Abstract
Cancer stem cells (CSCs) are rare cancer cells that are postulated to be responsible for cancer relapse and metastasis. However, CSCs are difficult to isolate and poorly understood. Here, a bioinspired approach for label‐free isolation and culture of CSCs, by microencapsulating one cancer cell in the nanoliter‐scale hydrogel core of each prehatching embryo‐like core–shell microcapsule, is reported. Only a small percentage of the individually microencapsulated cancer cells can proliferate into a cell colony. Gene and protein expression analyses indicate high stemness of the cells in the colonies. Importantly, the colony cells are capable of cross‐tissue multilineage (e.g., endothelial, cardiac, neural, and osteogenic) differentiation, which is not observed for “CSCs” isolated using other contemporary approaches. Further studies demonstrate the colony cells are highly tumorigenic, metastatic, and drug resistant. These data show the colony cells obtained with the bioinspired one‐cell‐culture approach are truly CSCs. Significantly, multiple pathways are identified to upregulate in the CSCs and enrichment of genes related to the pathways is correlated with significantly decreased survival of breast cancer patients. Collectively, this study may provide a valuable method for isolating and culturing CSCs, to facilitate the understanding of cancer biology and etiology and the development of effective CSC‐targeted cancer therapies.
Highlights
There is mounting evidence that suggests a small subset of cancer cells possesses the exclusive capability of forming tumors, and these cells are often called cancer stem cells (CSCs) or tumor initiating cells.[1]
To address the aforementioned challenges and efficiently isolate and culture CSCs, we have been inspired by the nature’s approach of culturing stem cells in the prehatching embryos, which starts from one cell that proliferates into a cell colony in a miniaturized core surrounded by a shell known as the zona pellucida.[13]
Hyaluronic acid was found to be crucial for the CSCs to survive and form colonies under the 1csc culture and the CSCs take up ∼3–5% the whole cancer cell population
Summary
There is mounting evidence that suggests a small subset of cancer cells possesses the exclusive capability of forming tumors, and these cells are often called cancer stem cells (CSCs) or tumor initiating cells.[1]. “CSCs” have been isolated based on surface markers, such as CD44, CD133, CD24, epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase 1 (ALDH1), and adenosine triphosphate (ATP)-binding cassette B5 (ABCB5).[3] This isolation method often causes confusion This is because two or more surface makers have been used to identify CSCs from the same type of cancer in different studies, but co-expression of the different surface markers among the selected CSCs is limited.[4] For example, either ALDH1+ or CD44+CD24−/low has been used to select CSCs of breast cancer, but a surprisingly small percentage (0.1–1.2%) of the CSCs expresses both markers simultaneously.[5] For pancreatic cancer, either CD44+CD24+ESA(epithelial-specific antigen)+ or CD133 has been used to select its CSCs, while only 10–40% of the CD44+CD24+ESA+ cells in primary tumors are shown to be positive for CD133 expression.[6] the EpCAM+CD44+ colorectal CSCs exhibit little overlap with the CD133+ population.[7] In essence, it appears that none of these markers are consistently expressed on the solid tumor CSCs and the specific CSC marker(s) for a given type of cancer is still unknown. The development of a marker-free method for effective isolation and culture of true CSCs is in need
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