Aldehyde Dehydrogenase (ALDH) Activity Does Not Select for Cells with Enhanced Aggressive Properties in Malignant Melanoma

Abstract

BackgroundMalignant melanoma is an exceptionally aggressive, drug-resistant and heterogeneous cancer. Recently it has been shown that melanoma cells with high clonogenic and tumourigenic abilities are common, but markers distinguishing such cells from cells lacking these abilities have not been identified. There is therefore no definite evidence that an exclusive cell subpopulation, i.e. cancer stem cells (CSC), exists in malignant melanoma. Rather, it is suggested that multiple cell populations are implicated in initiation and progression of the disease, making it of importance to identify subpopulations with elevated aggressive properties.Methods and FindingsIn several other cancer forms, Aldehyde Dehydrogenase (ALDH), which plays a role in stem cell biology and resistance, is a valuable functional marker for identification of cells that show enhanced aggressiveness and drug-resistance. Furthermore, the presence of ALDH+ cells is linked to poor clinical prognosis in these cancers. By analyzing cell cultures, xenografts and patient biopsies, we showed that aggressive melanoma harboured a large, distinguishable ALDH+ subpopulation. In vivo, ALDH+ cells gave rise to ALDH− cells, while the opposite conversion was rare, indicating a higher abilities of ALDH+ cells to reestablish tumour heterogeneity with respect to the ALDH phenotype. However, both ALDH+ and ALDH− cells demonstrated similarly high abilities for clone formation in vitro and tumour initiation in vivo. Furthermore, both subpopulations showed similar sensitivity to the anti-melanoma drugs, dacarbazine and lexatumumab.ConclusionsThese findings suggest that ALDH does not distinguish tumour-initiating and/or therapy-resistant cells, implying that the ALDH phenotype is not associated with more-aggressive subpopulations in malignant melanoma, and arguing against ALDH as a “universal” marker. Besides, it was shown that the ability to reestablish tumour heterogeneity is not necessarily linked to the more aggressive phenotype.

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

“…For the hierarchy assay, the xenografts were collected after 6 weeks, dissociated into single cells and TRA-1-85-positive cells analysed using the ALDH assays 57 . Single cells were suspended in ALDH assay buffer containing the BAAA (1 mM) and incubated 30 min at 37°C.…”

Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets

“…ALDH1+ breast cancer cells are at least 100 fold more tumorigenic than ALDH-cells in mice (44). Curiously, unlike most other tumors studied, in melanoma, high ALDH activity actually correlates with good patient prognosis (55). ALDHs have been proposed as a universal marker for identification for both normal stem cells as well as CSCs (6).…”

The correlation between aldehyde dehydrogenase-1A1 level and tumor shrinkage after preoperative chemoradiation in locally advanced rectal cancer

“…In the following years, ALDH1 activity would be used successfully as a CSC marker for many cancers including lung, liver, bone, colon, pancreatic, prostate, head and neck, bladder, thyroid, brain, melanoma and cervical [6] . With the exception of one recent study on malignant melanoma, increasing evidence suggests that ALDH1 activity is a universal CSC marker [7] . The role of ALDH1 in rectal cancer is not fully understood.…”