Profiling Cancer Stem Cells in Androgen‐Responsive and Refractory Human Prostate Tumor Cell Lines

Abstract

In this study, we investigated androgen metabolism in two different human prostate cancer cell lines, the androgen-responsive LNCaP cells and the nonresponsive PC3 cells. Following 24-h and 72-h incubation with either testosterone (T) or androstenedione (Ad) used as precursor, divergent patterns and rates of androgen metabolism were observed. Given the recent interest in the multiple uses of embryonic and adult stem cells for basic and applied research, we compared the expression of three presumptive stem cell markers (Oct-4, SUZ-12, and Cripto-1), along with connexin 43 (Cx43), Cx32, and androgen receptor (AR), used as cell differentiation gene markers. In anchorage-independent cell growth conditions, the expression levels of candidate markers of cancer stem cells initially increased (days 2-4) but drastically fell thereafter (day 6) in both cell lines. Results of immunocytochemical assay (ICA) largely confirmed those obtained by RT-PCR. Interestingly, both symmetrical and asymmetrical cell divisions were revealed in PC3 cells using Oct-4 immunostaining. Our data suggest that both androgen-responsive and androgen-nonresponsive prostate tumor cell lines contain a presumptive cancer stem cell population that can be identified using a panel of selected gene markers, including Oct-4, SUZ-12, and Cripto-1.

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

“…On the other hand, a breast cancer cell, expressing the ERB2/neu oncogene, or a prostate cancer that expresses various nonfunctional connexin genes (83), specific inhibitors to the specific oncogene being expressed might restore the function of the connexins, thereby restoring growth control, differentiation or apoptosis of the malignant cell.…”

Cripto-1: At the Crossroads of Embryonic Stem Cells and Cancer

“…The Cripto-1 positive subpopulation of melanoma cells represented a relatively smaller size population with a more spindle-shaped morphology, and showed increased expression of the stem cell associated transcription factors, Oct-4 and Nanog, as compared to the parental melanoma cells. Finally, Cripto-1 and the stem cell markers Oct-4 and SUZ-12 were identified in a small subpopulation of stem-like cells in hormone-responsive and nonresponsive prostate tumor cell (Cocciadiferro et al, 2009). Altogether, these findings suggest that Cripto-1 might be useful in the identification of a subpopulation of cancer cells with stem like behavior that are resistant to conventional therapy and are therefore a major obstacle in the clinical treatment of cancer patients.…”

“…Interestingly, Cripto-1 and other embryonic genes that regulate stem cell function are also overexpressed in human tumors, confirming this connection between stem cells and cancer. Recently, Cripto-1 has been shown to be highly expressed in a small subset of stem-like cells in human embryonal carcinoma cells, in human malignant melanomas and in androgen-responsive and refractory human prostate cancer cells (Cocciadiferro et al, 2009;Strizzi et al, 2008;Watanabe et al, 2010). Therefore, Cripto-1 signaling pathway may represent an attractive target for treatment in cancer, because Cripto-1 targeting will eliminate not only differentiated cancer cells but also might target an undifferentiated subpopulation of tumor cells that exhibit stem-like characteristics, thereby leading to eradication of the tumor.…”

Biochemical and Cellular Analysis Reveals Ligand Binding Specificities, a Molecular Basis for Ligand Recognition, and Membrane Association-dependent Activities of Cripto-1 and Cryptic

“…Biological functions beyond embryogenesis are not known, but both play major roles in human diseases. Cripto-1 is associated with colon, breast, pancreatic, ovarian, lung, and other cancers (15)(16)(17)(18). Cryptic is associated with heterotaxy syndromes and other laterality defects (19 -21).…”