Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

Kerzeli, Iliana; Kostakis, Alexandros; Türker, Polat; Malmström, Per‐Uno; Hemdan, Tammer; Mezheyeuski, Artur; Ward, Douglas G.; Bryan, Richard T.; Segersten, Ulrika; Lord, Martin; Mangsbo, Sara M.

doi:10.1186/s12885-023-11100-0

Cited by 6 publications

(3 citation statements)

References 50 publications

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“…MMP12 is a macrophage-secreted protein that has been previously associated with pro-inflammatory functions in a variety of pathological conditions in humans and in animal models [ 16 , 17 , 21 , 23 , 54 ]. Several studies have also addressed its role in individual pathologies encompassed by CMDs such as insulin resistance or CVDs [ 27 , 30 – 32 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

Amor,

Bianco,

Buerger

et al. 2023

Cardiovasc Diabetol

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Background Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. Methods We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16–20 weeks. Results DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. Conclusion We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

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Section: Discussionmentioning

confidence: 99%

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

Amor,

Bianco,

Buerger

et al. 2023

Cardiovasc Diabetol

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“…In contrast, CIS and invasive tumors have alterations in TP53 and RB1 [31]. Muscle-invasive tumors are characterized by changes in vascular endothelial growth factors (VEGF), cadherins, and matrix metalloproteinases (MMPs) [32].…”

Section: Invasive and Non-invasive Uccmentioning

confidence: 99%

“…Frequency of genetic alterations in select genes for MIBC tumors. Compiled and adapted from references[25,[29][30][31][32][33][34][35][36][37][38][39].…”

mentioning

confidence: 99%

Current and Emerging Strategies to Treat Urothelial Carcinoma

Rani,

Ignatz-Hoover,

Rana

et al. 2023

Cancers

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Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients.

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Protein profile in urinary extracellular vesicles is a marker of malignancy and correlates with muscle invasiveness in urinary bladder cancer

Steiner,

Eldh,

Offens

et al. 2025

Cancer Letters

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Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

Cited by 6 publications

References 50 publications

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

Current and Emerging Strategies to Treat Urothelial Carcinoma

Protein profile in urinary extracellular vesicles is a marker of malignancy and correlates with muscle invasiveness in urinary bladder cancer

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