Antitumor effects of EMAP II against pancreatic cancer through inhibition of fibronectin-dependent proliferation

Schwarz, Roderich E.; Awasthi, Niranjan; Konduri, Srivani; Caldwell, Lauren; Cafasso, Danielle E.; Schwarz, Margaret A.

doi:10.4161/cbt.9.8.11265

Cited by 35 publications

(30 citation statements)

References 31 publications

(45 reference statements)

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“…Lastly, a recent study identified that the cytokine endothelial monocyte activating polypeptide II (EMAP II) suppresses PDA progression by impeding FN-integrin interactions [119]. EMAP II binds directly to α5β1 integrin and significantly decreased proliferation, angiogenesis, and overall tumor growth of subcutaneous xenograft models of PDA.…”

Section: Regulation Of Fn Signaling In Pdamentioning

confidence: 99%

Matrix control of pancreatic cancer: New insights into fibronectin signaling

Topalovski

Brekken

2016

Cancer Letters

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Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease that resists most current therapies. A defining characteristic of PDA is an intense fibrotic response that promotes tumor cell invasion and chemoresistance. Efforts to understand the complex relationship between the tumor and its extracellular network and to therapeutically perturb tumor-stroma interactions are ongoing. Fibronectin (FN), a provisional matrix protein abundant in PDA stroma but not normal tissues, supports metastatic spread and chemoresistance of this deadly disease. FN also supports angiogenesis, which is required for even hypovascular tumors such as PDA to develop and progress. Targeting components of the tumor stroma, such as FN, can effectively reduce tumor growth and spread while also enhancing delivery of chemotherapy. Here, we review the molecular mechanisms by which FN drives angiogenesis, metastasis and chemoresistance in PDA. In light of these new findings, we also discuss therapeutic strategies to inhibit FN signaling.

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Section: Regulation Of Fn Signaling In Pdamentioning

confidence: 99%

Matrix control of pancreatic cancer: New insights into fibronectin signaling

Topalovski

Brekken

2016

Cancer Letters

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“…In ECs, EMAP has been shown to induce apoptosis and inhibit proliferation, vascularization, and neovessel formation [Schwarz et al, 1999a;Berger et al, 2000]. EMAP inhibits primary and metastatic tumor growth due to its antiangiogenic activities [Schwarz et al, 1999a[Schwarz et al, , 2010bSchwarz and Schwarz, 2004]. The mechanism appears to involve its ability to bind to a5b1 integrin and vascular endothelial growth factor (VEGF) receptors, leading to an inhibition of fibronectin and VEGF signaling [Schwarz et al, 2005;Awasthi et al, 2009].…”

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confidence: 99%

The efficacy of a novel, dual PI3K/mTOR inhibitor NVP‐BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer

Awasthi

Yen

Schwarz

et al. 2012

J of Cellular Biochemistry

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Gemcitabine has limited clinical benefits for pancreatic ductal adenocarcinoma (PDAC). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in PDAC. We investigated the effects of NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival experiments were performed in murine xenografts. BEZ235 caused a decrease in phospho-AKT and phospho-mTOR expression in PDAC (AsPC-1), endothelial (HUVECs), and fibroblast (WI-38) cells. BEZ235 inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on proliferation inhibition were observed in the BEZ235-gemcitabine combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with gemcitabine and EMAP, induced apoptosis in AsPC-1, HUVECs, and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and gemcitabine monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235 + gemcitabine (30 days, P = 0.007), BEZ235 + EMAP (27 days, P = 0.02), gemcitabine + EMAP (31 days, P = 0.001), and BEZ235 + gemcitabine + EMAP (33 days, P = 0.004). BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of gemcitabine and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

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“…36 Fibronectin (FN1) has been shown to be regulated in tumorigenesis and proliferation related to pancreatic cancer. 37,38 α-2-HS-glycoprotein (AHSG), also known as fetuin-A, is a secreted serum protein produced by the liver that is involved in several functions including endocytosis. 39 With regard to pancreatic disease, changes in fetuin-A levels represent a potential marker of acute pancreatitis.…”

Section: Resultsmentioning

confidence: 99%

The Proteome of Postsurgical Pancreatic Juice

Marchegiani

Paulo

Sahora³

et al. 2015

Pancreas

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Objective This study aimed to evaluate the proteome of the pancreatic juice after pancreatectomy. Methods Pancreatic juice samples were obtained during surgery and the postoperative period. Proteins were identified by mass spectrometry–based protein quantification technology and compared with published data of the nonoperated pancreas. Subgroup analyses were done in patients with pancreatic ductal adenocarcinoma (PDAC) receiving neoadjuvant chemotherapy and in smokers. Results Five hundred eighteen proteins were identified in the postoperative pancreatic juice, encompassing all of the main organ functions. Sixty-seven of these were also present in the published data of the nonoperated pancreas and 7 of these had significant variation of concentration after surgery. Growth factors that have been described in postsurgical regeneration of the liver were not found to be overexpressed, whereas clusterin did, confirming the finding of previous experimental studies on pancreatic regeneration. Several proteins involved in immunomodulation and organ functions were differently expressed, depending on PDAC, neoadjuvant therapy, and smoking. Conclusions The proteome of the pancreas after surgical resection contains factors related to all main organ functions, changes over time, and is different in patients with PDAC receiving neoadjuvant therapy and in smokers. The pancreas reacts to the surgical trauma by producing proteins that protect the organ and stimulate the restoration of its function.

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Antitumor effects of EMAP II against pancreatic cancer through inhibition of fibronectin-dependent proliferation

Cited by 35 publications

References 31 publications

Matrix control of pancreatic cancer: New insights into fibronectin signaling

Matrix control of pancreatic cancer: New insights into fibronectin signaling

The efficacy of a novel, dual PI3K/mTOR inhibitor NVP‐BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer

The Proteome of Postsurgical Pancreatic Juice

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