PTEN Tumor-Suppressor: The Dam of Stemness in Cancer
Francesca Luongo1, Francesca Colonna1, Federica Calapà1
1Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy.
Abstract:
PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.
Insights
The tumor suppressor PTEN (phosphatase and tensin homolog) is crucial for controlling cancer stem cells (CSCs). Loss of PTEN function promotes CSCs, driving tumor growth and therapy resistance, highlighting PTEN as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN (phosphatase and tensin homolog) is a frequently inactivated tumor suppressor gene in various cancers.
- Loss or mutation of PTEN is linked to inherited cancer predisposition syndromes and promotes tumorigenesis.
- PTEN regulates critical cellular functions including growth, proliferation, survival, DNA repair, and motility, primarily via the PI3K/AKT/mTOR pathway.
Purpose of the Study:
- To review the critical role of PTEN in maintaining normal and cancer stem cell (CSC) homeostasis.
- To elucidate how PTEN alterations impact CSC hallmarks like self-renewal, quiescence, and epithelial-to-mesenchymal transition (EMT).
- To explore PTEN's role in therapy resistance and its potential for novel cancer treatment strategies.
Main Methods:
- Literature review and synthesis of existing research findings on PTEN and cancer stem cells.
- Analysis of PTEN's phosphatase-dependent and independent activities, subcellular localization, and protein interactions.
- Focus on PTEN's regulation of CSC-specific mechanisms and therapy resistance pathways.
Main Results:
- PTEN loss or variation significantly fosters the cancer stem cell compartment in both solid and hematologic malignancies.
- PTEN inactivation contributes to tumor propagation, metastasis, and resistance to cancer therapies.
- Understanding PTEN's role in CSC regulation is key to developing effective therapeutic approaches.
Conclusions:
- PTEN is a critical regulator of cancer stem cell state and function.
- Targeting PTEN-mediated pathways holds promise for overcoming therapy resistance and improving cancer treatment outcomes.
- Further research into PTEN's multifaceted roles can unlock new therapeutic strategies against cancer.
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