Characterization of cervical cancer stem cell-like cells: phenotyping, stemness, and human papilloma virus co-receptor expression

Oncotarget. 2016 May 31;7(22):31943-54. doi: 10.18632/oncotarget.8218.

Abstract

Cancer stem cells (CSC) exhibit high tumorigenic capacity in several tumor models. We have now determined an extended phenotype for cervical cancer stem cells. Our results showed increased CK-17, p63+, AII+, CD49f+ expression in these cells, together with higher Aldehyde dehydrogenase (ALDHbright)activity in Cervical CSC (CCSC) enriched in cervospheres. An increase in stem cell markers, represented by OCT-4, Nanog, and β-catenin proteins, was also observed, indicating that under our culture conditions, CCSC are enriched in cervospheres, as compared to monolayer cultures. In addition, we were able to show that an increased ALDHbright activity correlated with higher tumorigenic activity. Flow cytometry and immunflorescence assays demonstrated that CCSC in cervosphere cultures contain a sub-population of cells that contain Annexin II, a Human papillomavirus (HPV) co-receptor. Taken together, under our conditions there is an increase in the number of CCSC in cervosphere cultures which exhibit the following phenotype: CK-17, p63+, AII+, CD49f+ and high ALDH activity, which in turn correlates with higher tumorigenicity. The presence of Annexin II and CD49f in CCSC opens the possibility that normal cervical stem cells could be the initial target of infection by high risk HPV.

Keywords: ALDH activity; cervical cancer; cervical cancer stem cell phenotype; cervospheres; stemness markers.

MeSH terms

  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Annexin A2 / metabolism*
  • Biomarkers, Tumor / metabolism
  • Female
  • HeLa Cells
  • Humans
  • Integrin alpha6 / metabolism
  • Keratin-17 / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Spheroids, Cellular
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology

Substances

  • ANXA2 protein, human
  • Annexin A2
  • Biomarkers, Tumor
  • Integrin alpha6
  • Keratin-17
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Aldehyde Dehydrogenase