Research

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16 pages, 2412 KiB

Open AccessArticle

The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells

by Anna S. Kirstein, Adrien Augustin, Melanie Penke, Michele Cea, Antje Körner, Wieland Kiess and Antje Garten

Cancers 2019, 11(10), 1586; https://doi.org/10.3390/cancers11101586 - 17 Oct 2019

Cited by 17 | Viewed by 4456

Abstract

Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients with PHTS frequently develop lipomas. Treatment attempts with the mTORC1 inhibitor rapamycin were unable to reverse lipoma growth. Recently, lipomas associated with PIK3CA-related overgrowth syndrome were successfully [...] Read more.

Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients with PHTS frequently develop lipomas. Treatment attempts with the mTORC1 inhibitor rapamycin were unable to reverse lipoma growth. Recently, lipomas associated with PIK3CA-related overgrowth syndrome were successfully treated with the novel PI3K inhibitor alpelisib. Here, we tested whether alpelisib has growth-restrictive effects and induces cell death in lipoma cells. We used PTEN-haploinsufficient lipoma cells from three patients and treated them with alpelisib alone or in combination with rapamycin. We tested the effect of alpelisib on viability, proliferation, cell death, induction of senescence, adipocyte differentiation, and signaling at 1–100 µM alpelisib. Alpelisib alone or in combination with rapamycin reduced proliferation in a concentration- and time-dependent manner. No cell death but an induction of senescence was detected after alpelisib incubation for 72 h. Alpelisib treatment led to a reduced phosphorylation of AKT, mTOR, and ribosomal protein S6. Rapamycin treatment alone led to increased AKT phosphorylation. This effect could be reversed by combining rapamycin with alpelisib. Alpelisib reduced the size of lipoma spheroids by attenuating adipocyte differentiation. Since alpelisib was well tolerated in first clinical trials, this drug alone or in combination with rapamycin is a potential new treatment option for PHTS-related adipose tissue overgrowth. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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10 pages, 914 KiB

Open AccessArticle

Phenotype-Driven Diagnostic of PTEN Hamartoma Tumor Syndrome: Macrocephaly, But Neither Height nor Weight Development, Is the Important Trait in Children

by Michaela Plamper, Bettina Gohlke, Felix Schreiner and Joachim Woelfle

Cancers 2019, 11(7), 975; https://doi.org/10.3390/cancers11070975 - 11 Jul 2019

Cited by 8 | Viewed by 3181

Abstract

PTEN hamartoma tumor syndrome (PHTS) encompasses different syndromic disorders which are associated with autosomal-dominant mutations of the tumor suppressor gene PTEN. Patients are at high risk to develop benign and malignant tumors. Macrocephaly is a diagnostic feature, but there is a paucity [...] Read more.

PTEN hamartoma tumor syndrome (PHTS) encompasses different syndromic disorders which are associated with autosomal-dominant mutations of the tumor suppressor gene PTEN. Patients are at high risk to develop benign and malignant tumors. Macrocephaly is a diagnostic feature, but there is a paucity of data on auxological development during childhood. Growth charts for height, weight and head circumference for PHTS do not exist yet. In this study, patient data for height, weight and head circumferences (HC) were collected from repeated medical exams or prevention check-up visits starting at birth. Growth charts were generated and compared to German reference data. Standard deviation scores (SDS) of HC, height and body mass index (BMI) were calculated. We included 23 pediatric patients (8 female, 15 male) with molecular proven PTEN gene mutation. Most male patients already demonstrated macrocephaly at birth (73%), whereas only one female patient had documented congenital macrocephaly. By the age of two years all patients exhibited a head circumference above the 97th percentile. Stratified for different age groups the median HC-SDSs were between +3.3 and +5.5 in male patients and between +2.9 and +4.1 in female patients. Height, weight and BMI measurements for both sexes were mostly within the normal range. We conclude that macrocephaly, but not height, weight or BMI, is useful in the identification of PHTS patients. The increased HC in PHTS patients develops early in life and is more pronounced in males than in females, which might explain the finding of a higher percentage of male PHTS patients diagnosed during childhood. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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Review

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15 pages, 938 KiB

Open AccessReview

PTEN in Colorectal Cancer: Shedding Light on Its Role as Predictor and Target

by Lisa Salvatore, Maria Alessandra Calegari, Fotios Loupakis, Matteo Fassan, Brunella Di Stefano, Maria Bensi, Emilio Bria and Giampaolo Tortora

Cancers 2019, 11(11), 1765; https://doi.org/10.3390/cancers11111765 - 09 Nov 2019

Cited by 49 | Viewed by 5592

Abstract

Molecular assessment of colorectal cancer (CRC) is receiving growing attention, beyond RAS and BRAF, because of its influence on prognosis and prediction in cancer treatment. PTEN (phosphatase and tensin homologue), a tumor suppressor, regulating cell division and apoptosis, has been explored, and significant [...] Read more.

Molecular assessment of colorectal cancer (CRC) is receiving growing attention, beyond RAS and BRAF, because of its influence on prognosis and prediction in cancer treatment. PTEN (phosphatase and tensin homologue), a tumor suppressor, regulating cell division and apoptosis, has been explored, and significant evidence suggests a role in cetuximab and panitumumab resistance linked to the epidermal growth factor receptor (EGFR) signal transduction pathway. Factors influencing PTEN activity should be analyzed to develop strategies to maximize the tumor suppressor role and to improve tumor response to cancer treatment. Therefore, an in-depth knowledge of the PI3K-Akt pathway—one of the major cancer survival pathways—and the role of PTEN—a major brake of this pathway—is essential in the era of precision medicine. The purpose of this literature review is to summarize the role of PTEN as a predictive factor and possible therapeutic target in CRC, focusing on ongoing studies and the possible implications in clinical practice. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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22 pages, 1736 KiB

Open AccessReview

Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story

by Geny Piro, Carmine Carbone, Luisa Carbognin, Sara Pilotto, Chiara Ciccarese, Roberto Iacovelli, Michele Milella, Emilio Bria and Giampaolo Tortora

Cancers 2019, 11(10), 1525; https://doi.org/10.3390/cancers11101525 - 10 Oct 2019

Cited by 27 | Viewed by 4929

Abstract

Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the [...] Read more.

Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the usefulness of immunotherapy due to the activation of several escape mechanisms. Indeed, the tumor microenvironment has an almost full immunosuppressive profile, creating an obstacle to therapeutic treatment. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) governs a plethora of cellular processes, including maintenance of genomic stability, cell survival/apoptosis, migration, and metabolism. The repertoire of PTEN functions has recently been expanded to include regulation of the tumor microenvironment and immune system, leading to a drastic reevaluation of the canonical paradigm of PTEN action with new potential implications for immunotherapy-based approaches. Understanding the implication of PTEN in cancer immunoediting and immune evasion is crucial to develop new cancer intervention strategies. Recent evidence has shown a double context-dependent role of PTEN in anticancer immunity. Here we summarize the current knowledge of PTEN’s role at a crossroads between tumor and immune compartments, highlighting the most recent findings that are likely to change future clinical practice. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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17 pages, 1885 KiB

Open AccessReview

PTEN and Gynecological Cancers

by Camilla Nero, Francesca Ciccarone, Antonella Pietragalla and Giovanni Scambia

Cancers 2019, 11(10), 1458; https://doi.org/10.3390/cancers11101458 - 28 Sep 2019

Cited by 32 | Viewed by 4609

Abstract

PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better [...] Read more.

PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better understanding of PTEN activity and regulation has therefore emerged as a subject of primary interest in cancer research. Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored. Here, we present the most significant findings on PTEN in gynaecological cancers (ovarian, endometrial, cervical, vulvar and uterine cancer) focusing on PTEN alterations incidence, biological role and clinical implications. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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18 pages, 252 KiB

Open AccessReview

Prognostic and Predictive Implications of PTEN in Breast Cancer: Unfulfilled Promises but Intriguing Perspectives

by Luisa Carbognin, Federica Miglietta, Ida Paris and Maria Vittoria Dieci

Cancers 2019, 11(9), 1401; https://doi.org/10.3390/cancers11091401 - 19 Sep 2019

Cited by 67 | Viewed by 4942

Abstract

The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase [...] Read more.

The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, constitutes one of the most intriguing tumor suppressor genes involved in a series of biological processes, such as cell growth and survival, cellular migration and genomic stability. Loss of PTEN activity, due to protein, genetic or epigenetic alterations, was reported in up to almost half of BC cases. Recently, besides the role of PTEN in the pathogenesis of BC, investigated for over 20 years after the PTEN discovery, several retrospective and prospective translational studies, in the early and advanced setting, reported controversial results regarding the association between PTEN functional status and both clinical outcome and response to various BC treatments. This review explores the pre-clinical and clinical role of PTEN in BC with regard to the potential association of PTEN with prognosis and treatment response or resistance, underlying the complexity of the interpretation of available results and suggesting potential future perspectives. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

17 pages, 1357 KiB

Open AccessReview

PTEN Alterations as a Potential Mechanism for Tumor Cell Escape from PD-1/PD-L1 Inhibition

by Daniele Cretella, Graziana Digiacomo, Elisa Giovannetti and Andrea Cavazzoni

Cancers 2019, 11(9), 1318; https://doi.org/10.3390/cancers11091318 - 06 Sep 2019

Cited by 65 | Viewed by 5961

Abstract

The recent approval of immune checkpoint inhibitors drastically changed the standard treatments in many advanced cancer patients, but molecular changes within the tumor can prevent the activity of immunotherapy drugs. Thus, the introduction of the inhibitors of the immune checkpoint programmed death-1/programmed death [...] Read more.

The recent approval of immune checkpoint inhibitors drastically changed the standard treatments in many advanced cancer patients, but molecular changes within the tumor can prevent the activity of immunotherapy drugs. Thus, the introduction of the inhibitors of the immune checkpoint programmed death-1/programmed death ligand-1 (PD-1/PD-L1), should prompt deeper studies on resistance mechanisms, which can be caused by oncogenic mutations detected in cancer cells. PTEN, a tumor suppressor gene, dephosphorylates the lipid signaling intermediate PIP₃ with inhibition of AKT activity, one of the main effectors of the PI3K signaling axis. As a consequence of genetic or epigenetic aberrations, PTEN expression is often altered, with increased activation of PI3K axis. Interestingly, some data confirmed that loss of PTEN expression modified the pattern of cytokine secretion creating an immune-suppressive microenvironment with increase of immune cell populations that can promote tumor progression. Moreover, PTEN loss may be ascribed to reduction of tumor infiltrating lymphocytes (TILs), which can explain the absence of activity of immune checkpoint inhibitors. This review describes the role of PTEN loss as a mechanism responsible for resistance to anti PD-1/PD-L1 treatment. Moreover, combinatorial strategies between PD-1/PD-L1 inhibitors and PI3K/AKT targeting drugs are proposed as a new strategy to overcome resistance to immune checkpoint inhibition. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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27 pages, 1601 KiB

Open AccessReview

Multifaceted Regulation of PTEN Subcellular Distributions and Biological Functions

by Tian Liu, Yiwei Wang, Yubing Wang and Andrew M. Chan

Cancers 2019, 11(9), 1247; https://doi.org/10.3390/cancers11091247 - 26 Aug 2019

Cited by 30 | Viewed by 5258

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene frequently found to be inactivated in over 30% of human cancers. PTEN encodes a 54-kDa lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase pathway [...] Read more.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene frequently found to be inactivated in over 30% of human cancers. PTEN encodes a 54-kDa lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase pathway involved in the promotion of multiple pro-tumorigenic phenotypes. Although the PTEN protein plays a pivotal role in carcinogenesis, cumulative evidence has implicated it as a key signaling molecule in several other diseases as well, such as diabetes, Alzheimer’s disease, and autism spectrum disorders. This finding suggests that diverse cell types, especially differentiated cells, express PTEN. At the cellular level, PTEN is widely distributed in all subcellular compartments and organelles. Surprisingly, the cytoplasmic compartment, not the plasma membrane, is the predominant subcellular location of PTEN. More recently, the finding of a secreted ‘long’ isoform of PTEN and the presence of PTEN in the cell nucleus further revealed unexpected biological functions of this multifaceted molecule. At the regulatory level, PTEN activity, stability, and subcellular distribution are modulated by a fascinating array of post-translational modification events, including phosphorylation, ubiquitination, and sumoylation. Dysregulation of these regulatory mechanisms has been observed in various human diseases. In this review, we provide an up-to-date overview of the knowledge gained in the last decade on how different functional domains of PTEN regulate its biological functions, with special emphasis on its subcellular distribution. This review also highlights the findings of published studies that have reported how mutational alterations in specific PTEN domains can lead to pathogenesis in humans. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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22 pages, 1031 KiB

Open AccessReview

The PTEN Tumor Suppressor Gene in Soft Tissue Sarcoma

by Sioletic Stefano and Scambia Giovanni

Cancers 2019, 11(8), 1169; https://doi.org/10.3390/cancers11081169 - 14 Aug 2019

Cited by 13 | Viewed by 5287

Abstract

Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely [...] Read more.

Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely due to the rarity and heterogeneity of these tumors. Therefore, the discovery of new prognostic and predictive biomarkers, together with new therapeutic targets, is of enormous interest. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes. The loss of PTEN function has consequent alterations in important pathways implicated in cell proliferation, survival, migration, and genomic stability. PTEN can also interact with other tumor suppressors and oncogenic signaling pathways that have important implications for the pathogenesis in certain STSs. The aim of the present review is to summarize the biological significance of PTEN in STS and its potential role in the development of new therapeutic strategies. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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19 pages, 1085 KiB

Open AccessReview

PTEN in Lung Cancer: Dealing with the Problem, Building on New Knowledge and Turning the Game Around

by Anastasios Gkountakos, Giulia Sartori, Italia Falcone, Geny Piro, Ludovica Ciuffreda, Carmine Carbone, Giampaolo Tortora, Aldo Scarpa, Emilio Bria, Michele Milella, Rafael Rosell, Vincenzo Corbo and Sara Pilotto

Cancers 2019, 11(8), 1141; https://doi.org/10.3390/cancers11081141 - 09 Aug 2019

Cited by 69 | Viewed by 9486

Abstract

Lung cancer is the most common malignancy and cause of cancer deaths worldwide, owing to the dismal prognosis for most affected patients. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) acts as a powerful tumor suppressor gene and even partial reduction of [...] Read more.

Lung cancer is the most common malignancy and cause of cancer deaths worldwide, owing to the dismal prognosis for most affected patients. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) acts as a powerful tumor suppressor gene and even partial reduction of its levels increases cancer susceptibility. While the most validated anti-oncogenic duty of PTEN is the negative regulation of the PI3K/mTOR/Akt oncogenic signaling pathway, further tumor suppressor functions, such as chromosomal integrity and DNA repair have been reported. PTEN protein loss is a frequent event in lung cancer, but genetic alterations are not equally detected. It has been demonstrated that its expression is regulated at multiple genetic and epigenetic levels and deeper delineation of these mechanisms might provide fertile ground for upgrading lung cancer therapeutics. Today, PTEN expression is usually determined by immunohistochemistry and low protein levels have been associated with decreased survival in lung cancer. Moreover, available data involve PTEN mutations and loss of activity with resistance to targeted treatments and immunotherapy. This review discusses the current knowledge about PTEN status in lung cancer, highlighting the prevalence of its alterations in the disease, the regulatory mechanisms and the implications of PTEN on available treatment options. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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26 pages, 2957 KiB

Open AccessReview

PTEN Tumor-Suppressor: The Dam of Stemness in Cancer

by Francesca Luongo, Francesca Colonna, Federica Calapà, Sara Vitale, Micol E. Fiori and Ruggero De Maria

Cancers 2019, 11(8), 1076; https://doi.org/10.3390/cancers11081076 - 30 Jul 2019

Cited by 109 | Viewed by 13264

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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16 pages, 276 KiB

Open AccessReview

PTEN Hamartoma Tumor Syndrome: A Clinical Overview

by Robert Pilarski

Cancers 2019, 11(6), 844; https://doi.org/10.3390/cancers11060844 - 18 Jun 2019

Cited by 101 | Viewed by 8976

Abstract

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a grouping of related genetic disorders that has been linked to germline mutations in the PTEN gene. These disorders include Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, adult Lhermitte–Duclos disease, and autism spectrum [...] Read more.

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a grouping of related genetic disorders that has been linked to germline mutations in the PTEN gene. These disorders include Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, adult Lhermitte–Duclos disease, and autism spectrum disorders associated with macrocephaly. The majority of the clinical information available on PHTS, however, is related to individuals diagnosed with CS. There is still much to be learned about this disorder, since diagnostic criteria for CS were only established in 1996, before the identification of the PTEN gene, and were based primarily on features seen in cases reported in the existing literature. More recently, however, data from several large series of patients have shown that a number of the clinical features associated with PTEN mutations are either more or less common than previously reported. In addition, we now know that only about 30–35% of patients meeting clinical diagnostic criteria for Cowden syndrome actually have a detectable PTEN mutation. Thus, our understanding of PTEN-related diseases and their management has evolved significantly over time. The United States National Comprehensive Cancer Network (NCCN) has produced and regularly updates practice guidelines which include clinical diagnostic criteria as well as guidelines for PTEN testing and management of patients with mutations. This review will summarize the overall literature on PHTS as well as recent findings which are broadening our understanding of this set of disorders. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

21 pages, 1132 KiB

Open AccessReview

The Key Roles of PTEN in T-Cell Acute Lymphoblastic Leukemia Development, Progression, and Therapeutic Response

by Alberto M. Martelli, Francesca Paganelli, Antonietta Fazio, Chiara Bazzichetto, Fabiana Conciatori and James A. McCubrey

Cancers 2019, 11(5), 629; https://doi.org/10.3390/cancers11050629 - 06 May 2019

Cited by 26 | Viewed by 4490

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that comprises 10–15% of pediatric and ~25% of adult ALL cases. Although the curative rates have significantly improved over the past 10 years, especially in pediatric patients, T-ALL remains a challenge from a [...] Read more.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that comprises 10–15% of pediatric and ~25% of adult ALL cases. Although the curative rates have significantly improved over the past 10 years, especially in pediatric patients, T-ALL remains a challenge from a therapeutic point of view, due to the high number of early relapses that are for the most part resistant to further treatment. Considerable advances in the understanding of the genes, signaling networks, and mechanisms that play crucial roles in the pathobiology of T-ALL have led to the identification of the key drivers of the disease, thereby paving the way for new therapeutic approaches. PTEN is critical to prevent the malignant transformation of T-cells. However, its expression and functions are altered in human T-ALL. PTEN is frequently deleted or mutated, while PTEN protein is often phosphorylated and functionally inactivated by casein kinase 2. Different murine knockout models recapitulating the development of T-ALL have demonstrated that PTEN abnormalities are at the hub of an intricate oncogenic network sustaining and driving leukemia development by activating several signaling cascades associated with drug-resistance and poor outcome. These aspects and their possible therapeutic implications are highlighted in this review. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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22 pages, 13350 KiB

Open AccessFeature PaperEditor’s ChoiceReview

PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

by Chiara Bazzichetto, Fabiana Conciatori, Matteo Pallocca, Italia Falcone, Maurizio Fanciulli, Francesco Cognetti, Michele Milella and Ludovica Ciuffreda

Cancers 2019, 11(4), 435; https://doi.org/10.3390/cancers11040435 - 28 Mar 2019

Cited by 88 | Viewed by 7650

Abstract

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of [...] Read more.

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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