Induction of cell fusion/apoptosis in anaplastic thyroid carcinoma in orthotopic mouse model by urokinase‐specific oncolytic Sendai virus

Abstract

Background This study was designed to assess the therapeutic effect of urokinase‐targeted recombinant oncolytic Sendai virus, termed “BioKnife,” on anaplastic thyroid carcinoma (ATC). Methods Urokinase activity was investigated in human ATC cell lines, and BioKnife cytotoxicity against the cell lines was evaluated in vitro. Orthotopic mouse models of ATC were treated with three intratumoral injections of BioKnife, control virus, or phosphate‐buffered saline (PBS) and were observed daily until >20% weight loss occurred. Results All three ATC cell lines showed a high level of urokinase activity. BioKnife induced urokinase‐dependent cell fusion and cytotoxicity in all cell lines. Orthotopic models treated with BioKnife showed significantly prolonged survival compared with models treated with control virus or PBS (BioKnife 41.6 ± 15.0, control virus 17.0 ± 2.9, PBS 17.7 ± 6.3 days). Conclusions BioKnife exerted therapeutic effects in orthotopic ATC mouse models. Thus, BioKnife represents a possible treatment option for ATC.

In Vitro and In Vivo Effects of the Urokinase Plasminogen Activator Inhibitor WX-340 on Anaplastic Thyroid Cancer Cell Lines

“…As a consequence of the impaired uPA activity, ATC cells showed reduced invasive capacity in vitro, and a slight but significant delay in the formation of new cell adhesions. Contrarily from what was reported by Miyagawa and colleagues [ 33 ], we did not notice induction of cell death nor fusion in treated cultures. Although these authors used different ATC cell lines, this discrepancy is presumably due to the different mode of uPA blockade, i.e., viral infection of cells and subsequent protein cleavage rather than competitive inhibition by a small molecule.…”

“…Secondly, it is noteworthy that while some uPA or uPAR inhibitors have been found capable of producing cytotoxic damage and decreased proliferation in some tumor cell types, induction of cell fusion was achieved only with this virotherapy approach, and it is most likely caused by the viral infection itself regardless of the uPA cleavage. This effect, combined with the intrinsic cytotoxicity recognized for the control viral vector, is supposed to contribute considerably to the observed antitumor effect [ 33 ].…”

“…Anticancer effects on ATC cells were observed both in vivo and in vitro by inhibiting transcription factors that promote uPA expression, i.e., NF-κB and FOXM1, but multiple genes are regulated by these factors and thus the final result could be due to the simultaneous dampening of several pathways [ 31 , 32 ]. More direct evidence emerged from a recent study showing that infection of ATC cells with a urokinase-targeted recombinant oncolytic Sendai virus induced uPA-dependent cell fusion and cytotoxicity, and had remarkable therapeutic efficacy in orthotopic ATC mouse models [ 33 ].…”

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

“…Sendai virus is a natural OV lacking pathogenic effects in humans, but causing respiratory disease in mice. The administration of BioKnife prolonged survival in an orthotopic mouse model (BALB/c nu/nu mice) of ATC following intra-tumor injections [119], this finding also confirms the feasibility of the local treatments.…”

Delivery routes matter: Safety and efficacy of intratumoral immunotherapy

“…This is as a result of spreading via cell-to-cell fusion between urokinase-type plasminogen activator (uPA)-positive tumor cells and avoiding formation of new viral particles rather than selfreplicating in infected tumor cells and forming secondary viral particles. Sendai virus-induced cytotoxicity in tumors that express uPA was seen for the first time in orthotopic mouse models with anaplastic thyroid carcinoma, making it an appropriate candidate for clinical translation against this kind of carcinoma [35].…”