The differentiation of pancreatic tumor-initiating cells by vitronectin can be blocked by cilengitide.

Paradigms and Technologies
Methods Development

Abstract

OBJECTIVE: Pancreatic cancer is a leading cancer type and its molecular pathology is poorly understood. The only potentially curative therapeutic option available is complete surgical resection; however, this is inadequate as most of the patients are diagnosed at an advanced or metastatic stage. Tumor-initiating cells (TICs) constitute a subpopulation of cells within a solid tumor that sustain tumor growth, metastasis, and chemo/radioresistance. Within pancreatic cancer, TICs have been identified based on the expression of specific cell surface markers. METHODS: We use a sphere formation assay to enrich putative TICs and use human serum as a driver of differentiation. We demonstrate by using specific blocking reagents that we can inhibit the differentiation process and maintain TIC-associated markers and genes. RESULTS: We can induce differentiation of pancreatospheres with the addition of human serum, and we identified vitronectin as an inducer of differentiation. We inhibit differentiation by human serum using an arginine-glycine-aspartate-specific peptide, which is Cilengitide; hence, demonstrating this differentiation is mediated via specific integrin receptors. CONCLUSIONS: Overall, our studies further the definition of pancreatic TICs and provide further insight into both the maintenance and differentiation of this lethal population.

Authors

Cabarcas, Stephanie M; Sun, Lei; Mathews, Lesley; Thomas, Suneetha; Zhang, Xiaohu; Farrar, William L;

Keywords

  • Biomarkers, Tumor/ genetics
  • Cell Differentiation/ drug effects
  • Cell Differentiation/ genetics
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic/ drug effects
  • Humans
  • Integrin alphaVbeta3/ genetics
  • Neoplastic Stem Cells/ drug effects
  • Neoplastic Stem Cells/ metabolism
  • Neoplastic Stem Cells/ pathology
  • Pancreatic Neoplasms/ genetics
  • Pancreatic Neoplasms/ pathology
  • Receptors, Vitronectin/ genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serum/ physiology
  • Snake Venoms/ pharmacology
  • Spheroids, Cellular/ drug effects
  • Spheroids, Cellular/ metabolism
  • Spheroids, Cellular/ pathology
  • Tumor Cells, Cultured
  • Vitronectin/ pharmacology

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