ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets

Abstract

Although the concept of cancer stem cells (CSCs) is well accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In the present study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into NOD/SCID mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis and decreased cell viability in vitro and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

“…ALDH (aldehyde dehydrogenase) activity, often measured via ALDEFLUOR assay, has been successfully used as a marker to enrich CSC populations 11,[17][18][19][20][21][22] in a variety of cancers including human melanoma 23 and head and neck squamous cell cancer. 18 We characterized CSC-enriched populations in 2 histologically distinct murine tumors (melanoma D5 and squamous cell cancer SCC7) and evaluated their immunogenicity by administering CSC-based vaccines in 2 genetically different syngeneic immunocompetent hosts followed by tumor challenge.…”

NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

“…Later, other groups developed a convenient method to measure intracellular ALDH1 activity in live cells (7,9). To date, this method is widely used to isolate HSCs from blood and CSCs from many tumor types, including leukemia (5,8,9), breast cancer (6), melanoma (10), lung cancer (11), and others (12,13). Ginestier et al found that ALDH1 is a good marker for malignant human mammary stem cells and that high-ALDH1 activity cell populations leads to substantial tumorigenesis, poor prognosis, and increased metastasis in xenografted mouse models (6).…”

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

“…Moreover, above therapy following surgical resection of primary tumor inhibited recurrence of the disease and extended survival of mice. Luo et al 21 have shown that ALDH1A isoenzymes are markers of human MSC as well. Moreover, they demonstrated that ALDH1-positive melanoma cells are more tumorigenic and more resistant to chemotherapeutics in mice models.…”