Human lysyl oxidase-like 2

Moon, Hee-Jung; Finney, Joel; Ronnebaum, Trey; Mure, Minae

doi:10.1016/j.bioorg.2014.07.003

Cited by 121 publications

(116 citation statements)

References 85 publications

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“…LOXL2 (lysyl oxidase like-2) belongs to the lysyl oxidase (LOX) family of proteins composed of five members (LOX and four related enzymes, LOXL1-4) whose conventional function is to catalyze the crosslinking of extracellular matrix (ECM) components, mainly collagens and elastin (1–3). LOX family members thus play an essential role in tissue homeostasis contributing to ECM remodeling, but can also participate in diverse pathological conditions as organ fibrosis and cancer (4–7).…”

Section: Introductionmentioning

confidence: 99%

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

et al. 2017

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The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote pre-metastatic niche formation. Taken together, our findings established a pathophysiological role and new function for LOXL2 in breast cancer metastasis.

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Section: Introductionmentioning

confidence: 99%

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

et al. 2017

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“…Lysyl oxidase-like 2 (LOXL2) belongs to the lysyl oxidase protein family responsible for cross-linking of collagen and elastin considered as final step in the fibrogenic pathway causing tissue stiffness and further enhancing transforming growth factor β tissue driven remodeling [49]. Simtuzumab (GS-6624), a monoclonal antibody highly selective for LOXL2, is currently studied in patients with advanced liver fibrosis and cirrhosis caused by NASH.…”

Section: Treatments Directed At Mechanisms Of Liver Fibrogenesismentioning

confidence: 99%

New Medical Treatment Strategies for Nonalcoholic Steatohepatitis

Fuchs

2015

Curr Treat Options Gastro

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Nonalcoholic steatohepatitis (NASH) is a severe form of fatty liver disease unrelated to chronic alcohol consumption. As nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and is becoming the most common cause for chronic liver disease, NASH likely will replace chronic hepatitis C as leading indication for liver cirrhosis and liver transplantation in this decade. Despite this alarming trend, effective treatment is lacking and continues to rely on dietary interventions and physical exercise, known to be of limited effect. Hence, there is an urgent need for safe pharmacologic therapy that successfully reverses or prevents progression of liver injury and fibrosis in patients with NASH. Employing emerging concepts of disease development and progression that involve in parallel ongoing events originating from the liver, adipose tissue, and intestine will ultimately promote the development of effective agents for targeted therapies for NASH. Novel agents must be safe, optimally dosed, and finally pass clinical trials providing proof of concept and efficacy. In the case of NASH, trial design is not necessarily straightforward as surrogate end points to predict clinical benefits are not yet established. The level of unmet needs for NASH goes however even beyond therapeutic agents and also includes patient and physician awareness. This article focuses on identifying potential pathophysiology-guided targets for medical therapy of NASH.

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“…Since PSC is a fibro-obliterative disease, targeting lysyl oxidase like 2 (LOXL2) protein, copper-dependent enzyme that initiates the cross-linking of collagens and elastin [89] , may be another reasonable approach. Upregulation of LOXL2 was found not only in different animal models of liver fibrosis [90] , including Mdr2 (Abcb4) -/-mice, a mouse model of sclerosing cholangitis [91] , but also in the liver tissue of patients suffering from Wilson's disease, primary biliary cirrhosis (PBC) [92] and also in PSC patients [93] .…”

Section: Novel Therapeutic Approaches To Psc -Therapy Tomorrowmentioning

confidence: 99%

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

Halilbasic

Fuchs

Hofer

et al. 2015

Dig Dis

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Primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy. Due to our incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited. Bile acids play a key role in mediating cholangiocellular and hepatocellular injury in cholangiopathies such as PSC. Therefore, strategies targeting bile composition and homeostasis are valid approaches in PSC. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C₂₃ homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid). Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs. Furthermore, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to inflammatory bowel disease and the emerging relevance of the gut microbiome for the development of PSC. Finally, fibrosis represents a valid therapeutic target for anti-fibrotic drugs (e.g. simtuzumab) in PSC as paradigm fibro-obliterative disease. This review summarizes the current status and recent progress in the development of targeted therapeutic approaches based on increasing knowledge about the pathogenesis of this disease.

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Human lysyl oxidase-like 2

Cited by 121 publications

References 85 publications

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

New Medical Treatment Strategies for Nonalcoholic Steatohepatitis

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

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