Fibronectin-targeted drug delivery in cancer

Kumra, Heena; Reinhardt, Dieter P.

doi:10.1016/j.addr.2015.11.014

Cited by 111 publications

(88 citation statements)

References 127 publications

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“…Polymerization and pericellular FN matrix assembly (periFN) engaging disulfide bond-dependent and -independent dimerization of FN subunits, self-binding activity that associates FN dimers into fibrils, and cell-binding activity enable FN to participate various physiological and pathological functionalities. Illustrations regarding detailed biology of FN can be referred to other review articles [49,50].…”

Section: Structure and Functions Of Fnmentioning

confidence: 99%

“…Indeed, FN upregulation has been deemed as one of prominent senescent marker [113,115] (Figure 2). It is reasonable to associate FN overexpression with premature cellular senescence that is triggered by a variety of stresses, including ER stresses, due to tumor transformation factors, e.g., oncogene-induced senescence (OIS) or senescence induced by loss of TSG, as FN is a large and highly structured ECM glycoprotein synthesized in the ER with a molecular weight of a disulfide-bonded dimer as high as~500 kDa [50] and may easily suffer structural misfolding due to diverse reasons including mutations, inadequate stoichiometric amounts of oligomerization partners, shortage of chaperone availability, increase in nascent client proteins, nutrient deprivation, viral infection, hypoxia, and oxidative stress [116]. The newly synthesized FN monomer entering the lumen of the ER undergoes proper folding, posttranslational modifications, followed by the acquisition of disulfide bonds before it is in the appropriate structure to execute physiological functions [117].…”

Section: The Role Of Fn Expression In Epithelial Cell Senescence and mentioning

confidence: 99%

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Fibronectin in Cancer: Friend or Foe

Lin

Yang

et al. 2019

Cells

147

117

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The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Figure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). On the contrary, Among 46 publications after 2000, 7 (15.2%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 25 (54.4%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 14 (30.4%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). Abbreviations in boxes are referred to the context of this article. (C) Percentages of articles for the three various roles of FN (the same colors as depicted in (B) before 2000 and after 2000. Numbers in the parenthesis represent article numbers. The Pathobiology of CancerFigure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the r...

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Section: Structure and Functions Of Fnmentioning

confidence: 99%

Section: The Role Of Fn Expression In Epithelial Cell Senescence and mentioning

confidence: 99%

Fibronectin in Cancer: Friend or Foe

Lin

Yang

et al. 2019

Cells

147

117

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“…As an abundant molecule in ECM, FN takes part in a variety of processes that promote cancer cell progression, by interacting with cells and other ECM molecules. Over the past two decades, the role of FN in cancer has been recognized and FN-targeting strategies have been devised as promising cancer imaging and therapy approaches 3, 4 . In this article, we provide an overview of the interaction of FN with cancer cells and other ECM molecules, how this interaction correlates to cancer malignancy, and FN-targeting strategies in cancer imaging and therapy, highlighting their application in different types of cancers.…”

Section: Introductionmentioning

confidence: 99%

Targeting fibronectin for cancer imaging and therapy

2017

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During cancer progression, the extracellular matrix (ECM) undergoes dramatic changes, which promote cancer cell migration and invasion. In the remodeled tumor ECM, fibronectin (FN) level is upregulated to assist tumor growth, progression, and invasion. FN serves as a central organizer of ECM molecules and mediates the crosstalk between the tumor microenvironment and cancer cells. Its upregulation is correlated with angiogenesis, cancer progression, metastasis, and drug resistance. A number of FN-targeting ligands have been developed for cancer imaging and therapy. Thus far, FN-targeting imaging agents have been tested for nuclear imaging, MRI, and fluorescence imaging, for tumor detection and localization. FN-targeting therapeutics, including nuclear medicine, chemotherapy drugs, cytokines, and photothermal moieties, were also developed in cancer therapy. Because of the prevalence of FN overexpression in cancer, FN targeting imaging agents and therapeutics have the promise of broad applications in the diagnosis, treatment, and image-guided interventions of many types of cancers. This review will summarize current understanding on the role of FN in cancer, discuss the design and development of FN-targeting agents, and highlight the applications of these FN-targeting agents in cancer imaging and therapy.

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“…This suggests that the formation of ED-A FN is rather a result of enzymatic digestion or folding than synthesis. The association between ED-A FN expression and cellular density and presence of inflammatory molecules in the OA synovium is of particular interest because there are currently ongoing studies of utilizing ED-A FN as a drug delivery target in rheumatoid arthritis and other diseases [29]. E.g., Dekavil is a drug combining a human F8 antibody specific to the ED-A domain of FN fused to the anti-inflammatory cytokine IL-10 [30,31].…”

Section: Discussionmentioning

confidence: 99%

Tissue growth factor β stimulates fibroblast-like synovial cells to produce extra domain A fibronectin in osteoarthritis

Kragstrup

Sohn

Lepus

et al. 2018

Preprint

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2 Introduction: The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state 3 of low-grade inflammation. Wear and tear leads to tissue degradation and tissue repair 4 responses, including tissue growth factor beta (TGFβ)-induced myofibroblast production of 5 extracellular matrix (ECM). Fibronectins are an essential part of the ECM, and injection of 6 fibronectin fragments into rabbit joints is a previously established animal model of OA.7 Alternatively-spliced fibronectin contains the ED-A domain (ED-A FN) and has been shown 8 to activate Toll-like receptor 4. In this study, we tested the hypothesis that FN fragments 9 containing the ED-A domain could be one mechanism transducing mechanical events into 10 inflammatory signals in OA. 11 12 Methods: Samples of synovial membrane and cartilage were obtained from patients with 13 knee OA undergoing joint replacement surgery. Immunostaining for ED-A FN and the 14 myofibroblast marker alpha smooth muscle actin (αSMA) was performed on synovial 15 membranes and fibroblast-like synovial cells (FLS). FLS were stimulated with TGFβ, TNFα, 16 lipopolysaccharide, IL-6, OA synovial fluid, or chondrocyte lysate, and analyzed for ED-A 17 FN. Synovial cells isolated by enzymatic digestion and human monocyte-derived 18 macrophages (MDM) were incubated with recombinant ED-A FN, plasmin, cellular FN, or 19 cellular FN digested with plasmin; and culture supernatants were analyzed for MCP-1 and 20 TNFα.21 22 Results: We hypothesized that ED-A FN is produced by OA FLS in response to factors found 23 in the OA synovial joint. Indeed, the production of ED-A FN by OA FLS was increased by 24 TGFβ, OA synovial fluid, and lysed chondrocytes in all experiments (n=3). ED-A FN co-25 localized with the myofibroblast marker αSMA in both the OA FLS (n=3) and in the OA ED-A FN in OA 3 1 synovial membranes (n=8). We further hypothesized that ED-A FN expression is associated 2 with cellular density and expression of inflammatory molecules in OA. ED-A FN staining 3 was associated with both number of lining layer cells (rho=0.85 and p=0.011) and sublining 4 cells (rho=0.88 and p=0.007) in the OA synovium (n=8), and co-localized with both MCP-1 5 and TNFα (n=5). Recombinant ED-A FN increased the production of both MCP-1 and TNFα 6 by MDM (n=3) and OA FLS (n=3). Finally, we demonstrated that the FN fragments 7 containing the ED-A domain generated the same production of both MCP-1 and TNFα as 8 recombinant ED-A FN. 9 10 Conclusion: The disease process in OA shares features with the chronic wound healing 11 response including myofibroblast differentiation and production of mediators that promote 12 myofibroblast production of ED-A FN. We show that recombinant and plasmin-derived ED-A 13 fragments stimulate FLS and MDM to produce pro-inflammatory mediators. Our findings 14 support utilizing ED-A FN for drug delivery or therapeutic targeting of the formation of ED-15 A FN or the enzymatic fragmentation of FN to reduce pro-inflammatory responses in OA. 16 17

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Fibronectin-targeted drug delivery in cancer

Cited by 111 publications

References 127 publications

Fibronectin in Cancer: Friend or Foe

Fibronectin in Cancer: Friend or Foe

Targeting fibronectin for cancer imaging and therapy

Tissue growth factor β stimulates fibroblast-like synovial cells to produce extra domain A fibronectin in osteoarthritis

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