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      Digestive system deep infiltrating endometriosis: What do we know

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          Abstract

          Digestive system infiltrating endometriosis (DSIE) is an uncommon form of endometriosis in the digestive system. DSIE often occurs in the intestines (especially the sigmoid rectum), liver, gallbladder and pancreas. Clinically, DSIE presents with the same symptoms as endometriosis, including cyclic pain, bleeding and infertility, in addition to specific biliary/intestinal obstruction and gastrointestinal bleeding. Compared to general endometriosis, DSIE has unique biological behaviour and pathophysiological mechanisms. Most DSIEs are deep invasive endometrioses, characterized by metastasis to the lymph nodes and lymphatic vessels, angiogenesis, peripheral nerve recruitment, fibrosis and invasion of surrounding tissues. DSIE‐related peripheral angiogenesis is divided into three patterns: angiogenesis, vasculogenesis and inosculation. These patterns are regulated by interactions between multiple hypoxia‐hormone cytokines. The nerve growth factors regulate the extensive neurofibril recruitment in DSIE lesions, which accounts for severe symptoms of deep pain. They are also associated with fibrosis and the aggressiveness of DSIE. Cyclic changes in DSIE lesions, recurrent inflammation and oxidative stress promote repeated tissue injury and repair (ReTIAR) mechanisms in the lesions, accelerating fibril formation and cancer‐related mutations. Similar to malignant tumours, DSIE can also exhibit aggressiveness derived from collective cell migration mediated by E‐cadherin and N‐cadherin. This often makes DSIE misdiagnosed as a malignant tumour of the digestive system in clinical practice. In addition to surgery, novel treatments are urgently required to effectively eradicate this lesion.

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          Drugging the undruggable RAS: Mission possible?

          Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.
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            Targeting the tumour vasculature: insights from physiological angiogenesis.

            The cardiovascular system ensures the delivery of nutrients, oxygen, and blood and immune cells to all organs and tissues: it is also responsible for the removal of waste metabolites. The vascular system develops and matures through two tightly regulated processes: vasculogenesis and angiogenesis. Angiogenesis is active only under specific physiological conditions in healthy adults but the vasculature can be aberrantly activated to generate new blood vessels during pathological conditions such as cancer and chronic inflammation. In this Opinion article we discuss the parallels and differences in the angiogenic process under either a physiological or a pathological state, especially tumorigenesis.
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              ARID1A mutations in endometriosis-associated ovarian carcinomas.

              Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).
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                Author and article information

                Contributors
                yushan@hrbmu.edu.cn
                taisheng1973@163.com
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                25 August 2023
                December 2023
                : 27
                : 23 ( doiID: 10.1111/jcmm.v27.23 )
                : 3649-3661
                Affiliations
                [ 1 ] Department of Hepatic Surgery Second Affiliated Hospital of Harbin Medical University Harbin China
                [ 2 ] Department of Pathology Second Affiliated Hospital of Harbin Medical University Harbin China
                [ 3 ] Laboratory of Medical Genetics Harbin Medical University Harbin China
                [ 4 ] Department of Pathology Six Affiliated Hospital of Harbin Medical University Harbin China
                Author notes
                [*] [* ] Correspondence

                Shan Yu, Department of Pathology, Second Affiliated Hospital of Harbin Medical University, Harbin 150080, China.

                Email: yushan@ 123456hrbmu.edu.cn

                Sheng Tai, Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150080, China.

                Email: taisheng1973@ 123456163.com

                Author information
                https://orcid.org/0000-0002-1747-3854
                Article
                JCMM17921 JCMM-06-2023-162.R1
                10.1111/jcmm.17921
                10718155
                37632165
                968c44d8-d7f9-4520-8baf-bb96bf637afd
                © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 August 2023
                : 19 June 2023
                : 12 August 2023
                Page count
                Figures: 2, Tables: 2, Pages: 13, Words: 10368
                Funding
                Funded by: China Primary Health Care Foundation , doi 10.13039/501100004241;
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                December 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.5 mode:remove_FC converted:13.12.2023

                Molecular medicine
                aetiology,digestive system,endometriosis,intestines,molecular mechanisms
                Molecular medicine
                aetiology, digestive system, endometriosis, intestines, molecular mechanisms

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