Abstract
Several markers identify cancer stem cell-like populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. Here, we show that the endothelial protein C receptor (EPCR), a stem cell marker in hematopoietic, neuronal and epithelial cells, is crucial for breast cancer growth in the orthotopic microenvironment of the mammary gland. Mice with a hypomorphic allele of EPCR show reduced tumor growth in the PyMT-model of spontaneous breast cancer development and deletion of EPCR in established PyMT tumor cells significantly attenuates transplanted tumor take and growth. We find expansion of EPCR+ cancer stem cell-like populations in aggressive, mammary fat pad-enhanced human triple negative breast cancer cells. In this model, EPCR-expressing cells have markedly increased mammosphere- and tumor-cell initiating activity compared to another stable progenitor-like subpopulation present at comparable frequency. We show that receptor blocking antibodies to EPCR specifically attenuate in vivo tumor growth initiated by either EPCR+ cells or the heterogenous mixture of EPCR+ and EPCR- cells. Furthermore, we have identified tumor associated macrophages as a major source for recognized ligands of EPCR, suggesting a novel mechanism by which cancer stem cell-like populations are regulated by innate immune cells in the tumor microenvironment.
Highlights
The coagulation cascade is an evolutionary conserved pathway in vertebrates that maintains vascular integrity, protects from infection, and supports regenerative processes after injury
Our more recent data showed that the stem cell receptor endothelial protein C receptor (EPCR) is required for signaling of another tissue factor (TF) protease complex, i.e. TF-FVIIa-FXa in which FXa cleaves PAR2 or PAR1 [21,41]
In order to begin to evaluate potential contributions of EPCR to TF signaling in cancer progression, we determined the co-expression of TF and EPCR by FACS
Summary
The coagulation cascade is an evolutionary conserved pathway in vertebrates that maintains vascular integrity, protects from infection, and supports regenerative processes after injury. Oncogenic transformations induce TF expression by a variety of cancer types and TF promotes the prothrombotic state of cancer patients and thrombin-dependent activation of the host hemostatic system in metastasis [5]. TF-FVIIa regulates cancer cell migration and initiates proangiogenic cell signaling by proteolytic cleavage and activation of the G protein-coupled protease activated receptor (PAR) 2, supporting tumor development and growth in orthotopic tumor microenvironments [7,8,9,10,11]. I.e. thrombin and FXa, as well as matrix metalloproteases have pleiotropic pro-invasive and growth promoting effects on tumor cells and these effects are frequently dependent on activation of the thrombin receptor PAR1 [12,13]
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