Increased Resistance of Breast, Prostate, and Embryonic Carcinoma Cells against Herpes Simplex Virus in Three-Dimensional Cultures

Abstract

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.

Herpes Simplex Virus 1 Infection Promotes the Growth of a Subpopulation of Tumor Cells in Three-Dimensional Uveal Melanoma Cultures

“…Compared to traditional two-dimensional monolayer culture studies, 3D cultures have been shown to better simulate in vivo cellular behaviors such as growth, differentiation, invasion, and apoptosis ( 14 – 20 ). 3D cell cultures have also proven to be an effective design to study the interaction of HSV with tumor cells ( 12 , 13 , 23 , 24 ). Melanoma cells grown in 3D are more resistant to HSV-1 infection than cells grown in 2D, and HSV-1 may establish a quiescent infection in some melanoma cells in 3D cultures ( 12 , 13 ).…”

Three-dimensional tumor cell cultures employed in virotherapy research

“… 50 Later, the same group extended the experiments with breast, prostate, and embryonic cancer cells. 51 In this work, they found differences in growth patterns among the varying cells in three-dimensional cell cultures and obvious differences in common two-dimensional cell cultures. With herpes simplex virus 1 (HSV1), their results indicated massive inhibition of viral penetration through Matri-gel.…”

“…In summary, at least two mechanisms of resistance in Matrigel cell cultures were found: on one hand, the physical Matrigel barrier working quite efficiently against viral distribution and spread, and on the other, the ECM-mediated suppression of viral replication ( Table 3 ). 50 , 51 …”

Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

“…The extracellular matrix and areas of tissue necrosis, which can be seen in high-grade tumors, may impair the spread of oHSV. 79 , 80 Of note, many pediatric high-grade tumors, such as Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, and medulloblastoma to name a few, are classified as small round blue cell tumors. Histologically these tumors are highly cellular and composed of tight sheets of small, round cells with scant cytoplasm.…”