” indicates that a mouse developed ascites, “**” indicates that the 3B6C cells infiltrated in the liver and spleen (see E). B, Kinetics of tumor growth: the data shown are from experiments 1 & 2 in A. Each color in B corresponds to a specific cell line. C, Comparison of tumorigenesis between pCSCs (2C4) and differentiated cancer cells (3B11); (n = 10/group, each group includes 5 males and 5 females). D, A representative of gross tumors from a mouse injected i.p. with 3B5C clone. E, A histological representative of pCSC-derived tumors from the mice injected i.p. with 2C4 or 3B5C clones. F, A histological representative from the spleen of mice injected i.p. or s.c. with 3B6C clone. Note that megakaryocytes in the spleen of normal SCID mice were replaced by atypical neutrophils or eosinophils. G, Benign differentiation of pCSCs in the liver with metastatic cancers: (a) H & E staining of a liver section with metastatic cancers from a mouse injected i.p. with 2C4 cells (original magnification: ×200). (b) Immunohistochemical staining of the liver section from the same mouse with antibody to neomycin, showing neomycin+ cancer cells (original magnification: ×400). (c) Immunohistochemical staining of pCSC-derived hepatoid cells in the regenerative area of the liver sections from the same mouse (original magnification: ×200). (d) The enlarged micrographs of hepatoid cells demonstrated in (c).
Mentions: To test this hypothesis, pCSCs were injected s.c., i.p. or i.v. into severe combined immune deficient (SCID) mice, BM reconstituted, or naive B6 mice; conditions which may provide different levels of immune surveillance (see discussion). The results demonstrated that both the surveillance system and the injection route had an impact on pCSC development in recipients; they developed into either solid or leukemic tumors in immunodeficient mice (Supplementary Table S1). 2C4, 2C4G2 and 3B5C cells, but not 3B6C cells, developed into solid tumors at the site of injection, regardless of i.p. or s.c. inoculation. The latency, incidence, and growth kinetics of tumors were also variable with the experiments (Fig. 4a &b). For example, the tumors were palpable, respectively, at days 10 and 21 post inoculation in the expt 1 and expt 2 (Fig. 4b). In most of the experiments, once tumors were palpable, the tumor growth curves rose steeply, and the mice had to be sacrificed within one wk (Fig. 4b). Consistent with the properties of tumorigenic cancer cells [5], pCSC-derived tumors grew much faster than 3B11 cell-derived tumors (Fig. 4c).

Bottom Line: However, their precursors-namely, precancerous stem cells (pCSCs) -have not been characterized.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus