PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting

Ludovica Ciuffreda, Italia Falcone, Ursula Cesta Incani, Anais Del Curatolo, Fabiana Conciatori, Silvia Matteoni, Sabrina Vari, Vanja Vaccaro, Francesco Cognetti, Michele Milella

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Abstract

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a non-redundant lipid phosphatase that restrains and fine tunes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PTEN is involved in inherited syndromes, which predispose to different types of cancers and is among the most frequently inactivated tumor suppressor genes in sporadic cancers. Indeed, loss of PTEN function occurs in a wide spectrum of human cancers through a variety of mechanisms, including mutations, deletions, transcriptional silencing, or protein instability. PTEN prevents tumorigenesis through multiple mechanisms and regulates a plethora of cellular processes, including survival, proliferation, energy metabolism and cellular architecture. Moreover, recent studies have demonstrated that PTEN is able to exit, exist, and function outside the cell, allowing for inhibition of the PI3K pathway in neighboring cells in a paracrine fashion. Most recently, studies have shown that PTEN is also critical for stem cell maintenance and that PTEN loss can lead to the emergence and proliferation of cancer stem cell (CSC) clones. Depending on the cellular and tissue context of origin, PTEN deletion may result in increased self-renewal capacity or normal stem cell exhaustion and PTEN-defìcient stem and progenitor cells have been reported in prostate, lung, intestinal, and pancreatic tissues before tumor formation; moreover, reversible or irreversible PTEN loss is frequently observed in CSC from a variety of solid and hematologic malignancies, where it may contribute to the functional phenotype of CSC.In this review, we will focus on the role of PTEN expression and function and downstream pathway activation in cancer stem cell biology and regulation of the tumorigenic potential; the emerging role of PTEN in mediating the crosstalk between the PI3K and MAPK pathways will also be discussed, together with prospects for the therapeutic targeting of tumors lacking PTEN expression.

Original languageEnglish
Pages (from-to)66-80
Number of pages15
JournalAdvances in Biological Regulation
Volume56
DOIs
Publication statusPublished - 2014

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Keywords

  • Cancer stem cells
  • Combination therapy
  • Crosstalk
  • Feedback loops
  • MAPK
  • PI3K
  • PTEN

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Ciuffreda, L., Falcone, I., Cesta Incani, U., Del Curatolo, A., Conciatori, F., Matteoni, S., Vari, S., Vaccaro, V., Cognetti, F., & Milella, M. (2014). PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting. Advances in Biological Regulation, 56, 66-80. https://doi.org/10.1016/j.jbior.2014.07.002