Metastases Development Following Local Tumour Treatment ( metastases / experimental tumour / tumour irradiation / tumour surgery / mice )

Transplantable mouse methylcholanthrene-induced fibrosarcoma (CMC4 tumour growing in CBA/HZgr mice), characterized by lung metastases developing shortly after local tumour cell transplantation, was used as an experimental model to investigate the problem of tumour metastases after local tumour treatment. Surgery and/or irradiation were performed on locally growing tumour of particular size. Further, heavily irradiated, viable but not dividing tumour cells, imitating the situation in treated tumour-bearing organism, were injected intraperitoneally in a parallel group of treated tumour-bearing mice. The animals were killed 35 days after tumour transplantation and the number and volume of lung metastases were determined. Depending on the treatment performed, when the tumour mass was reduced or even eliminated, the number of lung metastases and their volume were significantly lower than in control mice, but the addition of tumour mass (injection of heavily irradiated tumour cells) resulted in a significant increase in lung metastases parameters, pointing to a possible role of the host’s immune reaction against the tumour. Further, the release of a simple molecule, such as nitric oxide, from tumour mass seems to be detrimental for the survival of tumour cells and subsequently their metastases through the induction of angiogenesis and possible suppression of immune reaction. Thus, complex mechanisms could be involved when a locally growing tumour is exposed to a particular therapeutic approach. Introduction Numerous approaches have been attempted in controlling tumour growth. Some of them, such as surgery, irradiation, or chemotherapy are still main clinical approaches either alone or in particular combinations. However, the fate of distant metastases after the treatment of locally growing tumour, particularly by using surgical treatment and/or tumour irradiation, is still an open question (Baum and Badwe,1994; Demicheli, 2001; Demicheli et al., 2001; Fidler, 2002; Baum et al., 2005; Khokha and Voura, 2005). Actually, numerous clinical reports point to the problem that metastasis growth could be accelerated following local tumor treatment (Demicheli et al., 2001; Benouchan and Colombo, 2005; Khokha and Voura, 2005; Mocellin et al., 2006). It should be mentioned that the immune reactivity of a tumour-bearing organism is detrimental either for tumour growth or for host survival (Heppner and Miller, 1998; Bubenik and Šimova, 2005; Indrova et al., 2008). This reactivity depends upon tumour mass and therapeutic approaches affecting local and/or disseminated tumour growth (Jurin and Suit, 1974; Heppner and Miller, 1998; Bubenik and Šimova, 2005; De Visser et al., 2006; Indrova et al., 2008). Further, it has been well documented that removal of the primary tumour reduces angiogenesis inhibitors, and a sharp spike in angiogenesis stimulators and growth factors is known to be involved in wound healing (Baum and Badwe, 1994; Baum et al., 2005). Thus, it is not surprising that tumour angiogenesis and its proliferation occur after (surgical) removal of locally growing tumour, and this act could be a trigger for “kick-starting” the growth of earlier established micro-metastases. Thus, the complex situation in a tumour-bearing organism could be further aggravated by anti-tumour therapy. In this study, transplantable, methylcholanthrene-induced fibrosarcoma in mice, characterized by lung metastases developing shortly after local tumour cell transplantation, was investigated. The surgical approach and/or irradiation were performed on a locally growing tumour of a particular size. To increase tumour mass (viable, but not growing tumour), heavily irradiated tumour cells were injected intraperitoneally (ip) in a parallel Received: March 12, 2009. Accepted: April 20, 2009. This research work was supported by the Ministry of Science of Republic Croatia (project 1-08-198). Corresponding author: Mislav Jurin, Department of Molecular Medicine, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia. Phone: (+385) 1 4680091; Fax. (+385) 1 4561010; e-mail: jurin@irb.hr Abbreviation: ip – intraperitoneally. Folia Biologica (Praha) 55, 177-182 (2009)