Distinct Expression Levels and Patterns of Stem Cell Marker, Aldehyde Dehydrogenase Isoform 1 (ALDH1), in Human Epithelial Cancers

Abstract

Aldehyde dehydrogenase isoform 1 (ALDH1) has been proved useful for the identification of cancer stem cells. However, our knowledge of the expression and activity of ALDH1 in common epithelial cancers and their corresponding normal tissues is still largely absent. Therefore, we characterized ALDH1 expression in 24 types of normal tissues and a large collection of epithelial tumor specimens (six cancer types, n = 792) by immunohistochemical staining. Using the ALDEFUOR assay, ALDH1 activity was also examined in 16 primary tumor specimens and 43 established epithelial cancer cell lines. In addition, an ovarian cancer transgenic mouse model and 7 murine ovarian cancer cell lines were analyzed. We found that the expression levels and patterns of ALDH1 in epithelial cancers are remarkably distinct, and they correlate with their corresponding normal tissues. ALDH1 protein expression levels are positively correlated with ALDH1 enzymatic activity measured by ALDEFLUOR assay. Long-term in vitro culture doesn't significantly affect ALDH1 activity in epithelial tumor cells. Consistent with research on other cancers, we found that high ALDH1 expression is significantly associated with poor clinical outcomes in serous ovarian cancer patients (n = 439, p = 0.0036). Finally, ALDHbr tumor cells exhibit cancer stem cell properties and are resistant to chemotherapy. As a novel cancer stem cell marker, ALDH1 can be used for tumors whose corresponding normal tissues express ALDH1 in relatively restricted or limited levels such as breast, lung, ovarian or colon cancer.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…Moreover, high ALDH1A expression has been associated with adverse prognosis in breast, lung, serous ovarian, pancreatic, bladder, prostate and oesophageal cancer [76]. With regard to GC, the findings are still conflicting and inconclusive [77][78][79][80][81][82][83] and, to our knowledge, no previous studies have investigated ALDH1A expression in HDGC and its precursor lesions, to assess the validity of this putative CSC biomarker in this specific setting.…”

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

“…Although several putative ovarian CSC markers have been identified (e.g., CD133, ALDH1, CD44, and CD117) (8,18,19,44,45), such markers also can be found on normal adult tissues, including normal stem cells (10,46,47). Therefore, targeting such antigens with mAbs or small molecules also may affect the normal tissues that express these antigens (48,49).…”

“…Compared with other ovarian cancer cells, ovarian CSCs have relatively high aldehyde dehydrogenase (ALDH1) enzymatic activity (9)(10)(11), which may serve to detoxify intracellular aldehydes or various cytotoxic drugs (12,13). Ovarian CSCs also can extrude small molecules, such as various chemotherapeutic drugs or fluorescent dyes, allowing for their identification as a less fluorescent "side population" in flowcytometric analysis of tumor cells stained with the DNA-binding dye Hoechst 33342 (14)(15)(16).…”

Understanding cancer stem cell heterogeneity and plasticity

“…Although the interrelationships between these different subsets of tumorigenic BCSCs remain unclear, these observations [49][50][51][52][53][54][55] suggest that human BCSCs are phenotypically diverse. Indeed, recent studies [53][54][55][56][57][58][59] indicate that not only CSC marker expression in breast cancer cells is heterogeneous but also there exist many subsets of BCSCs that vary from patient to patient, which may be related to individual tumor's genetic makeup [44]. The enrichment of BCSCs by different approaches also suggests that different phenotypes may identify overlapping tumorigenic populations and consequently, certain combinatorial strategies might further enrich tumor-initiating cells.…”