Abstract
Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to β1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression. We here report that a novel inhibitory anti-asTF monoclonal antibody curtails experimental PDAC progression. Moreover, we show that tumor-derived asTF is able to promote PDAC primary growth and spread during early as well as later stages of the disease. This raises the likelihood that asTF may comprise a viable target in early- and late-stage PDAC. In addition, we show that TF expressed by host cells plays a significant role in PDAC spread. Together, our data demonstrate that targeting asTF in PDAC is a novel strategy to stem PDAC progression and spread.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) survival rate remains dismal, with 5-year survival < 5%, and by 2030 is predicted to be the third leading cause of cancer-related death [1]
Because alternatively spliced Tissue Factor (TF) (asTF)- α6/β1 integrin interactions promote breast cancer cell proliferation [8], we sought to determine whether this enhanced scratch closure was mainly due to enhancement of PDAC cell migration rather than cell proliferation; we performed a 5-hour cell migration assay under a serum chemo-gradient using laminin-coated transmembrane inserts and Pt45.P1/asTFi cells
When untreated Pt45.P1/asTFi cells were pre-incubated with the inhibitory anti-asTF antibody RabMab1, their basal migration rate was significantly reduced (Figure 1D), indicating that even the relatively low basal levels of asTF constitutively expressed in Pt45.P1/asTFi cells significantly contribute to their migratory potential
Summary
Pancreatic ductal adenocarcinoma (PDAC) survival rate remains dismal, with 5-year survival < 5%, and by 2030 is predicted to be the third leading cause of cancer-related death [1]. Pancreatic cancer is commonly associated with thrombotic events, which contribute to its morbidity and mortality [2, 3]. Multiple oncogenic events that are characteristic of PDAC, e.g. activation of the proto-oncogene K-RAS and inactivation/loss of p53 and PTEN, promote TF expression [6]. We reported that the secreted isoform of TF, termed alternatively spliced TF (asTF), is expressed in early-stage PDAC lesions (pancreatic intraepithelial neoplasia, PanIN) and abundant in advanced PDAC, in contrast to normal pancreas [7]. Our groups recently demonstrated that asTF acts on cancer cells in an auto/ paracrine manner via β1 integrins, promoting disease progression by fueling cancer cell proliferation, survival, metastatic spread, neovascularization, and monocyte accumulation in the tumor stroma [7, 8]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have