Abstract
Versican is highly expressed during the early stages of tissue development and its expression is elevated during wound repair and tumor growth. There is little literature on the potential role of breast cancer stem cells on the cellular-extracellular matrix interactions involving versican. An anti-versican short hairpin RNA (shRNA) was used to observe the effect of reduction of versican on breast cancer self-renewal. A versican G3 construct was exogenously expressed in breast cancer cell lines. Colony formation and mammosphere formation assays were conducted; flow cytometry was applied to analyze the prevalence of side population cells. The versican G3- and vector-transfected 66c14 cells were injected transdermally into BALB/c mice as a 10-fold dilution series from 1 × 10(5) to 1 × 10(2) cells per mouse. Versican G3 domain enhanced breast cancer self-renewal in both experimental in vitro and in vivo models. Versican G3-transfected cells contained high levels of side population cells, formed more mammospheres when cultured in the serum-free medium, and formed a greater number and larger colonies. Reduction of versican's functionality through anti-versican shRNA or knocking out the EGF-like motifs reduced the effect of versican on enhancing mammosphere and colony formation. Versican-enhanced self-renewal played a role in enhanced chemotherapeutic drug resistance, relating partly to the upregulated expression of EGF receptor (EGFR) signaling. Versican is highly expressed in breast cancer progenitor cells and was maintained at high levels before cell differentiation. Overexpression of versican enhanced breast cancer self-renewal through EGFR/AKT/GSK-3β (S9P) signaling and conferred resistant to chemotherapeutic drugs tested.
Highlights
Experimental and clinical evidence support the understanding that tumorigenesis is sustained by a small population of cells that function as tumor stem/progenitor cells[1, 2]
Immunoblotting demonstrated that the expression of versican is greater in stem/progenitor cells contained within mammospheres than in differentiated cells cultured in serum medium (Fig. 1c)
Immunostaining demonstrated that mammosphere 4T-1 cells expressed high levels of versican, and expressed high levels of characteristic breast cancer stem cell markers Sca-1, Sox2, and ALDH1 (Fig. S1). These results indicated that versican was highly expressed in mammary tumor stem/progenitor cells and its expression appeared to be down-regulated during cell differentiation
Summary
Experimental and clinical evidence support the understanding that tumorigenesis is sustained by a small population of cells that function as tumor stem/progenitor cells[1, 2] In breast cancer, these cells arise from mutated mammary stem/progenitor cells, which have been characterized by the expression of key cell surface markers (e.g., CD24, CD44, CD29, or Sca-1) as well as dye efflux assays based on the differential release of incorporated Hoechst dyes or rhodamine-121 through over-expressed or over-activated drug transporters in the cell membrane[3,4,5]. A number of developmental signaling pathways, such as Wnt, Notch, and Hedgehog, have been observed to play pivotal roles in governing both self-renewal and the process of malignant transformation[10, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
