Cancer therapy targeting the fibrinolytic system

Heissig, Beate; Eiamboonsert, Salita; Salama, Yousef; Shimazu, Hiroshi; Dhahri, Douaa; Munakata, Shinya; Tashiro, Yoshihiko; Hattori, Koichi

doi:10.1016/j.addr.2015.11.010

Cited by 23 publications

(19 citation statements)

References 92 publications

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“…Plasmin can alter the activity status of growth factors, thereby changing the biologic function of cells ( e.g. , their migratory abilities) (14).…”

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Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

et al. 2017

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Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; ) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as and In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1 mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.

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“…Plasmin can alter the activity status of growth factors, thereby changing the biologic function of cells ( e.g. , their migratory abilities) (14).…”

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confidence: 99%

“…EGF also enhances cell migration and adhesion to extracellular matrix molecules (13). Plasmin can alter the activity status of growth factors, thereby changing the biologic function of cells (e.g., their migratory abilities) (14).…”

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confidence: 99%

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

et al. 2017

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“…The fibrinolytic activity found in the extracts of greater amberjack S. dumerili indicates the biotechnological potential of these neglected digestive wastes. Thrombolytic agents are used for thrombosis of the cardiac valve [29], in the enzymatic debridement of the pleural cavity [30], cancer therapy [31] and pathophysiological action in the nervous system [32]. To our knowledge, no record of fibrinolytic agents from fish processing residues has been reported to date; the present study was the first report.…”

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confidence: 71%

Study on enzymes of industrial interest in digestive viscera: Greater amberjack (Seriola dumerili)

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“…To date, most studies have focused on the fibrinolysispromoting role of tPA in cancer. However, one study has clearly demonstrated that tPA modulates the cell behavior and cellular composition of the tumor (26). High tPA expression levels have been reported in human melanoma.…”

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confidence: 99%

“…Tumor-associated mesenchymal stroma cells, such as the cancer-associated fibroblasts mesenchymal stem cells (MSCs), smooth muscle cells, myofibroblasts, endothelial cells, pericytes, and inflammatory cells, are recruited to the melanoma tumor bed (25). The tumor niche is recognized as a key factor in the multiple stages of cancer progression, mediating local resistance, immune escape, and metastasis (26). We showed that tPA can expand platelet-derived growth factor receptor (PDGFR) a-MSCs in noncancerous tissues (27).…”

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The fibrinolytic factor tPA drives LRP1‐mediated melanoma growth and metastasis

et al. 2018

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The multifunctional endocytic receptor low‐density lipoprotein receptor‐related protein (LRP)1 has recently been identified as a hub within a biomarker network for multicancer clinical outcome prediction. The mechanism how LRP1 modulates cancer progression is poorly understood. In this study we found that LRP1 and one of its ligands, tissue plasminogen activator (tPA), are expressed in melanoma cells and control melanoma growth and lung metastasis in vivo. Mechanistic studies were performed on 2 melanoma cancer cell lines, B16F10 and the B16F1 cells, both of which form primary melanoma tumors, but only B16F10 cells metastasize to the lungs. Tumor‐, but not niche cell‐derived tPA, enhanced melanoma cell proliferation in tPA−/− mice. Gain‐of‐function experiments revealed that melanoma LRP1 is critical for tumor growth, recruitment of mesenchymal stem cells into the tumor bed, and metastasis. Melanoma LRP1 was found to enhance ERK activation, resulting in increased matrix metalloproteinase (MMP)‐9 RNA, protein, and secreted activity, a well‐known modulator of melanoma metastasis. Restoration of LRP1 and tPA in the less aggressive, poorly metastatic B16F1 tumor cells enhanced tumor cell proliferation and led to massive lung metastasis in murine tumor models. Antimelanoma drug treatment induced tPA and LRP1 expression. tPA or LRP1 knockdown enhanced chemosensitivity in melanoma cells. Our results identify the tPA‐LRPl pathway as a key switch that drives melanoma progression, in part by modulating the cellular composition and proteolytic makeup of the tumor niche. Targeting this pathway may be a novel treatment strategy in combination treatments for melanoma.—Salama, Y., Lin, S.‐Y., Dhahri, D., Hattori, K., Heissig, B. The fibrinolytic factor tPA drives LRP1‐mediated melanoma growth and metastasis. FASEB J. 33, 3465–3480 (2019). http://www.fasebj.org

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Cancer therapy targeting the fibrinolytic system

Cited by 23 publications

References 92 publications

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

Study on enzymes of industrial interest in digestive viscera: Greater amberjack (Seriola dumerili)

The fibrinolytic factor tPA drives LRP1‐mediated melanoma growth and metastasis

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