Abstract
Although the cancer stem cell (CSC) concept has provided a reasonable explanation for cancer recurrence following chemotherapy, the relationship between CSCs and chemotherapy resistance has not been thoroughly investigated, especially in solid tumors. We aimed to identify the mechanism underlying colorectal cancer (CRC) chemoresistance focusing on the cell cycle mediator F-Box/WD repeat domain-containing 7 (FBXW7). From 55 consecutive CRC cases who underwent neoadjuvant chemotherapy (NAC) or neoadjuvant chemoradiotherapy (NACRT) at Kyoto University Hospital, pre-treatment endoscopic biopsy specimens were collected and divided into two groups upon immunohistochemical (IHC) analysis: 21 cases of FBXW7 high expression (FBXW7-high group) and 34 cases of low expression (FBXW7-low group). High FBXW7 expression in pre-treatment biopsy specimen was significantly associated with poor pathological therapeutic effect (p = 0.019). The proportion of FBXW7-positive cells in surgically resected CRC specimens from patients who underwent NAC or NACRT was significantly higher than that in the pre-treatment biopsy specimens (p < 0.001). The expression of FBXW7 was inversely correlated with that of Ki67 in both pre-treatment biopsy specimens and surgically resected specimens. FBXW7 expression in the EpCAMhigh/CD44high subpopulation isolated by flow cytometry from CRC samples was significantly higher than that in the EpCAMhigh/CD44low subpopulation. Cell-cycle analysis in CRC cell lines revealed that, upon FBXW7 silencing, the proportion of G0/G1 cells was significantly lower than that in control cells. Moreover, knockdown of FBXW7 in CRC cell lines increased the sensitivity to anti-cancer drugs in vitro and in vivo. A subset of CRC stem cells possesses chemoresistance through FBXW7 expression. Cell cycle arrest induced by FBXW7 expression should be considered as a potential therapeutic target to overcome chemoresistance in CRC stem cell subsets.
Highlights
Colorectal cancer (CRC) is one of the most common causes of cancer deaths worldwide due to its recurrence and chemoresistanse [1]
We first investigated the relationship between F-Box/WD repeat domain-containing 7 (FBXW7) expression in the pre-treatment biopsy specimens and the pathological therapeutic effect of neoadjuvant chemotherapy (NAC)/neoadjuvant chemoradiotherapy (NACRT) followed by surgical resection
We characterized FBXW7 expression in the pre-treatment biopsy specimens as low (IHC score, 1, 2) or high (IHC score, 3, 4, 6; Figure 1A)
Summary
Colorectal cancer (CRC) is one of the most common causes of cancer deaths worldwide due to its recurrence and chemoresistanse [1]. Recent studies have suggested that tumors show cellular hierarchy with a subpopulation of cancer cells that can renew and generate differentiated tumor cells [5,6,7,8]. This highly tumorigenic cells have been defined as cancer stem cells (CSCs), conventionally sorted based on the expression of several cell surface markers such as CD44, CD133 and CD166 [9,10,11,12]. Failure to eliminate quiescent CSCs may result in regrowth or clinical recurrence of the tumor. The development of therapeutic approaches that target quiescent CSCs is necessary to eradicate cancers
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