Tumor necrosis factor-α-induced accentuation in cryoinjury

Mechanisms in vitro and in vivo

Jing Jiang, Raghav Goel, M. Arif Iftekhar, Rachana Visaria, John D Belcher, Gregory M Vercellotti, John C Bischof

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-α (TNF-α) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5°C) over the current clinical recommendation of reaching temperatures lower than -40°C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-α-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-α. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-α doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-κB-mediated inflammatory or caspase-mediated apoptosis pathways. The amount of cryo-injury increased in a dose-dependent manner with TNF-α both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-α. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-α doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-κB-mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelial-mediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-α to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball.

Original languageEnglish (US)
Pages (from-to)2547-2555
Number of pages9
JournalMolecular Cancer Therapeutics
Volume7
Issue number8
DOIs
StatePublished - Oct 13 2008

Fingerprint

Tumor Necrosis Factor-alpha
Neoplasms
Caspases
Cell Death
Apoptosis
In Vitro Techniques
Wounds and Injuries
Microvessels
Nude Mice
Blood Vessels
Prostatic Neoplasms
Cytokines
Inflammation
Skin
Temperature

Cite this

Tumor necrosis factor-α-induced accentuation in cryoinjury : Mechanisms in vitro and in vivo. / Jiang, Jing; Goel, Raghav; Iftekhar, M. Arif; Visaria, Rachana; Belcher, John D; Vercellotti, Gregory M; Bischof, John C.

In: Molecular Cancer Therapeutics, Vol. 7, No. 8, 13.10.2008, p. 2547-2555.

Research output: Contribution to journalArticle

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