PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation

Russo, Angela; Czarnecki, Austin; Dean, Matthew; Modi, Dimple; Lantvit, Daniel D.; Hardy, Laura; Baligod, Seth; Davis, David A.; Wei, Jian Jun; Burdette, Joanna E.

doi:10.1038/s41388-017-0097-8

Cited by 63 publications

(54 citation statements)

References 53 publications

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“…Human fallopian tube cells transformed in vitro produce tumours that are morphologically and genetically similar to HGSOC [15][16][17]. Genetically engineered mouse OC models containing mutations commonly found in HGSOC such as p53, PTEN, BRCA1, BRCA2, and Rb1 in tubal secretory cells have shown the phenotype of STIC formation and emergence of HGSOC [18][19][20]. Clinical studies have confirmed that the majority of women who undertook salpingo-oophorectomy due to the presence of BRCA1, 2 mutations had STICs in the fallopian tube.…”

Section: Different Origins Of Ocmentioning

confidence: 97%

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...

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Section: Different Origins Of Ocmentioning

confidence: 97%

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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“…These mice developed STIC lesions and serous carcinomas 31 . Interestingly, loss of PTEN alone in the fallopian tube (via Pax-8-Cre) was sufficient to generate endometrioid and serous borderline tumors 34 . This raises the possibility of fallopian tube origins for some Type I tumors and non-HGS tumors.…”

Section: Histologic Types Of Ovarian Cancermentioning

confidence: 99%

Can Stemness and Chemoresistance be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Roy

Dahl²

2018

Preprint

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Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, are often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to targeted in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.

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“…This study highlights the numerous possibilities offered by the non-coding part of the genome in the development of HGSC and gives a glimpse of the pathway and the ceRNA network by which MAGI2-AS3 positively restricts the activity of HGSC cells. The mRNAs HOXA5, MTSS1, PTEN, and RECK are reported to have important tumor-suppressive roles in OC [42,45,63,64], though their role in HGSC is not specifically shown. This study has not only experimentally validated the regulation of the expression of tumor-suppressive mRNAs such as HOXA5, MTSS1, PTEN, and RECK by MAGI2-AS3 in HGSC but also has suggested a network of how various pathways converge to aid in tumor suppression.…”

Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNA MAGI2-AS3 is a New Player with a Tumor Suppressive Role in High Grade Serous Ovarian Carcinoma

Gokulnath

Cristofaro

Manipur

et al. 2019

Cancers

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High-Grade Serous Ovarian Carcinoma (HGSC) is the most incidental and lethal subtype of epithelial ovarian cancer (EOC) with a high mortality rate of nearly 65%. Recent findings aimed at understanding the pathogenesis of HGSC have attributed its principal source as the Fallopian Tube (FT). To further comprehend the exact mechanism of carcinogenesis, which is still less known, we performed a transcriptome analysis comparing FT and HGSC. Our study aims at exploring new players involved in the development of HGSC from FT, along with their signaling network, and we chose to focus on non-coding RNAs. Non-coding RNAs (ncRNAs) are increasingly observed to be the major regulators of several cellular processes and could have key functions as biological markers, as well as even a therapeutic approach. The most physiologically relevant and significantly dysregulated non-coding RNAs were identified bioinformatically. After analyzing the trend in HGSC and other cancers, MAGI2-AS3 was observed to be an important player in EOC. We assessed its tumor-suppressive role in EOC by means of various assays. Further, we mapped its signaling pathway using its role as a miRNA sponge to predict the miRNAs binding to MAGI2AS3 and showed it experimentally. We conclude that MAGI2-AS3 acts as a tumor suppressor in EOC, specifically in HGSC by sponging miR-15-5p, miR-374a-5p and miR-374b-5p, and altering downstream signaling of certain mRNAs through a ceRNA network.

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PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation

Cited by 63 publications

References 53 publications

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Can Stemness and Chemoresistance be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Long Non-Coding RNA MAGI2-AS3 is a New Player with a Tumor Suppressive Role in High Grade Serous Ovarian Carcinoma

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