Abstract
Cancer stem-like cells (CSCs) are a topic of increasing importance in cancer research, but are difficult to study due to their rarity and ability to rapidly divide to produce non-self-cells. We developed a simple model to describe transitions between aldehyde dehydrogenase (ALDH) positive CSCs and ALDH(-) bulk ovarian cancer cells. Microfluidics device-isolated single cell experiments demonstrated that ALDH+ cells were more proliferative than ALDH(-) cells. Based on our model we used ALDH+ and ALDH(-) cell division and proliferation properties to develop an empiric sampling algorithm and predict growth rate and CSC proportion for both ovarian cancer cell line and primary ovarian cancer cells, in-vitro and in-vivo. In both cell line and primary ovarian cancer cells, the algorithm predictions demonstrated a high correlation with observed ovarian cancer cell proliferation and CSC proportion. High correlation was maintained even in the presence of the EGF-like domain multiple 6 (EGFL6), a growth factor which changes ALDH+ cell asymmetric division rates and thereby tumor growth rates. Thus, based on sampling from the heterogeneity of in-vitro cell growth and division characteristics of a few hundred single cells, the simple algorithm described here provides rapid and inexpensive means to generate predictions that correlate with in-vivo tumor growth.
Highlights
Recent laboratory work has identified a limited subset of ovarian cancer cells with stem cell marker expression
Using growth rates and division patterns, we produced Cancer stem-like cells (CSCs) and non-CSC simulation-based predictions for larger mixed populations in-vitro and in-vivo. We show that this simple approach accurately predicts changes in growth associated with the CSC-oriented growth factor EGF-like domain multiple 6 (EGFL6)
While aldehyde dehydrogenase (ALDH)+ cells represent a small portion of total ovarian cancer cells, they play an important role in chemotherapy resistance and tumor initiation [5, 7]
Summary
Recent laboratory work has identified a limited subset of ovarian cancer cells with stem cell marker expression These cancer stem-like cells (CSC) have been found to have unique biologic properties, including increased tumor initiation capacity and, in some cases, chemotherapy resistance [1,2,3,4]. Our group and others have reported that aldehyde dehydrogenase (ALDH) activity, alone or in combination with other stem cell markers, identifies CSC in ovarian cancer [5,6,7,8] These ALDH+ cells have increased chemotherapy resistance, increased tumor initiation capacity, and the ability to produce both ALDH+ and ALDH(-) cells [9]. Suggesting a role in disease chemotherapy resistance and disease recurrence, ALDH+ cells are enriched in both patient derived www.impactjournals.com/oncotarget xenografts and primary chemo-refractory tumor specimens [10, 11] Given these unique properties, CSCs are an important focus in translational research. Understanding how the small CSCs fraction drives self-renewal and tumor growth will provide insights into tumorigenesis
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