Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma

Abstract

Background: Experiments with tumor necrosis factor ␣ (TNF) in rodents have shown that a high dose can lead to hemorrhagic necrosis in tumors. Endothelial monocyte-activating polypeptide II (EMAP-II) is a novel tumor-derived cytokine, and its expression increases the TNF-1 receptor on tumor endothelium, enhances the induction of tissue factor on tumor endothelial cells, and has an antiangiogenic effect. It has recently been shown that in vivo sensitivity of tumor vasculature to TNF is determined by tumor production of EMAP-II. Methods:We measured the level of EMAP-II in a TNF-resistant soft tissue sarcoma. We subsequently stabile-transfected this cell line with a retroviral construct containing the EMAP gene.In an extremity perfusion model in tumor-bearing rats, we measured response rates to TNF therapy.Results: Functional EMAP-II production was increased after this transfection. Immunostaining of paraffin-embedded tumor tissue sections in rats showed an overexpression of human EMAP-II. Results of the TNF perfusions in rats suggest that this tumor is more sensitive to TNF therapy.Conclusions: EMAP-II is produced in various levels. One can increase the sensitivity of tumor for TNF therapy in vivo by upregulating the EMAP-II production. This result leaves an opportunity for enhanced TNF response of tumors in future settings.

Tumoricidal activity of high‐dose tumor necrosis factor‐α is mediated by macrophage‐derived nitric oxide burst and permanent blood flow shutdown

“…Its expression appears to increase the TNF receptor on tumor endothelium, and enhance the induction of tissue factor on endothelial cells, resulting in an antiangiogenic effect. It has been shown that in vivo sensitivity of the tumor vasculature to TNF is determined by the tumor production of EMAP‐II 48–50. This work also showed that EMAP‐II is produced in various levels and that one can increase the sensitivity of tumor to TNF therapy in vivo by upregulating EMAP‐II production.…”

Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis

“…EMAP-II is a 22 kDa proteolytically-cleaved fragment of AIMP1, first purified from conditioned medium of methycholoanthrene A-induced murine fibrosarcoma cells, and exhibiting endothelial cell (EC)-activating and monocyte pro-migratory properties [ 101 , 102 ]. EMAP-II overexpression renders TNF (tumor necrosis factor)-α-resistant soft tissue sarcoma sensitive to TNF-α therapy, and is dependent on TNF-receptor-1 relocalization from Golgi storage pools to the cell plasma membrane [103] , [104] , [105] . In prostate adenocarcinoma cells, chemotherapeutic agents induce EMAP II expression, thereby potentiating localized activation of host cell effector mechanisms, as well as anti-angiogenic and pro-apoptotic activities in melanoma lines [ 106 , 107 ].…”

Рівень Ендотеліального Моноцитактивуючого Пептиду-Іі У Сироватці Крові Хворих На Цукровий Діабет Типу 1, Що Виник В Дитинстві, Та В Осіб Молодого Віку З Ожирінням

“…Вплив на моноцити та ендотеліальні клітини проаналізовано більш детально для виявлення всіх молекулярних чинників цього процесу [6]. В ендотеліальних клітинах ЕМАР-ІІ викликає експресію Е-та Р-селектину, виділення фактора Віллебранда і продукування туморнекротичного фактора-альфа моноцитами [9].…”