Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets DOI Creative Commons
Shaosen Zhang,

Xinyi Xiao,

Yonglin Yi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 18, 2024

Abstract Tumorigenesis is a multistep process, with oncogenic mutations in normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic and expansion tissues, their transformation into cancer remains rare event, indicating presence of additional driver events for progression to an irreversible, highly heterogeneous, invasive lesion. Recently, researchers are emphasizing mechanisms environmental tumor risk factors epigenetic alterations that profoundly influencing early malignant evolution, independently inducing mutations. Additionally, evolution tumorigenesis reflects multifaceted interplay between cell-intrinsic identities various cell-extrinsic exert selective pressures either restrain uncontrolled proliferation or allow specific clones progress tumors. by which induce both intrinsic cellular competency remodel stress facilitate not fully understood. In this review, we summarize genetic, epigenetic, external events, effects on co-evolution transformed cells ecosystem during initiation evolution. A deeper understanding earliest molecular holds promise translational applications, predicting individuals at high-risk developing strategies intercept transformation.

Language: Английский

Endometriosis DOI
Krina T. Zondervan, Christian M. Becker, Stacey A. Missmer

et al.

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 382(13), P. 1244 - 1256

Published: March 25, 2020

About 10% of reproductive-age women have endometriosis. Symptoms can include severe pain, dysmenorrhea, dyspareunia, dysuria, infertility, and fatigue. The pathogenesis is unclear. Hormonal therapy controls symptoms in some women; others require surgery, which may not be effective.

Language: Английский

Citations

1420
Endometriosis DOI Creative Commons
Serdar E. Bulun, Bahar D. Yilmaz,

Christia Sison

et al.

Endocrine Reviews, Journal Year: 2019, Volume and Issue: 40(4), P. 1048 - 1079

Published: April 17, 2019

Abstract Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It caused when shed endometrial tissue travels retrograde into lower abdominal cavity. Endometriosis most common cause of pain in women and associated with infertility. The underlying pathologic mechanisms intracavitary endometrium extrauterine endometriotic involve defectively programmed mesenchymal progenitor/stem cells. Although stromal cells, which compose bulk lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities alter expression key transcription factors. For example, GATA-binding factor-6 overexpression transforms cell to phenotype, steroidogenic factor-1 causes excessive production estrogen, drives inflammation via pathologically high levels estrogen receptor-β. Progesterone receptor deficiency progesterone resistance. Populations epithelial cells also harbor multiple cancer driver such as KRAS, may be establishment or ovarian cancer. known how interactions between epigenomically defective mutated genes contribute pathogenesis endometriosis. Endometriosis-associated managed suppression ovulatory menses production, cyclooxygenase inhibitors, surgical removal vitro fertilization frequently used overcome novel targeted treatments are becoming available, pathophysiology better understood, preventive approaches long-term ovulation play critical role future.

Language: Английский

Citations

620
The landscape of somatic mutation in normal colorectal epithelial cells DOI
Henry Lee-Six, Sigurgeir Ólafsson, Peter Ellis

et al.

Nature, Journal Year: 2019, Volume and Issue: 574(7779), P. 532 - 537

Published: Oct. 23, 2019

Language: Английский

Citations

619
Cancer therapy shapes the fitness landscape of clonal hematopoiesis DOI
Kelly L. Bolton, Ryan Ptashkin, Teng Gao

et al.

Nature Genetics, Journal Year: 2020, Volume and Issue: 52(11), P. 1219 - 1226

Published: Oct. 26, 2020

Language: Английский

Citations

552
The mutational landscape of normal human endometrial epithelium DOI
Luiza Moore, Daniel Leongamornlert, Tim H. H. Coorens

et al.

Nature, Journal Year: 2020, Volume and Issue: 580(7805), P. 640 - 646

Published: April 22, 2020

Language: Английский

Citations

428
The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights DOI Open Access
Antonio Simone Laganà, Simone Garzon, Martin Götte

et al.

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(22), P. 5615 - 5615

Published: Nov. 10, 2019

The etiopathogenesis of endometriosis is a multifactorial process resulting in heterogeneous disease. Considering that etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer comprehensive summary available evidence. We performed narrative synthesizing findings English literature retrieved computerized databases inception June 2019, using Medical Subject Headings (MeSH) unique ID term “Endometriosis” (ID:D004715) with “Etiology” (ID:Q000209), “Immunology” (ID:Q000276), “Genetics” (ID:D005823) “Epigenesis, Genetic” (ID:D044127). Endometriosis may origin Müllerian or non-Müllerian stem cells including those endometrial basal layer, remnants, bone marrow, peritoneum. innate ability regenerate cyclically seems play key role, as well dysregulated hormonal pathways. presence such peritoneal cavity what leads development complex large number interconnected factors, potentially both inherited acquired. Genetic predisposition related combined action several genes limited influence. epigenetic mechanisms control many processes involved immunologic, immunohistochemical, histological, biological aberrations characterize eutopic ectopic endometrium affected patients. However, triggers alterations not clear be genetically epigenetically inherited, it acquired by particular combination elements persistent menstrual reflux exogenous factors. heterogeneity different contexts which develops suggest single etiopathogenetic model sufficient explain its pathobiology.

Language: Английский

Citations

403
Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening DOI
Matteo Boretto, Nina Maenhoudt, Xinlong Luo

et al.

Nature Cell Biology, Journal Year: 2019, Volume and Issue: 21(8), P. 1041 - 1051

Published: Aug. 1, 2019

Language: Английский

Citations

385
The Origin and Pathogenesis of Endometriosis DOI Open Access
Yeh Wang,

Kristen Nicholes,

Ie‐Ming Shih

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2019, Volume and Issue: 15(1), P. 71 - 95

Published: Sept. 3, 2019

Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine after menstruation may become overreactive trapped outside the uterus. These epithelium-committed form nascent glands through clonal expansion recruit polyclonal stromal cells, leading establishment of deep infiltrating endometriosis. Once formed, ectopic tissue becomes subject immune surveillance, resulting chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated aberrations estrogen receptor-β progesterone receptor pathways, are also affected local inflammation, forming dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic harbors cancer-associated mutations that frequently detected endometriosis-related ovarian cancers. In this review, we summarize recent advances have illuminated origin pathogenesis provided new avenues for research promise improve early diagnosis management

Language: Английский

Citations

351
Clinical actionability of molecular targets in endometrial cancer DOI
Mary Ellen Urick, Daphne W. Bell

Nature reviews. Cancer, Journal Year: 2019, Volume and Issue: 19(9), P. 510 - 521

Published: Aug. 6, 2019

Language: Английский

Citations

344
Clonal dynamics of haematopoiesis across the human lifespan DOI Creative Commons
Emily Mitchell, Michael Spencer Chapman, Nicholas Williams

et al.

Nature, Journal Year: 2022, Volume and Issue: 606(7913), P. 343 - 350

Published: June 1, 2022

Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer 4–6 but the reason for such abrupt functional decline after 70 years age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies haematopoietic cells across 10 subjects 0 to 81 age. Haematopoietic stem or multipotent progenitors (HSC/MPPs) accumulated a mean 17 mutations per year birth lost 30 base pairs telomere length. Haematopoiesis adults less than 65 was massively polyclonal, with high clonal diversity stable population 20,000–200,000 HSC/MPPs contributing evenly production. By contrast, individuals aged over 75 showed profoundly decreased diversity. In each older subjects, 30–60% accounted by 12–18 independent clones, 1–34% Most clones had begun their expansion before subject 40 old, only 22% known driver mutations. Genome-wide selection analysis estimated that between 34 12 non-synonymous were drivers, accruing at constant rates throughout life, affecting more genes identified cancers. Loss Y chromosome conferred selective benefits males. Simulations haematopoiesis, cell size acquisition conferring moderate fitness benefits, entirely explained structure elderly. Rapidly decreasing is universal feature humans, underpinned pervasive positive acting on many currently identified.

Language: Английский

Citations

328