In previous studies we found that uveal melanoma cells grown in extracellular matrix (ECM)-containing three-dimensional (3D) cultures have increased resistance against herpes simplex virus type 1 (HSV-1)-mediated destruction relative to cells cultured without ECM. Using additional tumor cell types including MB-231 human breast cancer cells, PC-3 human prostate cancer cells, and P19 mouse embryonal carcinoma cells, we show here that tumor cell lines other than melanoma are also more resistant to HSV-1-mediated destruction in 3D cultures than cells grown in 2D. We also demonstrate here that one mechanism responsible for the increased resistance of tumor cells to HSV-1 infection in 3D cultures is an ECM-mediated inhibition of virus replication following virus entry into cells. These findings confirm and extend previous observations related to the role of the ECM in tumor resistance against HSV-1 and may lead to improved strategies of oncolytic virotherapy. 1. Introduction The oncolytic potential of herpes simplex virus type 1 (HSV-1) has been widely studied both in vitro and in vivo and genetically engineered HSV-1 strains for tumor therapy are under clinical trials [1–8]. Interestingly, while tumor cells grown in conventional two-dimensional (2D) monolayer cultures are typically quickly killed by HSV-1, virus infection-mediated destruction of tumors in vivo is often incomplete [5, 9]. The reasons of increased resistance of tumors against HSV-1 in vivo are not well understood but possible mechanisms involved include (i) an impairment of intratumoral virus spread by the extracellular matrix (ECM), (ii) a decreased expression of viral entry receptors, (iii) activation of intracellular tumor defences to viral infection, and (iv) virus clearance by the host immune system [9–18]. It is clear that several of these potential tumor resistance mechanisms are difficult to impossible to study in traditional monolayer tumor cultures. It is well known that the behaviour of cells is influenced by the ECM and that cancer cells grown in 3D cultures in a polymeric ECM closely mimic many aspects of in vivo tumor behavior [19–22]. Numerous data indicate that 3D cultures are more suitable to study key cellular processes, for example, differentiation, proliferation, invasion, and apoptosis, than conventionally used 2D cultures [22–28]. There is evidence that cancer cells grown in 3D culture are more resistant to chemotherapeutic agents and radiation than cells cultured under 2D conditions [27–29]. It is also known that multiple cell types within individual tumors have
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