Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis

Goldin-Lang, Petra; Tran, Quoc-Viet; Fichtner, Iduna; Eisenreich, Andreas; Antoniak, Silvio; Schulze, Karsten; Coupland, Sarah E.; Poller, Wolfgang; Schultheiss, Heinz‐Peter; Rauch, Ursula

doi:10.3892/or.20.1.123

Cited by 61 publications

(84 citation statements)

References 27 publications

(38 reference statements)

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“…Interestingly, in a panel of 10 cervical tumors, we found that nine out of 10 tumors contained asTF at levels in the range within which asTF is pro-angiogenic, rendering asTF a potential key player in tumor angiogenesis. In agreement, asTF is expressed in pancreatic cell lines (18), squamous cell carcinoma of the lung (27), and advanced stages of non-small cell lung cancer (19); asTF appears to drive tumor growth in xenograft models (20). It remains controversial whether asTF always displays coagulant activity and can be effectively secreted (16).…”

Section: Discussionmentioning

confidence: 82%

“…asTF incorporates in thrombi and asTF secreted by endothelium exhibits pro-coagulant activity (16). While some groups failed to detect pro-coagulant activity of asTF in transfected cells (15)(16)(17), native asTF can be pro-coagulant (16) and is expressed in malignancies such as pancreatic and lung cancer (18,19). Hobbs et al demonstrated that pancreatic cancer cells transfected to express asTF produce more blood vessels (20), but it remained mechanistically unclear if and how angiogenesis is regulated by asTF.…”

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confidence: 99%

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Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Berg¹,

Hengel²,

Myers³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

176

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The initiator of coagulation, full-length tissue factor (flTF), in complex with factor VIIa, influences angiogenesis through PAR-2. Recently, an alternatively spliced variant of TF (asTF) was discovered, in which part of the TF extracellular domain, the transmembrane, and cytoplasmic domains are replaced by a unique C terminus. Subcutaneous tumors produced by asTF-secreting cells revealed increased angiogenesis, but it remained unclear if and how angiogenesis is regulated by asTF. Here, we show that asTF enhances angiogenesis in matrigel plugs in mice, whereas a soluble form of flTF only modestly enhances angiogenesis. asTF dose-dependently upregulates angiogenesis ex vivo independent of either PAR-2 or VIIa. Rather, asTF was found to ligate integrins, resulting in downstream signaling. asTF-␣V␤3 integrin interaction induces endothelial cell migration, whereas asTFdependent formation of capillaries in vitro is dependent on ␣6␤1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to ␤1 and ␤3 integrin blockade and a TF-antibody that disrupts asTFintegrin interaction. We conclude that asTF, unlike flTF, does not affect angiogenesis via PAR-dependent pathways but relies on integrin ligation. These findings indicate that asTF may serve as a target to prevent pathological angiogenesis.cancer ͉ coagulation ͉ endothelial cells ͉ integrins

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Berg¹,

Hengel²,

Myers³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

176

View full text Add to dashboard Cite

show abstract

“…The expression of TF and its isoforms is induced and highly regulated in several types of cancer, i.e., in lung and breast cancer (3,4,16 ). Several factors are involved in enhanced TF expression in tumor tissues, such as hypoxia or genetic modifications of oncogenes and tumor suppressor genes, e.g.…”

Section: Tf Isoform Expression In Cancermentioning

confidence: 99%

“…Thrombotic events play a clinically significant role in the pathophysiology of cancer (3,8 ). The procoagulant activity of asTF is controversial (7,8,25 ).…”

Section: The Role Of Tf Isoforms In Cancer-related Thrombosismentioning

confidence: 99%

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

2016

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BACKGROUND:Tissue factor (TF) is an evolutionary conserved glycoprotein that plays an important role in the pathogenesis of cancer. TF is expressed in 2 naturally occurring protein isoforms, membrane-bound full-length (fl)TF and soluble alternatively spliced (as)TF. Both isoforms have been shown to affect a variety of pathophysiologically relevant functions, such as tumor-associated angiogenesis, thrombogenicity, tumor growth, and metastasis. Therefore, targeting TF either by direct inhibition or indirectly, i.e., on a posttranscriptional level, offers a novel therapeutic option for cancer treatment.CONTENT: In this review we summarize the latest findings regarding the role of TF and its isoforms in cancer biology. Moreover, we briefly depict and discuss the therapeutic potential of direct and/or indirect inhibition of TF activity and expression for the treatment of cancer.

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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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Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis

Cited by 61 publications

References 27 publications

Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

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

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