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Identification and Characterization of Cancer Stem Cells Responsible for Drug-Resistance and Metastasis

小林, 慎太 筑波大学 DOI:10.15068/0002000838

2021.08.02

概要

Cancer stem cell (CSC) theory posits that a subset of cancer cells has the indefinite self-renewal ability to initiate and maintain tumor reconstitution. Therefore, tumors are organized in a hierarchical fashion, equivalent to the normal tissue hierarchy supported by stem cells. To accurately characterize CSCs, I focused on normal stem cell related molecules (LGR5: Leucine-rich repeat-containing G-protein-coupled Receptor 5 and Insm1: Insulinoma-associated protein 1) and evaluated the relationship between CSCs, drug resistance, and metastasis.

In colorectal tumors, LGR5-posotive (LGR5+) cells were shown to have CSC properties. In the presence of anticancer drugs, LGR5+ cells were transformed into LGR5-negative (LGR5-) drug-resistant cells. Upon removal of anticancer drugs, LGR5- cells reverted to LGR5+ and reconstituted hierarchical tumors in vitro and in vivo. In addition, I found that HLA-DMA and epiregulin (EREG) can be used as markers of LGR5- drug-resistant cells. Using these markers, I detected both LGR5+ and HLA- DMA+/EREG+ cells in colon patients. For pancreatic neuroendocrine tumors, I used RIP1-Tag2 (RT2) transgenic mice to establish a functional tumor (RT2 B6) model and a non-functional stem cell type tumor (RT2 AB6F1) model. The results showed that

Insm1 was strongly expressed in RT2 B6, but only slightly expressed in highly metastatic RT2 AB6F1. Using human cell lines, Insm1 deletion induced a CSC phenotype and increased cancer invasion in vitro and cancer metastasis rates in vivo. Thus, LGR5 and Insm1, which play important roles in normal stem cells, were found to be associated with drug resistance and metastasis in CSCs. The results provide new biological insights into drug resistance and metastasis of CSCs.

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