Abstract
Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell-derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Aurora-A resulted in growth inhibition of CR-CSC, alteration of cell cycle kinetics, and downregulation of the expression levels of antiapoptotic Bcl-2 family members, strongly sensitizing to chemotherapy-induced cell death. Moreover, Aurora-A silencing compromised the ability to form tumor xenografts in immunocompromised mice and reduced the migratory capacity of CR-CSC. Altogether, these results indicate that Aurora-A is essential for CR-CSC regeneration and resistance to cytotoxic stimuli and suggest that therapies directed against Aurora-A may effectively target the stem cell population in colorectal cancer.
Highlights
Emerging evidence suggests the existence of a functional heterogeneity in different cell populations shaping the tumor mass
Colorectal cancer stem cells” (CSC) (CR-CSC) were characterized through the CD133+CD29+CK20− phenotype (Fig. 1A) and further validated through the capacity to form colon tumor xenografts in immunodeficient mice
RNA analysis performed on five different samples showed that Aurora-A was barely detectable in normal colon tissue, whereas it was clearly expressed in primary tumor cells, CR-CSC, sphere-derived adherent cells (SDAC), CD133+, and CD133− colon tumor populations (Fig. 1B)
Summary
Emerging evidence suggests the existence of a functional heterogeneity in different cell populations shaping the tumor mass. A small subpopulation of cells within the tumor mass called “cancer stem cells” (CSC) or “cancer-initiating cells” was shown to sustain tumor growth upon injection into immunocompromised mice, in contrast to more differentiated cells that are nontumorigenic [1]. The mechanisms underlying GIN have been investigated in embryonic stem cells, in which it has been shown that the mitotic-spindle checkpoint, functional, does not initiate apoptosis, contributing to karyotypic instability [10]. It was recently shown that embryonic germ cells transplanted in the testis of severe combined immunodeficient mice could generate a highly metastatic CSC population characterized by new nonclonal genomic rearrangements [11]. Chromosomal instability is observed in ∼85% of colon cancers occurring as the consequence of mutation or amplification of several genes such as hBUB1, BRCA1, BRCA2, and Aurora-A [12]
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