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Cells
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The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis
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The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 23045

Special Issue Editors

Prof. Dr. Bangyan L. Stiles

E-Mail Website
Guest Editor
Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
Interests: PTEN; PI3K; AKT; liver cancer; lipid metabolism; cancer stem cells; mitochondria
Dr. Reginald Hill

E-Mail Website
Guest Editor
Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
Interests: PTEN; inflammation; pancreatic cancer; exosomes; tumor microenvironment; ER stress

Special Issue Information

Dear Colleagues,

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) encodes a 403-amino acid protein that has an N-terminal domain that shares sequence homology with the actin-binding protein tensin and the putative tyrosine–protein phosphatase auxilin. Since its discovery in 1997, PTEN has been identified to be the 2nd most commonly lost tumor suppressor in primary malignancies. Alterations including point mutations, deletions, and genomic rearrangements of PTEN have been identified in numerous cancers. Epigenetic modifications, promotor methylation and microRNAs that target PTEN have also been identified that play important roles in regulating PTEN in tumors. Germline deletion of PTEN is found in familial syndromes such as Cowden’s and Bannayan–Riley–Ruvalcaba (BRR), now collectively termed PHTS (PTEN hamartoma tumor syndrome). Patients with PHTS are prone to develop multiple tumors in their life time due to loss of PTEN function. On the molecular level, PTEN regulates a variety of cellular processes via its phosphatase function including its primary target, the PI3K/AKT signaling pathway. In this Special Issue of Cells, titled “The PTEN Tumor Suppressor and Its Role in Tumour Pathogenesis”, we would like to welcome original research and review articles that focus on the role of PTEN in tumor development; explore the pathogenesis of PTEN regulated tumorigenesis; explore past and ongoing efforts to target PTEN regulated signals in tumor development; and provide perspectives on future directions in PTEN research and drug development.

Prof. Bangyan L. Stiles
Dr. Reginald Hill
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PTEN
  • PI3K
  • AKT
  • mTOR
  • tumor
  • metabolism
  • PHTS

Published Papers (5 papers)

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Research

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20 pages, 4318 KiB  
Article
The Novel Phosphatase Domain Mutations Q171R and Y65S Switch PTEN from Tumor Suppressor to Oncogene
by Jose Antonio Ma. G. Garrido, Krizelle Mae M. Alcantara, Joshua Miguel C. Danac, Fidel Emmanuel C. Serrano, Eva Maria Cutiongco-de la Paz and Reynaldo L. Garcia
Cells 2021, 10(12), 3423; https://doi.org/10.3390/cells10123423 - 5 Dec 2021
Cited by 1 | Viewed by 4069
Abstract
Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway. Large datasets [...] Read more.
Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors. Full article
(This article belongs to the Special Issue The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis)
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12 pages, 945 KiB  
Article
Molecular Protein and Expression Profile in the Primary Tumors of Clear Cell Renal Carcinoma and Metastases
by Liudmila V. Spirina, Zahar A. Yurmazov, Alexey K. Gorbunov, Evgeny A. Usynin, Nadezhda A. Lushnikova and Irina V. Kovaleva
Cells 2020, 9(7), 1680; https://doi.org/10.3390/cells9071680 - 13 Jul 2020
Cited by 7 | Viewed by 2189
Abstract
Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and distant organs and is the primary cause of cancer morbidity and mortality. The aim of the study was the determination of change in molecular factors expression in primary [...] Read more.
Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and distant organs and is the primary cause of cancer morbidity and mortality. The aim of the study was the determination of change in molecular factors expression in primary kidney cancers (ccRCC) and metastatic sites. In total, 62 patients with RCC were enrolled in the study. The mRNA levels of molecular markers were studied by real-time PCR, and the content of the studied parameters was determined by Western blotting and ELISA. The features in the intracellular signal metabolites in the series of normal renal parenchyma, tumor tissue of localized, disseminated kidney cancer and metastatic tissue were studied. A decrease in some indicators in the tissue of the metastatic lesion was noted. Protein products of transcription factors HIF-1, CAIX, PTEN and activated AKT kinase, as well as expression of the VEGFR2 receptor and m-TOR protein kinase were revealed to be reduced in the metastatic sites. In addition, some indicators increased in metastasis: the protein levels of NF-κB p 50, NF-κB p 65, HIF-2, VEGF, VEGFR2, m-TOR and mRNA of HIF-1, CAIX, PTEN and PDK. There were indicators with multidirectional changes. HIF-1, CAIX, PTEN, VEGFR2 and m-TOR mRNA: VEGFR2, m-TOR, HIF-1, CAIX, PTEN and PDK had an opposite change in protein content and mRNA level. PTEN loss resulted in the downstream activation of AKT/mTOR signaling in secondary cancer lesions and determined the overall ccRCC patient’s survival. The AKT/mTOR signaling cascade activation was found in the primary kidney tumors. The PTEN content and mRNA level were correlated with total AKT, GSK-3β, the 70S 6 kinases and AKT expression. Full article
(This article belongs to the Special Issue The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis)
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16 pages, 1283 KiB  
Article
Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children?
by Michaela Plamper, Mark Born, Bettina Gohlke, Felix Schreiner, Sandra Schulte, Vera Splittstößer and Joachim Woelfle
Cells 2020, 9(7), 1668; https://doi.org/10.3390/cells9071668 - 10 Jul 2020
Cited by 11 | Viewed by 3592
Abstract
Background: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children [...] Read more.
Background: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. Methods: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. Results: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. Conclusion: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood. Full article
(This article belongs to the Special Issue The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis)
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Review

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48 pages, 2799 KiB  
Review
The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer
by Daniel J. Turnham, Nicholas Bullock, Manisha S. Dass, John N. Staffurth and Helen B. Pearson
Cells 2020, 9(11), 2342; https://doi.org/10.3390/cells9112342 - 22 Oct 2020
Cited by 38 | Viewed by 7546
Abstract
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient [...] Read more.
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care. Full article
(This article belongs to the Special Issue The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis)
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19 pages, 1037 KiB  
Review
The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment
by Saveria Aquila, Marta Santoro, Annalisa Caputo, Maria Luisa Panno, Vincenzo Pezzi and Francesca De Amicis
Cells 2020, 9(7), 1725; https://doi.org/10.3390/cells9071725 - 18 Jul 2020
Cited by 54 | Viewed by 5100
Abstract
Recent studies conducted over the past 10 years evidence the intriguing role of the tumor suppressor gene Phosphatase and Tensin Homolog deleted on Chromosome 10 PTEN in the regulation of cellular energy expenditure, together with its capability to modulate proliferation and survival, thus [...] Read more.
Recent studies conducted over the past 10 years evidence the intriguing role of the tumor suppressor gene Phosphatase and Tensin Homolog deleted on Chromosome 10 PTEN in the regulation of cellular energy expenditure, together with its capability to modulate proliferation and survival, thus expanding our knowledge of its physiological functions. Transgenic PTEN mice models are resistant to oncogenic transformation, present decreased adiposity and reduced cellular glucose and glutamine uptake, together with increased mitochondrial oxidative phosphorylation. These acquisitions led to a novel understanding regarding the role of PTEN to counteract cancer cell metabolic reprogramming. Particularly, PTEN drives an “anti-Warburg state” in which less glucose is taken up, but it is more efficiently directed to the mitochondrial Krebs cycle. The maintenance of cellular homeostasis together with reduction of metabolic stress are controlled by specific pathways among which autophagy, a catabolic process strictly governed by mTOR and PTEN. Besides, a role of PTEN in metabolic reprogramming and tumor/stroma interactions in cancer models, has recently been established. The genetic inactivation of PTEN in stromal fibroblasts of mouse mammary glands, accelerates breast cancer initiation and progression. This review will discuss our novel understanding in the molecular connection between cell metabolism and autophagy by PTEN, highlighting novel implications regarding tumor/stroma/immune system interplay. The newly discovered action of PTEN opens innovative avenues for investigations relevant to counteract cancer development and progression. Full article
(This article belongs to the Special Issue The PTEN Tumor Suppressor and Its Role in Tumor Pathogenesis)
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