Abstract
Simple SummaryAlternatively spliced tissue factor (asTF) is a naturally occurring isoform of tissue factor (TF) generated via the omission of exon 5 during the processing of TF’s primary transcript. In human and mouse, asTF protein features a unique C-terminus that lacks a transmembrane domain, rendering it soluble. asTF protein is able to associate with a subset on integrins on cell surfaces, which can trigger outside-in signaling programs in a variety of cell types. In this review, we discuss recent findings on asTF’s proto-oncogenic effects, regulatory mechanisms enabling asTF’s biosynthesis, and asTF’s potential as a biomarker and therapeutic target.In human and mouse, alternative splicing of tissue factor’s primary transcript yields two mRNA species: one features all six TF exons and encodes full-length tissue factor (flTF), and the other lacks exon 5 and encodes alternatively spliced tissue factor (asTF). flTF, which is oftentimes referred to as “TF”, is an integral membrane glycoprotein due to the presence of an alpha-helical domain in its C-terminus, while asTF is soluble due to the frameshift resulting from the joining of exon 4 directly to exon 6. In this review, we focus on asTF—the more recently discovered isoform of TF that appears to significantly contribute to the pathobiology of several solid malignancies. There is currently a consensus in the field that asTF, while dispensable to normal hemostasis, can activate a subset of integrins on benign and malignant cells and promote outside-in signaling eliciting angiogenesis; cancer cell proliferation, migration, and invasion; and monocyte recruitment. We provide a general overview of the pioneering, as well as more recent, asTF research; discuss the current concepts of how asTF contributes to cancer progression; and open a conversation about the emerging utility of asTF as a biomarker and a therapeutic target.
Highlights
In human and mouse, alternatively spliced tissue factor (asTF) protein features a unique C-terminus that lacks a transmembrane domain, rendering it soluble. asTF protein is able to associate with a subset on integrins on cell surfaces, which can trigger outside-in signaling programs in a variety of cell types
We showed that human asTF was overexpressed in pancreatic ductal adenocarcinoma (PDAC) lesions, and its protein levels positively correlated with CD68+ cell staining, indicating an increased macrophage infiltration in tumors with high asTF expression [31]
In collaboration with Dr Weber’s laboratory, we found that subjecting asTF-overexpressing Pt45.P1 cells to hypoxia promoted the overexpression of carbonic anhydrase IX, a cell surface receptor that can help promote tumor acidosis by catalyzing the conversion of water and carbon dioxide to bicarbonate and protons [50,51,52]
Summary
After 30+ years following its cloning and initial characterization [1,2], tissue factor (TF) remains an intensely studied molecule, largely because there is still a lot to be learned in the realm of TF’s contribution to the pathobiology of various disease states—most notably, vascular and neoplastic pathologies. Throughout the decades, TF has acquired multiple aliases, e.g., thromboplastin, tissue factor, CD142, and “coagulation factor III”, which was used by Human Genome Organization to set the gene name “F3” (analogously, the name of the murine gene is cf). Throughout the decades, TF has acquired multiple aliases, e.g., thromboplastin, tissue factor, CD142, and “coagulation factor III”, which was used by Human Genome Organization to set the gene name “F3” (analogously, the name of the murine gene is cf3) As recently as this year, vascular TF was reported, for the first time, to contribute to trimethylamine N-oxide (TMAO). We provide an overview of recent data pertaining to asTF’s expression in various nisms ofasTF’s actionmechanisms and the consequences of itsthe biosynthesis by various cell types in by certain tissues; of action and consequences of its biosynthesis various tissue compartments; and asTF’s emerging potential as a circulating biomarker and a ther‐.
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