Abstract 1091: Procoagulant receptor tissue factor provokes the escape from brain tumor dormancy.
Authors: Magnus Nathalie , Garnier Delphine , Meehan Brian , Hashemi Maryam , Lee Tae-Hoon , Milsom Chloe , Jabado Nada , Pawlinski Rafal , Mackman Nigel , Rak Janusz 
Published: August 2014

Occult persistence of transformed cells is known to precede the onset of clinically apparent malignancies, accompany disease remission and micrometastasis. While the mechanisms governing this dormant state remain poorly understood, tissue injury and wound healing responses have often been implicated in its cessation, but the surrounding circumstances remain largely obscure. Notably, the activation of hemostasis represents the first response to the exogenous and endogenous tissue injury, and is linked to inflammation, angiogenesis and growth promoting microenvironment. Tissue factor (TF) acts as the main trigger of the coagulation cascade in this setting, and is known to be overexpressed in cancer cells, including in high grade brain tumors such as glioblastoma (GBM). Here we report that in a model of GBM, the TF-mediated activation of the coagulation system may act as the sufficient initial trigger in the cessation of tumor dormancy, and the onset of inflammation and angiogenesis. We also document that while TF may play a role in the subsequent tumor progression, its expression by cancer and host cells may no longer be absolutely required in established tumors.

Thus, we observed that indolent human glioma cells (U373) remain viable, but dormant for over 250 days post subcutaneous and orthotopic inoculation, with no evidence of tumor growth, as detected by bioluminescent monitoring. The enforced expression of TF is sufficient to trigger tumor formation by these cells, albeit after long latency (30-90 days). During this latent phase TF-expressing glioma cells, but not their TF-negative counterparts, are able to recruit rich stroma, containing CD11b+ myeloid cells and CD105+ blood vessels. These cells also evolve to become rapidly tumorigenic and gain a dramatic change to their transcriptome. Similar aggressiveness can also be induced in U373 cells by the expression of the oncogenic epidermal growth factor receptor variant (EGFRvIII), which also provokes upregulation of TF and onset of the procoagulant phenotype (U373vIII cells). Targeting TF in U373vIII tumors, as well as their implantation into TF-hypomorphic recipients (low-TF mice) delays, but does not abrogate experimental GBM progression. We generated spontaneous GBM tumors by intracranial injection of the oncogenic cDNA (SV40, N-ras), which becomes expressed in brain astrocytes under the control of the Sleeping Beauty (SB) transposase. Disruption of the TF gene in the astrocytic lineage of such mice (Cre/nestinTF-/-) resulted in a partial tumor growth inhibition.

We postulate that activation of the coagulation system (via TF) may play a role in disruption of the dormant behavior of brain tumor cells and can serve as targets in prevention of disease onset. However, targeting TF alone is only partially effective as a measure to control the growth of established astrocytic tumors. Acknowledgments: We thank Dr. John Ohlfest for providing us with the SB transposon system.

Citation Format: Nathalie Magnus, Delphine Garnier, Brian Meehan, Maryam Hashemi, Tae-Hoon Lee, Chloe Milsom, Nada Jabado, Rafal Pawlinski, Nigel Mackman, Janusz Rak. Procoagulant receptor tissue factor provokes the escape from brain tumor dormancy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1091. doi:10.1158/1538-7445.AM2013-1091