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Metastasis
Published in John Melford, Pocket Guide to Cancer, 2017
A single cell assesses whether it is in the right location using receptors on its outer membrane that interact with surrounding cells and the extracellular matrix. When normal cells lose interactions with their surroundings, the cell cycle is arrested and a process, termed anoikis, triggers cell death. It is in effect apoptosis, induced by a lack of correct cell attachment. There are many diverse ways in which apoptosis is initiated through the passage of signals via adhesion receptors between cells. The appropriate signals from the extracellular matrix also are required to prevent the triggering of anoikis. The way a particular type of cell responds to incorrect adhesion may differ from that of another cell type. Each cell type possess its own unique collection of signaling proteins, wired in its own unique configuration.
Tumor Biology
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Apoptosis can be initiated either through a “cell extrinsic pathway” or through a “cell intrinsic pathway.” The cell extrinsic pathway involves the death receptors in the cell membrane. Fas receptor when bound to Fas ligand, or TNFa receptor when bound to its TNFα ligand, can initiate the cell extrinsic pathway of apoptosis. Whole hosts of integrin receptors present at the basal surface of epithelial cells are attached to the basement membrane underneath and can induce apoptosis when they are not bound to their ligand. These phenomena in epithelial cells are called “anoikis”—detachment-induced cell death. The cell intrinsic pathway involves the mitochondrial apoptotic pathway initiated by a DNA damage signal from the nucleus. Exposure to chemical genotoxins or radiation results in the blockage of DNA replication, which leads to collapse of replication forks and DNA double strand breaks (DSB) formation. These DSBs are thought to be crucial downstream apoptosis–triggering lesions. DSBs are detected by ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases), and p53. p53 induces transcriptional activation of proapoptotic factors such as FAS, p53 upregulated modulator of apoptosis (PUMA), and BCL-2 associated X protein (BAX). Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1- and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA, and NOXA. The end point of the mitochondrial pathway of apoptosis is release of cytochrome C.
Targeting BRAF Activity as a Novel Paradigm for Melanoma Therapy
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Keiran S.M. Smalley, Keith T. Flaherty
One important characteristic of melanoma is its propensity for metastatic spread at an early stage, and there is evidence that BRAF-mediated signaling contributes to this. Initially, nascent melanoma cells remain under the control of the surrounding keratinocytes through homotypic E-cadherin-mediated adhesion (35), and there is evidence that BRAF/MAPK activity downregulates E-cadherin expression (Fig. 2). After escape from keratinocyte control, the melanoma cells must be able to survive in the dermis by resisting anoikis. One mechanism for overcoming anoikis is through the upregulation of the integrin family of heterodimeric adhesion proteins, which generate “outside-in” survival signals. There is strong evidence that αvβ3 integrin is critical for the adhesion of melanoma cells to dermal collagen, and the suppression of apoptosis and expression of these integrins correlates well with tumor progression (36–38). Sustained activation of the MAPK pathway increases expression of β3 integrin, and inhibition of this pathway using the MEK inhibitor U0126 can reduce β3 integrin expression (39). BRAF/MAPK activity also contributes toward cell invasion through the regulation of the expression of two families of enzymes, the urokinase plasminogen activation (uPA) and matrix metalloproteinases (MMPs). Of these, MMP-1, which is an interstitial collagenase, and MMPs 2–9, which degrade the basement membrane, are thought to be particularly important. In various melanoma cell lines, BRAF/MAPK activity has been shown to induce MMP expression. Conversely, the pharmacological inhibition of BRAF/MEK signaling is known to inhibit invasion of melanoma cells (40–42). Consistent with an antimetastatic role for inhibitors of the MAPK pathway, recent studies have shown that U0126 treatment suppressed lung metastasis in a mouse melanoma model (43).
Construction of stomach adenocarcinoma prognostic signature based on anoikis-related lncRNAs and clinical significance
Published in Libyan Journal of Medicine, 2023
Lina Lu, Min Yu, Wei Huang, Hui Chen, Guofa Jiang, Gangxiu Li
As a specific form of programmed cell death, anoikis refers to apoptosis triggered by the detachment of normal epithelial cells or solid tumor cells without metastatic nature in situ into the blood [4]. When cells are detached from the extracellular matrix, anoikis prevents tumor cells isolated from the primary tumor from continuing to survive [5]. In this way, the anoikis factor is vital in the development and metastasis of STAD. Analysis of the prognosis of STAD based on the anoikis factor is conducive to the correct assessment of tumor development and metastasis risk. More than 200 nt in length, long non-coding RNAs (lncRNAs) are involved in many human cancers such as GC, lung cancer, liver cancer, pancreatic cancer, and colorectal cancer. Besides, lncRNAs are crucial in various biological processes such as cell proliferation, invasion, apoptosis, and stem cell maintenance [6–10]. Li et al. pointed out that lncRNAs may be potential targets for cancer diagnosis and therapy [10]. There is association between lncRNA expression and anoikis resistance and metastasis in cancer [11–13]. Investigating the effect of anoikis-related lncRNAs on STAD may help doctors better evaluate the prognosis of STAD patients and explore possible targets for disease treatment.
Bone morphogenetic protein (BMP)9 in cancer development: mechanistic, diagnostic, and therapeutic approaches?
Published in Journal of Drug Targeting, 2023
Ali G. Alkhathami, Mustafa Ryadh Abdullah, Muhjaha Ahmed, Hanan Hassan Ahmed, Sarab W. Alwash, Zahra Muhammed Mahdi, Fahad Alsaikhan, Ayed A. Dera
The crucial step in tumour cell migration and metastasis is cell detachment from the tumour nest. In normal physiological conditions, cell detachment from ECM leads to a type of cell death called anoikis. In fact, anoikis is a type of programmed cell death that its inhibition is a critical mechanism to promote adherent (anchorage)-independent cell growth and epithelial-mesenchymal transition (EMT). These two features are vital procedures during tumour progression and metastasis [59]. It has been found that BMP9 robustly activates SMAD1/5 signalling through binding to BMPRI (ALK3 and ALK6) and BMPRII. Subsequent to BMP9-dependent activation of SMAD1/5, epithelial cells regulate adherent-independent growth through increasing sensitisation to anoikis. In line with BMP9-dependent anoikis susceptibility, it has been found that BMP9 promoter in cell line and patients with ovarian and breast cancer was methylated, indicating that the anti-metastatic effect of BMP9 was abrogated in breast and ovarian cancers through promoter methylation [51].
Rebuilding a better home for transplanted islets
Published in Organogenesis, 2018
Daniel M. Tremmel, Jon S. Odorico
Anoikis, meaning ‘without a home’, is an integrin-mediated form of apoptosis due to the absence of ECM in a tissue environment, and is a major contributor to cell death in isolated islets. High purity islet preps have high rates of apoptosis which can be reduced with anoikis inhibitors; impure preps, containing more intact ECM, have much better cell survival.8, 9 Islets cultured on purified ECM proteins: collagen (COL), laminins (LAM), and fibronectin (FN), have lower apoptosis rates and maintain better β cell function.10, 11 Soluble integrin-binding ligands, such as fibrinogen, RGD peptides and integrin antibodies, also reduce apoptosis in cultured islets.12, 13