Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures Through the Coordinated Regulation of Twist and the TGF-{beta}-Snail Signaling Axis [Cell Biology]

July 30th, 2014 by Chanmee, T., Ontong, P., Mochizuki, N., Kongtawelert, P., Konno, K., Itano, N.

The cancer stem cell (CSC) model suggests that a small subpopulation of cancer cells possesses the ability to self-renew and give rise to malignant progeny that drive cancer progression. Recent reports have also proposed the existence of certain extra- or intracellular signals that allow cancer progenitors to dynamically revert to a stem-cell state. However, the mechanisms underlying cancer cell plasticity and CSC expansion are not entirely clear. Our previous studies using a hyaluronan synthase 2 (Has2) transgenic mouse model demonstrated that hyaluronan overproduction caused rapid development of aggressive breast carcinoma at a high incidence. Thus, we hypothesize that hyaluronan overproduction may accelerate cancer progression by expanding CSC subpopulations during cancer development. Primary cancer cells were established from mammary tumors developed in transgenic mice and subjected to the Hoechst 33342 dye exclusion assay to sort side population (SP) from non-side population (non-SP) cells. Flow cytometric analysis demonstrated the enrichment of CD44high/CD24low CSC-like cells in the SP fraction of hyaluronan overproducing cancer cells. This subpopulation exhibited several characteristics that were similar to CSCs, including cancer-initiating and mammosphere-forming abilities. Excess hyaluronan production drove the epithelial-to-mesenchymal transition (EMT) process defined as the loss of epithelial phenotypes, up-regulation of transforming growth factor beta (TGF-β), and induction of the EMT-related transcriptional factors Snail and Twist. Inhibition of TGF-β-Snail signaling or silencing of Twist expression abrogated the entrance into a stem-cell state. Taken together, our findings suggest that hyaluronan overproduction allows plastic cancer cell populations to revert to stem-cell states via Twist and the TGF-β-Snail signaling axis.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures Through the Coordinated Regulation of Twist and the TGF-{beta}-Snail Signaling Axis [Cell Biology]