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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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ALDHhigh cervical cancer cells are capable of differentiating in vitro and in vivoA-D, ALDHhigh and ALDHlow cells were isolated from the SiHa (A), C33A (B), CaSki (C) or HT-3 (D) cell lines and cultured in DMEM medium supplemented with 10% FBS for 2 weeks. The ALDH enzyme activity was then analyzed by flow cytometry. Cells treated with DEAB served as a negative control. The gated cells represent the ALDHhigh cells. E, Expression of ALDH1 was detected by IHC in xenograft tumors from ALDHhigh and ALDHlow cells. Red arrows indicate ALDH1-positive cells
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Figure 4: ALDHhigh cervical cancer cells are capable of differentiating in vitro and in vivoA-D, ALDHhigh and ALDHlow cells were isolated from the SiHa (A), C33A (B), CaSki (C) or HT-3 (D) cell lines and cultured in DMEM medium supplemented with 10% FBS for 2 weeks. The ALDH enzyme activity was then analyzed by flow cytometry. Cells treated with DEAB served as a negative control. The gated cells represent the ALDHhigh cells. E, Expression of ALDH1 was detected by IHC in xenograft tumors from ALDHhigh and ALDHlow cells. Red arrows indicate ALDH1-positive cells

Mentions: One characteristic of CSCs is the capacity to differentiate into non-CSCs and give rise to the heterogeneous tumor cell populations. To determine whether ALDHhigh cells are capable of differentiation in vitro, ALDHhigh and ALDHlow cells were cultured separately in DMEM medium supplemented with 10% FBS for 2 weeks. After incubation, the cultured populations were analyzed using the ALDEFLUOR assay (Figure 4A-4D). Approximately 90% of the ALDHhigh SiHa cells differentiated into ALDHlow cells, and only 10% of the cells remained strongly ALDH-positive. However, greater than 99% of the ALDHlow SiHa cells retained the ALDHlow phenotype (Figure 4A). Similarly, 57.2% of the ALDHhigh C33A cells (Figure 4B), 72.1% of the ALDHhigh CaSki cells (Figure 4C) and 75.9% of the ALDHhigh HT-3cells (Figure 4D) generated ALDHlow cells. However, 98.52% of the ALDHlow C33A cells (Figure 4B), 99.45% of the ALDHlow CaSki cells (Figure 4C) and 99.86% of the ALDHlow HT-3 cells (Figure 4D) maintained the ALDHlow phenotype. Notably, 1.48% of the ALDHlow C33A cells generated ALDHhigh cells, which was a larger fraction than the other cell lines. Because C33A cells contain a larger population of ALDHhigh cells and higher ALDH activity than the other cell lines, this proportion of ALDHhigh cells may have resulted from errors during the cell sorting manipulation.


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

Liu SY, Zheng PS - Oncotarget (2013)

ALDHhigh cervical cancer cells are capable of differentiating in vitro and in vivoA-D, ALDHhigh and ALDHlow cells were isolated from the SiHa (A), C33A (B), CaSki (C) or HT-3 (D) cell lines and cultured in DMEM medium supplemented with 10% FBS for 2 weeks. The ALDH enzyme activity was then analyzed by flow cytometry. Cells treated with DEAB served as a negative control. The gated cells represent the ALDHhigh cells. E, Expression of ALDH1 was detected by IHC in xenograft tumors from ALDHhigh and ALDHlow cells. Red arrows indicate ALDH1-positive cells
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Figure 4: ALDHhigh cervical cancer cells are capable of differentiating in vitro and in vivoA-D, ALDHhigh and ALDHlow cells were isolated from the SiHa (A), C33A (B), CaSki (C) or HT-3 (D) cell lines and cultured in DMEM medium supplemented with 10% FBS for 2 weeks. The ALDH enzyme activity was then analyzed by flow cytometry. Cells treated with DEAB served as a negative control. The gated cells represent the ALDHhigh cells. E, Expression of ALDH1 was detected by IHC in xenograft tumors from ALDHhigh and ALDHlow cells. Red arrows indicate ALDH1-positive cells
Mentions: One characteristic of CSCs is the capacity to differentiate into non-CSCs and give rise to the heterogeneous tumor cell populations. To determine whether ALDHhigh cells are capable of differentiation in vitro, ALDHhigh and ALDHlow cells were cultured separately in DMEM medium supplemented with 10% FBS for 2 weeks. After incubation, the cultured populations were analyzed using the ALDEFLUOR assay (Figure 4A-4D). Approximately 90% of the ALDHhigh SiHa cells differentiated into ALDHlow cells, and only 10% of the cells remained strongly ALDH-positive. However, greater than 99% of the ALDHlow SiHa cells retained the ALDHlow phenotype (Figure 4A). Similarly, 57.2% of the ALDHhigh C33A cells (Figure 4B), 72.1% of the ALDHhigh CaSki cells (Figure 4C) and 75.9% of the ALDHhigh HT-3cells (Figure 4D) generated ALDHlow cells. However, 98.52% of the ALDHlow C33A cells (Figure 4B), 99.45% of the ALDHlow CaSki cells (Figure 4C) and 99.86% of the ALDHlow HT-3 cells (Figure 4D) maintained the ALDHlow phenotype. Notably, 1.48% of the ALDHlow C33A cells generated ALDHhigh cells, which was a larger fraction than the other cell lines. Because C33A cells contain a larger population of ALDHhigh cells and higher ALDH activity than the other cell lines, this proportion of ALDHhigh cells may have resulted from errors during the cell sorting manipulation.

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