Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review)

Kobayashi, Hiroshi

doi:10.3892/wasj.2019.12

Cited by 4 publications

(1 citation statement)

References 64 publications

(106 reference statements)

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“…Additionally, PIK3CA or KRAS mutated clones arising in the histologically normal uterine endometrium have been proposed as the cellular origins of endometriosis [3]. The transformation of a normal cell into a cancer cell is caused by the acquisition of driver mutations and epigenetic modifications, accompanied by changes in the cellular morphology and tissue architecture [22]. However, no behavioral and functional analysis of the aforementioned genes in endometriosis has been performed.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Novel In Vitro Model of Endometriosis with Oncogenic KRAS and PIK3CA Mutations for Understanding the Underlying Biology and Molecular Pathogenesis

Hossain

Nakayama

Shanta

et al. 2021

Cancers

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Endometriosis-harboring cancer-associated somatic mutations of PIK3CA and KRAS provides new opportunities for studying the multistep processes responsible for the functional and molecular changes in this disease. We aimed to establish a novel in vitro endometriosis model to clarify the functional behavior and molecular pathogenesis of this disorder. Immortalized HMOsisEC10 human ovarian endometriotic epithelial cell line was used in which KRAS and PIK3CA mutations were introduced. Migration, invasion, proliferation, and microarray analyses were performed using KRAS and PIK3CA mutant cell lines. In vitro assays showed that migration, invasion, and proliferation were significantly increased in KRAS and PIK3CA mutant cell lines, indicating that these mutations played causative roles in the aggressive behavior of endometriosis. Microarray analysis identified a cluster of gene signatures; among them, two significantly upregulated cancer-related genes, lysyl oxidase (LOX) and pentraxin3 (PTX3), were associated with cell proliferation, invasion, and migration capabilities. Furthermore, siRNA knockdown of the two genes markedly reduced the metastatic ability of the cells. These results suggest that endometriosis with KRAS or PIK3CA mutations can significantly enhance cell migration, invasion, and proliferation by upregulating LOX and PTX3. We propose that LOX and PTX3 silencing using small molecules could be an alternative therapeutic regimen for severe endometriosis.

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Section: Introductionmentioning

confidence: 99%

Establishment of a Novel In Vitro Model of Endometriosis with Oncogenic KRAS and PIK3CA Mutations for Understanding the Underlying Biology and Molecular Pathogenesis

Hossain

Nakayama

Shanta

et al. 2021

Cancers

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The prospects of cell therapy for endometriosis

Artemova

Vishnyakova

Gantsova

et al. 2023

J Assist Reprod Genet

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Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology

Guo

2020

Human Reproduction Update

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BACKGROUND Endometriosis is a benign gynaecological disease. Thus, it came as a complete surprise when it was reported recently that the majority of deep endometriosis lesions harbour somatic mutations and a sizeable portion of them contain known cancer-associated mutations (CAMs). Four more studies have since been published, all demonstrating the existence of CAMs in different subtypes of endometriosis. While the field is still evolving, the confirmation of CAMs has raised many questions that were previously overlooked. OBJECTIVE AND RATIONALE A comprehensive overview of CAMs in endometriosis has been produced. In addition, with the recently emerged understanding of the natural history of endometriotic lesions as well as CAMs in normal and apparently healthy tissues, this review attempts to address the following questions: Why has there been such a wild discrepancy in reported mutation frequencies? Why does ectopic endometrium have a higher mutation rate than that of eutopic endometrium? Would the presence of CAMs in endometriotic lesions increase the risk of cancer to the bearers? Why do endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart? What clinical implications, if any, do the CAMs have for the bearers? Do these CAMs tell us anything about the pathogenesis and/or pathophysiology of endometriosis? SEARCH METHODS The PubMed database was searched, from its inception to September 2019, for all papers in English using the term ‘endometriosis and CAM’, ‘endometriosis and cancer-driver mutation’, ‘somatic mutations’, ‘fibrosis’, ‘fibrosis and epigenetic’, ‘CAMs and tumorigenesis’, ‘somatic mutation and normal tissues’, ‘oestrogen receptor and fibrosis’, ‘oxidative stress and fibrosis’, ‘ARID1A mutation’, and ‘Kirsten rat sarcoma mutation and therapeutics’. All retrieved papers were read and, when relevant, incorporated into the review results. OUTCOMES Seven papers that identified CAMs in endometriosis using various sequencing methods were retrieved, and their results were somewhat different. Yet, it is apparent that those using microdissection techniques and more accurate sequencing methods found more CAMs, echoing recent discoveries that apparently healthy tissues also harbour CAMs as a result of the replicative aging process. Hence endometriotic lesions, irrespective of subtype, if left intact, would generate CAMs as part of replicative aging, oxidative stress and perhaps other factors yet to be identified and, in some rare cases, develop cancer. The published data still are unable to paint a clear picture on pathogenesis of endometriosis. However, since endometriotic epithelial cells have a higher turnover than their stromal counterpart due to cyclic bleeding, and since the endometriotic stromal component can be formed by refresh influx of mesenchymal cells through epithelial–mesenchymal transition, endothelial–mesenchymal transition, mesothelial–mesenchymal transition and other processes as well as recruitment of bone-marrow-derived stem cells and outflow due to smooth muscle metaplasia, endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart. The epithelial and stromal cellular components develop in a dependent and co-evolving manner. Genes involved in CAMs are likely to be active players in lesional fibrogenesis, and hyperestrogenism and oxidative stress are likely drivers of both CAMs and fibrogenesis. Finally, endometriotic lesions harbouring CAMs would conceivably be more refractory to medical treatment, due, in no small part, to their high fibrotic content and reduced vascularity and cellularity. WIDER IMPLICATIONS The accumulating data on CAMs in endometriosis have shed new light on the pathogenesis and pathophysiology of endometriosis. They also suggest new challenges in management. The distinct yet co-evolving developmental trajectories of endometriotic stroma and epithelium underscore the importance of the lesional microenvironment and ever-changing cellular identity. Mutational profiling of normal endometrium from women of different ages and reproductive history is needed in order to gain a deeper understanding of the pathogenesis. Moreover, one area that has conspicuously received scant attention is the epigenetic landscape of ectopic, eutopic and normal endometrium.

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Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review)

Cited by 4 publications

References 64 publications

Establishment of a Novel In Vitro Model of Endometriosis with Oncogenic KRAS and PIK3CA Mutations for Understanding the Underlying Biology and Molecular Pathogenesis

Establishment of a Novel In Vitro Model of Endometriosis with Oncogenic KRAS and PIK3CA Mutations for Understanding the Underlying Biology and Molecular Pathogenesis

The prospects of cell therapy for endometriosis

Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology

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