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High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer.

Liu SY, Zheng PS - Oncotarget (2013)

Bottom Line: Here, we demonstrate that cervical cancer cells with high ALDH activity fulfill the functional criteria for CSCs: (1) ALDH high cells, unlike ALDH low cells, are highly tumorigenic in vivo; (2) ALDH high cells can give rise to both ALDH high and ALDH low cells in vitro and in vivo, thereby establishing a cellular hierarchy; and (3) ALDH high cells have enhanced self-renewal and differentiation potentials.Finally, expression of the stem cell self-renewal-associated transcription factors OCT4, NANOG, KLF4 and BMI1 is elevated in ALDH high cervical cancer cells.Taken together, our data indicated that high ALDH activity may represent both a functional marker for CCSCs and a target for novel cervical cancer therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Reproductive Medicine, The First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, The People's Republic of China.

ABSTRACT
High aldehyde dehydrogenase (ALDH) activity characterizes a subpopulation of cells with cancer stem cell (CSC) properties in several malignancies. To clarify whether ALDH can be used as a marker of cervical cancer stem cells (CCSCs), ALDH high and ALDH low cells were sorted from 4 cervical cancer cell lines and 5 primary tumor xenografts and examined for CSC characteristics. Here, we demonstrate that cervical cancer cells with high ALDH activity fulfill the functional criteria for CSCs: (1) ALDH high cells, unlike ALDH low cells, are highly tumorigenic in vivo; (2) ALDH high cells can give rise to both ALDH high and ALDH low cells in vitro and in vivo, thereby establishing a cellular hierarchy; and (3) ALDH high cells have enhanced self-renewal and differentiation potentials. Additionally, ALDH high cervical cancer cells are more resistant to cisplatin treatment than ALDH low cells. Finally, expression of the stem cell self-renewal-associated transcription factors OCT4, NANOG, KLF4 and BMI1 is elevated in ALDH high cervical cancer cells. Taken together, our data indicated that high ALDH activity may represent both a functional marker for CCSCs and a target for novel cervical cancer therapies.

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ALDH expression in human cervical tissue specimens and cervical cancer cell linesA, Representative photos of immunostained specimens showing ALDH1 expression in normal cervical (a-d) and cervical cancer (e-h) tissues. a, no ALDH1-positive cells; b, dot-scattered ALDH1 expression; c, focal distribution of ALDH1-positive cells; d, all basal cells of the normal cervix are ALDH1-positive; e, dot-scattered ALDH1 expression; f, focal distribution of ALDH1-positive cells; g, diffuse ALDH1 expression; h, ALDH1-positive cells in xenograft tissue from mice. Red arrows indicate ALDH1-positive cells. S, Stroma; E, Epithelium; Magnifications, 1000×. B, Cells were labeled using the ALDEFLUOR kit, and ALDHhigh cells (bright green fluorescence) were detected by fluorescent microscopy. C, ALDH enzyme activity in 4 cervical cancer cell lines was analyzed by flow cytometry. As a negative control, cells were treated with the specific ALDH inhibitor DEAB. The gated cells represent the ALDHhigh cells.
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Figure 1: ALDH expression in human cervical tissue specimens and cervical cancer cell linesA, Representative photos of immunostained specimens showing ALDH1 expression in normal cervical (a-d) and cervical cancer (e-h) tissues. a, no ALDH1-positive cells; b, dot-scattered ALDH1 expression; c, focal distribution of ALDH1-positive cells; d, all basal cells of the normal cervix are ALDH1-positive; e, dot-scattered ALDH1 expression; f, focal distribution of ALDH1-positive cells; g, diffuse ALDH1 expression; h, ALDH1-positive cells in xenograft tissue from mice. Red arrows indicate ALDH1-positive cells. S, Stroma; E, Epithelium; Magnifications, 1000×. B, Cells were labeled using the ALDEFLUOR kit, and ALDHhigh cells (bright green fluorescence) were detected by fluorescent microscopy. C, ALDH enzyme activity in 4 cervical cancer cell lines was analyzed by flow cytometry. As a negative control, cells were treated with the specific ALDH inhibitor DEAB. The gated cells represent the ALDHhigh cells.

Mentions: ALDH1 expression was evaluated in normal and cancerous cervical tissues (Figure 1A). Notable differences were observed in the expression patterns of ALDH1 in the basal cells of normal human cervical tissues; these patterns were classified into 4 types: (1) No ALDH1 expression (Figure 1Aa); (2) Dot-scattered ALDH1 expression (Figure 1Ab); (3) Focal distribution of ALDH1-positive cells (Figure 1Ac); and (4) Positive ALDH1 expression in all basal cells (Figure 1Ad). Because basal cells are known to contain undifferentiated reserve cells of the normal cervix, we speculated that the ALDH1-positive basal cells may represent the stem cells of the normal cervix. A large number of ALDH1-positive cells were found in the stroma in all of the normal cervical tissues (Figure 1Aa-1Ad). Most of these ALDH1-positive cells in the normal cervical stroma are likely CD45-positive leukocytes, which have also been found in the stroma of normal breast tissues by Dr. Deng et al. [45].


High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer.

Liu SY, Zheng PS - Oncotarget (2013)

ALDH expression in human cervical tissue specimens and cervical cancer cell linesA, Representative photos of immunostained specimens showing ALDH1 expression in normal cervical (a-d) and cervical cancer (e-h) tissues. a, no ALDH1-positive cells; b, dot-scattered ALDH1 expression; c, focal distribution of ALDH1-positive cells; d, all basal cells of the normal cervix are ALDH1-positive; e, dot-scattered ALDH1 expression; f, focal distribution of ALDH1-positive cells; g, diffuse ALDH1 expression; h, ALDH1-positive cells in xenograft tissue from mice. Red arrows indicate ALDH1-positive cells. S, Stroma; E, Epithelium; Magnifications, 1000×. B, Cells were labeled using the ALDEFLUOR kit, and ALDHhigh cells (bright green fluorescence) were detected by fluorescent microscopy. C, ALDH enzyme activity in 4 cervical cancer cell lines was analyzed by flow cytometry. As a negative control, cells were treated with the specific ALDH inhibitor DEAB. The gated cells represent the ALDHhigh cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926841&req=5

Figure 1: ALDH expression in human cervical tissue specimens and cervical cancer cell linesA, Representative photos of immunostained specimens showing ALDH1 expression in normal cervical (a-d) and cervical cancer (e-h) tissues. a, no ALDH1-positive cells; b, dot-scattered ALDH1 expression; c, focal distribution of ALDH1-positive cells; d, all basal cells of the normal cervix are ALDH1-positive; e, dot-scattered ALDH1 expression; f, focal distribution of ALDH1-positive cells; g, diffuse ALDH1 expression; h, ALDH1-positive cells in xenograft tissue from mice. Red arrows indicate ALDH1-positive cells. S, Stroma; E, Epithelium; Magnifications, 1000×. B, Cells were labeled using the ALDEFLUOR kit, and ALDHhigh cells (bright green fluorescence) were detected by fluorescent microscopy. C, ALDH enzyme activity in 4 cervical cancer cell lines was analyzed by flow cytometry. As a negative control, cells were treated with the specific ALDH inhibitor DEAB. The gated cells represent the ALDHhigh cells.
Mentions: ALDH1 expression was evaluated in normal and cancerous cervical tissues (Figure 1A). Notable differences were observed in the expression patterns of ALDH1 in the basal cells of normal human cervical tissues; these patterns were classified into 4 types: (1) No ALDH1 expression (Figure 1Aa); (2) Dot-scattered ALDH1 expression (Figure 1Ab); (3) Focal distribution of ALDH1-positive cells (Figure 1Ac); and (4) Positive ALDH1 expression in all basal cells (Figure 1Ad). Because basal cells are known to contain undifferentiated reserve cells of the normal cervix, we speculated that the ALDH1-positive basal cells may represent the stem cells of the normal cervix. A large number of ALDH1-positive cells were found in the stroma in all of the normal cervical tissues (Figure 1Aa-1Ad). Most of these ALDH1-positive cells in the normal cervical stroma are likely CD45-positive leukocytes, which have also been found in the stroma of normal breast tissues by Dr. Deng et al. [45].

Bottom Line: Here, we demonstrate that cervical cancer cells with high ALDH activity fulfill the functional criteria for CSCs: (1) ALDH high cells, unlike ALDH low cells, are highly tumorigenic in vivo; (2) ALDH high cells can give rise to both ALDH high and ALDH low cells in vitro and in vivo, thereby establishing a cellular hierarchy; and (3) ALDH high cells have enhanced self-renewal and differentiation potentials.Finally, expression of the stem cell self-renewal-associated transcription factors OCT4, NANOG, KLF4 and BMI1 is elevated in ALDH high cervical cancer cells.Taken together, our data indicated that high ALDH activity may represent both a functional marker for CCSCs and a target for novel cervical cancer therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Reproductive Medicine, The First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, The People's Republic of China.

ABSTRACT
High aldehyde dehydrogenase (ALDH) activity characterizes a subpopulation of cells with cancer stem cell (CSC) properties in several malignancies. To clarify whether ALDH can be used as a marker of cervical cancer stem cells (CCSCs), ALDH high and ALDH low cells were sorted from 4 cervical cancer cell lines and 5 primary tumor xenografts and examined for CSC characteristics. Here, we demonstrate that cervical cancer cells with high ALDH activity fulfill the functional criteria for CSCs: (1) ALDH high cells, unlike ALDH low cells, are highly tumorigenic in vivo; (2) ALDH high cells can give rise to both ALDH high and ALDH low cells in vitro and in vivo, thereby establishing a cellular hierarchy; and (3) ALDH high cells have enhanced self-renewal and differentiation potentials. Additionally, ALDH high cervical cancer cells are more resistant to cisplatin treatment than ALDH low cells. Finally, expression of the stem cell self-renewal-associated transcription factors OCT4, NANOG, KLF4 and BMI1 is elevated in ALDH high cervical cancer cells. Taken together, our data indicated that high ALDH activity may represent both a functional marker for CCSCs and a target for novel cervical cancer therapies.

Show MeSH
Related in: MedlinePlus