Selective upregulation and amplification of the lysyl oxidase like‐4 (LOXL4) gene in head and neck squamous cell carcinoma

Görögh, Tibor; Jb, Weise; Holtmeier, Claudia; Rudolph, Pierre; Hedderich, Jürgen; Gottschlich, S.; Hoffmann, Markus; Ambrosch, Petra; Csiszár, Katalin

doi:10.1002/path.2137

Cited by 30 publications

(21 citation statements)

References 28 publications

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“…LOXL4, the least well-characterized family member, is overexpressed in head/neck and colorectal carcinomas (16,17). The HIF → LOXL4 pathway plays a significant role in collagen cross-linking, metastatic niche formation, and metastasis in a subset of breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation

Wong¹,

Gilkes²,

Zhang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

392

377

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Primary tumors facilitate metastasis by directing bone marrowderived cells (BMDCs) to colonize the lungs before the arrival of cancer cells. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of breast cancer metastatic niche formation through induction of multiple members of the lysyl oxidase (LOX) family, including LOX, LOX-like 2, and LOX-like 4, which catalyze collagen cross-linking in the lungs before BMDC recruitment. Only a subset of LOX family members was expressed in any individual breast cancer, but HIF-1 was required for expression in each case. Knockdown of HIF-1 or hypoxia-induced LOX family members reduced collagen cross-linking, CD11b+ BMDC recruitment, and metastasis formation in the lungs of mice after orthotopic transplantation of human breast cancer cells. Metastatic niche formation is an HIF-1-dependent event during breast cancer progression. extracellular matrix | lung metastasis I ntratumoral hypoxia is a common finding that is attributable to inadequate O 2 delivery to regions of rapidly growing cancers that are distant from functional blood vessels (1). Reduced O 2 availability leads to increased activity of hypoxia-inducible factors (HIFs), which consist of an O 2 -regulated HIF-1α or HIF-2α subunit and the constitutively expressed HIF-1β subunit (2, 3). HIF inhibition blocks tumor xenograft growth (2, 4).Metastasis is responsible for 90% of deaths among patients who have breast cancer and involves multiple steps, including cancer cell invasion through ECM, intravasation, extravasation, and colonization of distant organs (5). Recent studies have reported that prior recruitment of bone marrow-derived cells (BMDCs) to the metastatic site promotes subsequent colonization by cancer cells (6). The primary tumor is responsible for BMDC recruitment to the metastatic site. Breast tumors secrete lysyl oxidase (LOX), which localizes at metastatic sites in the lungs and remodels collagen, thereby facilitating BMDC recruitment (7,8). LOX oxidatively deaminates the ε-amino groups of lysine residues, resulting in intramolecular and intermolecular cross-linking of collagen molecules (9). Crosslinking stabilizes collagen by assembly into fibrils and fibers, which enhance ECM tensile strength, leading to focal adhesion formation and PI3K signaling (10). The LOX family is composed of LOX and LOX-like (LOXL) proteins LOXL1-4. So far, only LOX has been implicated in metastatic niche formation (7). In this study, we demonstrate that HIF-1 regulates metastatic niche formation by activating expression of LOX and LOXL proteins. HIF-1 silencing suppresses metastatic niche formation and metastasis regardless of which LOX family member is involved. ResultsHypoxia-Induced LOX/LOXL Expression in Breast Cancer Cell Lines.Two metastatic breast cancer cell lines, MDA-MB-231 (MDA-231) and MDA-MB-435 (MDA-435), as well as a nonmetastatic line, MCF-7, were cultured under standard, nonhypoxic tissue culture conditions of 95% air/5% CO 2 (vol/vol; 20% O 2 ) and under hypoxic culture conditi...

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Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation

Wong¹,

Gilkes²,

Zhang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

392

377

View full text Add to dashboard Cite

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“…LOXL1 has been reported to play a role in pseudoexfoliation glaucoma and primary open angle glaucoma. LOXL3 and LOX4 have been implicated in breast cancer invasion and head and neck squamous cell carcinoma (15,38). ECM accumulation is now considered to play a more mechanistic role in the development of compromised barrier function.…”

Section: Discussionmentioning

confidence: 99%

High Glucose Increases Lysyl Oxidase Expression and Activity in Retinal Endothelial Cells: Mechanism for Compromised Extracellular Matrix Barrier Function

et al. 2010

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OBJECTIVEIn diabetes, retinal vascular basement membrane (BM) undergoes significant thickening and compromises vessel function including increased vascular permeability, a prominent lesion of early diabetic retinopathy. In this study we determined whether altered expression and activity of lysyl oxidase (LOX), a cross-linking enzyme, may compromise vascular basement membrane functional integrity under high-glucose (HG) conditions.RESEARCH DESIGN AND METHODSRat retinal endothelial cells (RRECs) grown in normal (5 mmol/l) or HG (30 mmol/l glucose) medium for 7 days were assessed for expression of LOX and proLOX by Western blot analysis and LOX enzyme activity. To determine whether HG alters cellular distribution patterns of LOX and proLOX, immunostaining with respective antibodies was performed. Similarly, cells grown in normal or HG medium were subjected to both LOX inhibition with β-aminopropionitrile (BAPN) and by small interfering RNA knockdown, and respectively examined for cell monolayer permeability. Additionally, retinas of streptozotocin (STZ)-induced diabetic rats were analyzed to determine if diabetes altered LOX expression.RESULTSWestern blot analysis revealed significantly increased LOX and proLOX expression in cells grown in HG medium compared with those grown in normal medium. The increased LOX level was strikingly similar to LOX upegulation in the diabetic retinas. In cells grown in HG medium, LOX activity and cell monolayer permeability was significantly increased, as were LOX and proLOX immunostaining. Small interfering RNA- or BAPN–induced-specific blockage of LOX expression or activity, respectively, reduced cell monolayer permeability.CONCLUSIONSHG-induced increased LOX expression and activity compromises barrier functional integrity, a prominent lesion of diabetic retinopathy.

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“…Another interesting result came from a Spanish group. They used fluorescence in situ hybridization and showed that increased copies of the LOXL4 gene locus on chromosome 10q24 were associated with a higher invasiveness and frequency of lymph-node metastasis in head and neck cancer (Görögh et al, 2007).…”

Section: Lox and Hypoxia/invasivenessmentioning

confidence: 99%

Lysyl Oxidase: From Basic Science to Future Cancer Treatment

Nishioka

Eustace

West

2012

Cell Struct. Funct.

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ABSTRACT. In this mini-review, we discuss the physiological and pathological roles of lysyl oxidase (LOX) and its family, LOX-like proteins (LOXL), in relation to prognosis of major cancers. The number of reports on LOX family is numerous. We have decided to review the articles that were recently published (i.e. past 5 years). Experimental techniques in molecular biology have advanced surprisingly in the past decade. Accordingly, the results of the studies are more reliable. Most studies reached the same conclusion; a higher LOX-or LOXLexpression is associated with a poor prognosis. Molecular experiments have already started aiming for clinical application, and the results are encouraging. Suppressing LOX or LOXL activities resulted in lower cell motility in collagen gel and, moreover, succeeded in reducing metastases in mice. LOX family members were originally recognized as molecules that cross-link collagen fibers in the extracellular matrix. Recent studies demonstrated that they are also involved in a phenomenon called Epithelial Mesenchymal Transition (EMT). This may affect cell movement and cancer cell invasiveness. LOX and LOXL2 are regulated by hypoxia, a major factor in the failure of cancer treatment. Here we discuss the molecular biology of the LOX family in relation to its role in tumor biology.

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Selective upregulation and amplification of the lysyl oxidase like‐4 (LOXL4) gene in head and neck squamous cell carcinoma

Cited by 30 publications

References 28 publications

Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation

Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation

High Glucose Increases Lysyl Oxidase Expression and Activity in Retinal Endothelial Cells: Mechanism for Compromised Extracellular Matrix Barrier Function

Lysyl Oxidase: From Basic Science to Future Cancer Treatment

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