title: PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting.
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.
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. Electronic address: ludovicaciuffreda@hotmail.com.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Ciuffreda
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Italia
authors.initials: I
authors.lastname: Falcone
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Ursula Cesta
authors.initials: UC
authors.lastname: Incani
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Anais
authors.initials: A
authors.lastname: Del Curatolo
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Conciatori
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Matteoni
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Vari
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Cancer stem cells; Combination therapy; Crosstalk; Feedback loops; MAPK; PI3K; PTEN