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

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), ALDHhigh and ALDHlow 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) ALDHhigh cells, unlike ALDHlow cells, are highly tumorigenic in vivo; (2) ALDHhigh cells can give rise to both ALDHhigh and ALDHlow cells in vitro and in vivo, thereby establishing a cellular hierarchy; and (3) ALDHhigh cells have enhanced self-renewal and differentiation potentials. Additionally, ALDHhigh cervical cancer cells are more resistant to cisplatin treatment than ALDHlow cells. Finally, expression of the stem cell self-renewal-associated transcription factors OCT4, NANOG, KLF4 and BMI1 is elevated in ALDHhigh 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.

Characterization of cervical cancer stem cell-like cells: phenotyping, stemness, and human papilloma virus co-receptor expression

“…Due to this high ALDH activity, these cells were sorted and injected subcutaneously ( s.c.) into nude mice. The in vivo assay demonstrated that cells with high ALDH activity (Table 1) are more tumorigenic compared to ALDH dim cells, as was also observed by the Liu group [36]. This data suggested that CCSC are present in the ALDH bright subpopulation, and it is a marker that can be used for target therapy.…”

Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance

“…5). After 48 h of seeding, >60% of adherent cells were ALDH1-positive and those percentages were reduced to ~30% upon reaching confluency, which are compatible with previous reports that the ALDH1-positive population in CaSki cells are 20-30% (32). In our experiments of Gremlin 1-exposure, the cells were ~60-70% confluent after 48 h of seeding (when we exposed cells to Gremlin 1) and became 90-100% confluent when assessed after 72 h of seeding.…”

“…For instance, CD44-or CD133-positive cells are known to be more tumorigenic than negative ones in ovarian cancer (29,30). Similar findings have been suggested for side population (SP) cells in endometrial cancer and ALDH1-positive cells in cervical cancer (31)(32)(33)(34)(35)(36). Gremlin 1 is also reported to be expressed in cervical cancer compared to normal tissues of the cervix (37).…”

Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells

“…The ALDH enzymatic activity of the cells was measured as described previously (34), using the Aldefluor kit (StemCell Technologies, Vancouver, BC, Canada). CaSki cells (5x10 6 cells) were suspended in Aldefluor assay buffer containing ALDH substrate.…”

“…In cervical cancer, ALDH1-positive cells, like other solid tumors, are known to be more tumorigenic than negative ones, and we used ALDH1 as a marker of cervical CSCs (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). First, using the cervical cancer cell line CaSki we confirmed that the expression of PAI-1 was significantly increased by changing coatings of culture plates as described (35), especially collagen IV-coating, confirmed by enzyme-linked immunosorbent assay (ELISA).…”