Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer

Khorana, Alok A.; Ahrendt, Steven A.; Ryan, Charlotte; Francis, Charles W.; Hruban, Ralph H.; Ying, Haoqiang; Hostetter, Galen; Harvey, Jack; Taubman, Mark B.

doi:10.1158/1078-0432.ccr-06-2351

Cited by 330 publications

(275 citation statements)

References 36 publications

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“…A more practical dimension of these studies is related to the possibility of monitoring tumour progression and therapeutic responses through levels of TF. For instance, in pancreatic cancer, coagulopathy is relatively common, TF expression is upregulated [34] and the use of KSR1 targeting agents is being explored as a therapeutic strategy [14,35]. Our study suggests that it might be possible to predict the effects of these agents by assessing the levels of TF-positivity in tumour tissue, and that circulating in the blood of cancer patients as TFcontaining microvesicles.…”

Section: Discussionmentioning

confidence: 88%

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Xing

Milsom

et al. 2010

Thrombosis Research

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Introduction: Tissue factor (TF) is the key trigger of the coagulation cascade and the membrane signalling receptor for coagulation protease, factor VIIa. In cancer, TF has been implicated in cancer cell survival, growth, and angiogenesis, and is upregulated as a result of oncogenic transformation. Materials and Methods:We assayed TF expression and tumourigenicity in mice of human cancer cell lines expressing oncogenic receptor tyrosine kinases. These cells were subjected to modulation of the kinase suppressor of ras 1 (KSR1) levels and treated with oncoprotein inhibitors in vitro and in vivo.Results: Here we show that herceptin, AG1478 and CI-1033 inhibitors of two different members of the ErbB family of oncogenes (HER-2 and EGFR) reduce TF levels in epithelial cancer cells. In EGFR-driven A431 cells, TF upregulation is diminished upon genetic targeting of KSR1, the scaffolding protein involved in EGFR signalling. Conversely, upregulation of KSR1 in A431 cells increases their TF expression and tumourigenicity in mice. The latter property remains dependent on EGFR, as pan-Erb (EGFR) inhibitor, CI-1033 blocks TF promoter activity and tumour formation by parental and KSR1 overexpressing A431 cells.

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Section: Discussionmentioning

confidence: 88%

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Xing

Milsom

et al. 2010

Thrombosis Research

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“…TF, also called thromboplastin, factor III, or CD142, is aberrantly expressed in many types of cancers, including non-small cell lung cancer (5), colorectal cancer (6), genito-urethal (7,8), and gynecologic cancers (9)(10)(11), pancreatic cancer (12), head and neck cancer (13), glioma (14), and metastatic breast cancer (15). Under physiologic conditions, TF is expressed by fibroblasts, pericytes, and smooth muscle cells in the subendothelial vessel wall.…”

Section: Introductionmentioning

confidence: 99%

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Goeij

Satijn

Freitag

et al. 2015

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TFspecific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR-and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach.

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“…11 Increased TF expression is correlated with poor prognosis in pancreatic cancer. [12][13][14] Cultured human pancreatic tumor lines express variable levels of both flTF and asTF and release TF-positive MPs containing flTF into the culture medium. [14][15][16][17][18][19] In some patients with pancreatic cancer, high levels of TF-positive MPs are found in the circulation and, in a small pilot study, were predictive of VTE.…”

mentioning

confidence: 99%

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

Wang

Geddings

Aleman

et al. 2012

Blood

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167

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IntroductionThe link between cancer and venous thromboembolism (VTE) is referred to as Trousseau syndrome. Interestingly, different cancer types are associated with different rates of VTE, with pancreatic cancer having one of the highest rates. 1,2 A VTE risk-scoring model has been developed that stratifies ambulatory cancer patients undergoing chemotherapy into 3 VTE risk categories based on 5 parameters: (1) the site of the primary tumor, (2) prechemotherapy leukocyte count, (3) platelet count, (4) hemoglobin level, and (5) body mass index. 3 Recently, this model was expanded to include the biomarkers D-dimer and soluble P-selectin. 4 Another potential circulating biomarker of VTE risk in pancreatic cancer patients is microparticle (MP) tissue factor (TF). [5][6][7][8][9] Full-length TF (flTF) is a transmembrane protein that activates the coagulation cascade. 10 In addition, an alternatively spliced form of TF (asTF) has been identified that lacks a membrane anchor and therefore can be released as a soluble protein. 11 Increased TF expression is correlated with poor prognosis in pancreatic cancer. [12][13][14] Cultured human pancreatic tumor lines express variable levels of both flTF and asTF and release TF-positive MPs containing flTF into the culture medium. [14][15][16][17][18][19] In some patients with pancreatic cancer, high levels of TF-positive MPs are found in the circulation and, in a small pilot study, were predictive of VTE. [5][6][7]9,20 In a mouse model of human colorectal tumors, human TF protein is released into the circulation. 21 In nude mice bearing orthotopic human pancreatic tumors (L3.6pl) plasma levels of human TF protein were correlated with the levels of thrombin-antithrombin (TAT) complex, a marker of the activation of coagulation. 22 Further, plasma from these tumor-bearing mice was found to enhance thrombin generation in vitro in a human TF-dependent manner. 22 Another study found that human (SOJ-4) and mouse (PANC02) pancreatic cell lines expressed TF, and the investigators observed an accumulation of tumor-derived MPs at the site of thrombosis and increased thrombosis in a microvascular model. 18 The objective of the present study was to determine the role of tumor-derived TF in the activation of coagulation and thrombosis in a xenograft mouse model of human pancreatic tumors. We found that only TF-positive tumors activated coagulation and that this activation was abolished by inhibition of human TF. Two TF-positive pancreatic tumor cell lines activated coagulation, but only one had detectable levels of circulating TF-positive MPs, which suggested that activation of coagulation was due to TF expression by the tumor itself rather than to TF on the MPs. Mice with elevated levels of TF-positive MPs exhibited increased thrombosis in a saphenous vein model, but not in an inferior vena cava (IVC) stenosis model. Methods Cell linesHuman pancreatic (MIAPaCa-2 [CRL-1420] Abs and proteinsPE-labeled mouse IgG control (#555574), mouse anti-human TF (#550312) and FITC-conjugated anti-human MUC...

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Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer

Cited by 330 publications

References 36 publications

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

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