Abstract
Recent evidences have unveiled critical roles of cancer stem cells (CSCs) in tumorigenicity, but how interactions between CSC and tumor environments help maintain CSC initiation remains obscure. The small GTPases Rab27A regulates autocrine and paracrine cytokines by monitoring exocytosis of extracellular vesicles, and is reported to promote certain tumor progression. We observe that overexpression of Rab27A increased sphere formation efficiency (SFE) by increasing the proportion of CD44+ and PKH26high cells in HT29 cell lines, and accelerating the growth of colosphere with higher percentage of cells at S phase. Mechanism study revealed that the supernatant derived from HT29 sphere after Rab27A overexpression was able to expand sphere numbers with elevated secretion of VEGF and TGF-β. In tumor implanting nude mice model, tumor initiation rates and tumor sizes were enhanced by Rab27A with obvious angiogenesis. As a contrast, knocking down Rab27A impaired the above effects. More importantly, the correlation between higher p65 level and Rab27A in colon sphere was detected, p65 was sufficient to induce up-regulation of Rab27A and a functional NF-κB binding site in the Rab27A promoter was demonstrated. Altogether, our findings reveal a unique mechanism that tumor environment related NF-κB signaling promotes various colon cancer stem cells (cCSCs) properties via an amplified paracrine mechanism regulated by higher Rab27A level.
Highlights
The cancer stem cell hypothesis suggests that many cancers are maintained in a hierarchical fashion, consisting of rare, slowly dividing cancer stem cells (CSCs) or tumor-initiating cells (T-ICs), rapidly dividing amplifying cells or early precursor cells (EPC) and differentiated tumor cells [1,2,3]
We explored the function of Rab27A in cancer stem cells (cCSCs)
Colon cancer is one of the solid tumors comprising of a heterogeneous groups of cells [1,2,3], among which specific cancer stem cells can be marked, by CD133+ or CD44+, or the increased intensity of PKH26 dye labeling
Summary
The cancer stem cell hypothesis suggests that many cancers are maintained in a hierarchical fashion, consisting of rare, slowly dividing cancer stem cells (CSCs) or tumor-initiating cells (T-ICs), rapidly dividing amplifying cells or early precursor cells (EPC) and differentiated tumor cells [1,2,3]. CSCs can be enriched by sorting for stem markers, such as CD24, CD44, CD133 et al [4, 7, 11, 12], by selecting for www.impactjournals.com/oncotarget side-population (SP) cells that efflux Hoechst dyes [13, 14] or enhanced PKH26 dye-retaining capacity [15,16,17], or by isolating spherical clusters of self-replicating colospheres cells from suspension cultures [18, 19]. Genetic mutations of cCSCs is a key component in tumor progression (APC or Wnt/β-catenin) [21], inflammatory cytokines within the microenvironment affect cCSCs through activation of related pathways such as Notch, Hedgehog, STAT3 and NF-κB [22,23,24]. Schwitalla et al found that elevated NF-kB signaling enhances Wnt activation and induces dedifferentiation of non-stem cells that acquire tumor-initiating capacity [23]. Besides the direct effects of inflammation on CSC initiation, it will be interesting to know whether it can facilitate a cross-talk between CSC and its nearby environment
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