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• W2074446241 abstract "Reactive oxygen species (ROS) mediate various cell fate decisions in normal and transformed cells. In this issue of Cancer Cell, Zhu et al. demonstrate the ability of ANGPTL4 to engage integrin-dependent survival signals by activation of the NADPH oxidase Nox1, thus mimicking anchorage conditions and bypassing anoikis by controlling ROS. Reactive oxygen species (ROS) mediate various cell fate decisions in normal and transformed cells. In this issue of Cancer Cell, Zhu et al. demonstrate the ability of ANGPTL4 to engage integrin-dependent survival signals by activation of the NADPH oxidase Nox1, thus mimicking anchorage conditions and bypassing anoikis by controlling ROS. Cancer cells have long been known to display abnormal redox metabolism, releasing increased levels of reactive oxidants compared with normal cells. The exact significance of such reactive oxygen species (ROS) production as it pertains to malignant transformation, however, has been less clear. ROS cause oxidative stress, which results in mutations to both nuclear and mitochondrial DNA. With loss of fail-safe death and senescence mechanisms, such genomic damage has been proposed to accelerate transformation and cancer progression. Besides creating a stress response, however, ROS clearly participate in physiologic signaling at a variety of levels, requiring tight spatial and temporal regulation of oxidants by normal cells (Terada, 2006Terada L.S. J. Cell Biol. 2006; 174: 615-623Crossref PubMed Scopus (173) Google Scholar). In this capacity, ROS control proliferation, differentiation, junction formation, and response to cytokines and other soluble factors. Given their propensity to produce increased levels of ROS, are cancer cells able to appropriate these oxidant-dependent signals as a means of dysregulating proliferative and survival pathways? In this issue of Cancer Cell, Zhu et al., 2011Zhu P. Tan M.J. Huang R.-L. Tan C.K. Chong H.C. Pal M. Lam C.R.I. Boukamp P. Pan J.Y. Tan S.H. et al.Cancer Cell. 2011; 19 (this issue): 401-415Abstract Full Text Full Text PDF Scopus (194) Google Scholar uncover a role for angiopoietin-like 4 (ANGPTL4) in activating integrin-related, oxidant-dependent survival pathways, despite the loss of matrix attachment. This highjacking of normal anchorage-sensing mechanisms sheds further light on the complex role of ROS in malignant cell behavior. ANGPTL4 has previously been shown to regulate lipid metabolism; interestingly, fasting and hypoxia induce ANGPTL4, suggesting its possible importance in the tumor microenvironment. Accordingly, upregulation of ANGPTL4 predicts metastasis of breast cancer to the lung, possibly by preparing the lung microvascular bed for efficient tumor cell extravasation (Padua et al., 2008Padua D. Zhang X.H. Wang Q. Nadal C. Gerald W.L. Gomis R.R. Massague J. Cell. 2008; 133: 66-77Abstract Full Text Full Text PDF PubMed Scopus (749) Google Scholar). In the present study, Zhu et al., 2011Zhu P. Tan M.J. Huang R.-L. Tan C.K. Chong H.C. Pal M. Lam C.R.I. Boukamp P. Pan J.Y. Tan S.H. et al.Cancer Cell. 2011; 19 (this issue): 401-415Abstract Full Text Full Text PDF Scopus (194) Google Scholar first survey ANGPTL4 expression in normal and neoplastic cells and tissue and find elevated protein and mRNA levels in adenomas and carcinomas from a variety of tissues besides breast, suggesting broad relevance in human cancers. Further, in knockdown or knockout studies of both human skin carcinoma xenograft and mouse melanoma tumor models, the authors show that ANGPTL4 supports tumor growth in an autocrine or paracrine fashion. Of importance, treatment with an antibody against ANGPTL4 significantly retards melanoma growth in the mouse model, indicating that this pathway may be clinically targetable. The authors further studied the effects of ANGPTL4 on attachment sensation by tumor cells. Anchorage independence is a well-known mesenchymal phenotype that allows carcinomas to metastasize and possibly to expand as a mass without consistent basement membrane contact. The mechanisms by which normal epithelioid cells sense attachment and are committed to death following detachment are not well understood, but clearly involve outside-in integrin signals. Here, the authors demonstrate direct binding of ANGPTL4 to β1 and β5 integrins, resulting in the activation of both Rac1 and FAK and the downstream activation of Src, Akt/PKB, and ERK with consequent protection from anoikis. Thus, ANGPTL4 is capable of falsely reporting anchored conditions through integrin binding. The composition of the integrin-related signaling complex that reports anchorage conditions is not well understood. Rac1 in particular is critical to coupling integrin ligation with cell cycle progression (Mettouchi et al., 2001Mettouchi A. Klein S. Guo W. Lopez-Lago M. Lemichez E. Westwick J.K. Giancotti F.G. Mol. Cell. 2001; 8: 115-127Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). Among a number of Rac1 effectors, several members of the NADPH oxidase (Nox) family are of potential relevance in this regard. Increased ROS have been associated with both detachment from and attachment to matrix, and are thought to transduce either death or survival signals. In the latter instance, oxidative activation of Src has been shown to mediate survival effects (Giannoni et al., 2005Giannoni E. Buricchi F. Raugei G. Ramponi G. Chiarugi P. Mol. Cell. Biol. 2005; 25: 6391-6403Crossref Scopus (362) Google Scholar), though the specific oxidant source has been less clear. Of note, the Nox adaptor p47phox translocates to focal complexes and initiates local Rac1 and Src-dependent redox signaling in migrating cells, indicating Nox signaling that is restricted to sites of nascent integrin clustering (Wu et al., 2005Wu R.F. Xu Y.C. Ma Z. Nwariaku F.E. Sarosi Jr., G.A. Terada L.S. J. Cell Biol. 2005; 171: 893-904Crossref Scopus (151) Google Scholar). This adaptor serves Nox1 as well as Nox2, which both require Rac1 for activation. In the present article, the authors clearly demonstrate Nox1 as the predominant oxidase mediating ANGPTL4/β1-2 integrin-dependent survival signals (Zhu et al., 2011Zhu P. Tan M.J. Huang R.-L. Tan C.K. Chong H.C. Pal M. Lam C.R.I. Boukamp P. Pan J.Y. Tan S.H. et al.Cancer Cell. 2011; 19 (this issue): 401-415Abstract Full Text Full Text PDF Scopus (194) Google Scholar). Identification of this particular oxidase is notable, as it was originally described as a mitogenic oxidase associated with cell transformation (Suh et al., 1999Suh Y.A. Arnold R.S. Lassegue B. Shi J. Xu X. Sorescu D. Chung A.B. Griendling K.K. Lambeth J.D. Nature. 1999; 401: 79-82Crossref PubMed Scopus (1275) Google Scholar). Indeed, subsequent studies have linked Nox1 induction, downstream from oncogenic Ras, with anchorage independence and tumorigenesis (Mitsushita et al., 2004Mitsushita J. Lambeth J.D. Kamata T. Cancer Res. 2004; 64: 3580-3585Crossref PubMed Scopus (264) Google Scholar). More recently, Nox1 has also been shown to mediate β1 integrin signaling during directional migration and wound repair (Jun and Lau, 2010Jun J.I. Lau L.F. Nat. Cell Biol. 2010; 12: 676-685Crossref PubMed Scopus (614) Google Scholar, Sadok et al., 2009Sadok A. Pierres A. Dahan L. Prevot C. Lehmann M. Kovacic H. Mol. Cell. Biol. 2009; 29: 3915-3928Crossref Scopus (30) Google Scholar), suggesting a broader role for Nox1 in mediating β1 integrin signaling. Together, these data suggest that Nox1 may exert its signaling effects primarily through its integration into specific integrin complexes. This study has interesting implications and raises several general questions. First, the ability of ANGPTL4 to activate PI3K and ERK pathways suggests a common involvement of Ras, whose effects are known to be linked to integrin ligation context. While the authors did not specifically examine Ras involvement, Ras and Nox control broadly overlapping cellular functions, including proliferation, survival, cell shape change, and motility. Ras has been shown to be activated downstream of oxidants, either through direct cysteine modification or through upstream events; conversely, oncogenic Ras is known to exert mitogenic effects through ROS. In addition, both Ras and Nox gene families arose early in eukaryotic evolution, appear to collaborate in specific developmental and morphologic adaptations to environmental stress, and colocalize in relevant signaling compartments. Thus, it is conceivable that ANGPTL4 may feed into an evolutionarily conserved environment-sensing pathway. One question raised is the relevance of the specific oxidant produced. While the authors correlate ANGPTL4 effects with changes in O2-:H2O2 ratios, caution should be exerted with respect to the significance of this ratio. First, one rarely, if ever, encounters O2- without H2O2, owing to its rapid spontaneous dismutation, making it often difficult to distinguish the effects of one oxidant species from the other in vivo. Second, despite their differing chemical reactivity, common molecular targets have been ascribed to both. For instance, Src oxidation during cell adhesion, as postulated in the present study, is blocked by PEG-catalase, indicating H2O2 and not O2- as the proximal ROS (Giannoni et al., 2005Giannoni E. Buricchi F. Raugei G. Ramponi G. Chiarugi P. Mol. Cell. Biol. 2005; 25: 6391-6403Crossref Scopus (362) Google Scholar). Third, it is probable that the observed changes in O2-:H2O2 ratios reflect alterations in activity of specific oxidases induced by the various interventions. A shift in the activity or presence of various oxidases, which are differentially localized and regulated, is more likely to be responsible for changes in signal output. For example, Nox4, a predominantly H2O2-producing Nox, is localized to the ER and mediates ER stress signaling and cell fate decisions, and may in part be responsible for the increase in cell death. Perhaps the most interesting question has to do with how ANGPTL4 can fool the cell to believe that it is anchored to a solid environment. Soluble matrix fragments or peptide-coated microspheres will ligate and cluster integrins but not prevent anoikis, suggesting that proper anchorage sensing requires a mechanical readout of the stiffness of the surrounding matrix, beyond simple integrin ligation. Such mechanosensation appears to require RhoA-dependent tension against the underlying solid matrix (Ma et al., 2007Ma Z. Myers D.P. Wu R.F. Nwariaku F.E. Terada L.S. J. Cell Biol. 2007; 179: 23-31Crossref PubMed Scopus (54) Google Scholar). In this regard, it is noteworthy that Nox1 locally inactivates RhoA (Sadok et al., 2009Sadok A. Pierres A. Dahan L. Prevot C. Lehmann M. Kovacic H. Mol. Cell. Biol. 2009; 29: 3915-3928Crossref Scopus (30) Google Scholar), offering a possible means to defeat this tension test. Further study of this integrin-related signaling complex will lead to deeper insight into the mechanism of anchorage sensing and its loss in cancer cells. Angiopoietin-like 4 Protein Elevates the Prosurvival Intracellular O2−:H2O2 Ratio and Confers Anoikis Resistance to TumorsZhu et al.Cancer CellMarch 08, 2011In BriefCancer is a leading cause of death worldwide. Tumor cells exploit various signaling pathways to promote their growth and metastasis. To our knowledge, the role of angiopoietin-like 4 protein (ANGPTL4) in cancer remains undefined. Here, we found that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. Tumor-derived ANGPTL4 interacts with integrins to stimulate NADPH oxidase-dependent production of O2−. A high ratio of O2−:H2O2 oxidizes/activates Src, triggering the PI3K/PKBα and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. Full-Text PDF Open Archive" @default.
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• W2074446241 title "Escaping Anoikis through ROS: ANGPTL4 Controls Integrin Signaling through Nox1" @default.
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