Abstract 10: Characterization of ovarian CSC using ALDH and CD133 identifies a cancer stem cell hierarchy

Abstract

Abstract Recent studies in ovarian cancer suggest that the protein CD133 may be a marker of cancer stem cells (CSC). CSC studies in several solid tumors have identified Aldehyde dehyrogenase (ALDH) enzymatic activity as a CSC marker, however ALDH has not been studied in ovarian cancer. We sought to determine if ALDH alone or in combination with CD133 could better define CSC in ovarian cancer. We analyzed the expression of these markers in 13 consecutive primary human ovarian tumor specimens and 8 cell lines. 70% of primary ovarian tumors analyzed had CD133+ cells detectable in low number in, and many tumor cell lines lacked CD133 expression. In contrast, 100% of the primary human ovarian tumor specimens and ovarian cancer cell lines demonstrated ALDH activity. ALDH+ cells isolated from 6 ovarian cancer cell lines preferentially grew larger tumors at a faster rate compared to ALDH− cells. In some cases ALDH− cells were incapable of generating tumors, suggesting ALDH is a good marker of ovarian CSC in cell lines. Importantly, as few as 1000 ALDH+ cells directly isolated from human ovarian tumors were capable of generating tumors in immune deficient mice. ALDH− cells did not form tumors in mice. Interestingly, when ALDH was used in combination with CD133 to analyze ovarian cancer cell lines we observed greater growth in the ALDH+CD133+ cells compared to ALDH+CD133− cells suggesting a potential hierarchy of the stem cells. Consistent with this, as few as 11 ALDH+CD133+ cells freshly isolated from human tumors were capable of forming tumors in mice. Consistent with a stem cell hierarchy, tumors formed from ALDH+CD133+ cells demonstrated a poorly differentiated histology, whereas tumors formed from ALDH+ cells alone demonstrated a more differentiated histology. Finally analysis of tumors generated from ALDH+ and ALDH+CD133+ tumors demonstrated a significant increase in microvascular density compared to ALDH− tumors. qRT-PCR analysis demonstrated that ALDH+ cells compared to ALDH− cells preferentially express numerous angiogenic factors. Taken together our studies: (1) indicate ALDH as a marker of ovarian CSC, (2) suggest a hierarchy of ovarian cancer stem cell differentiation state, and (3) demonstrates that ovarian CSC are highly angiogenic to recruit vasculature to create a stem cell niche. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 10.