Enhanced basal autophagy supports ameloblastoma-derived cell survival and reactivation

Arch Oral Biol. 2019 Feb:98:61-67. doi: 10.1016/j.archoralbio.2018.11.013. Epub 2018 Nov 14.

Abstract

Objectives: Ameloblastoma is an aggressive odontogenic jaw neoplasm. Its unlimited growth confers high potential for malignant transformation and recurrence. It is unclear why ameloblastoma is highly recurrent despite surgical resection with a wide margin of normal tissue. While canonical autophagy can be used to degrade and eliminate damaged cellular components, it is also a protective mechanism that provides energy and vital metabolites for cell survival. We used ameloblastoma-derived cells to test the hypothesis that autophagic processes play a role in survival and reactivation of ameloblastoma.

Methods: Primary epithelial (EP-AMCs) and mesenchymal (MS-AMCs) ameloblastoma-derived cells were established from tissue samples of solid multicystic ameloblastoma. Clonogenic capacity and basal autophagic capacity were assessed in ameloblastoma-derived cells relative to human odontoma-derived cells (HODCs) and maxilla-mesenchymal stem cells (MX-MSCs). Ability of ameloblastoma-derived cells to survive and form new ameloblastoma was assessed in mouse tumor xenografts.

Results: EP-AMCs were highly clonogenic (p < 0.0001) and demonstrated enhanced basal levels of autophagic proteins microtubule-associated protein 1-light chain 3 (LC3) (p < 0.01), p62 (Sequestosome 1, SQSTM1) (p < 0.01), and the LC3-adapter, melanoregulin (MREG) (p < 0.05) relative to controls. EP-AMCs xenografts regenerated solid ameloblastoma-like tumor with histological features of columnar ameloblast-like cells, loose stellate reticulum-like cells and regions of cystic degeneration characteristic of follicular variant of solid multicystic ameloblastoma. The xenografts also displayed stromal epithelial invaginations strongly reactive to LC3 and p62 suggestive of epithelial-mesenchymal transition and neoplastic odontogenic epithelium.

Conclusions: EP-AMCs exhibit altered autophagic processes that can support survival and recurrence of post-surgical ameloblastoma cells.

Keywords: Ameloblastoma; Autophagy; Recurrence; Survival.

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Ameloblastoma* / pathology
  • Ameloblasts / metabolism
  • Ameloblasts / pathology
  • Animals
  • Autophagy / physiology*
  • Carrier Proteins / metabolism
  • Cell Survival*
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition
  • Epithelium / metabolism
  • Female
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mesenchymal Stem Cells
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Recurrence, Local
  • Odontogenic Tumors*
  • Sequestosome-1 Protein / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • melanoregulin protein, mouse