Spontaneous Fusion with Transformed Mesenchymal Stromal Cells Results in Complete Heterogeneity in Prostate Cancer Cells

Simple Summary We have previously demonstrated that the interaction between cancer cells and bystander cells in the tumor microenvironment can promote the development of tumor cell heterogeneity. This heterogeneity is the basis for cancer progression, therapeutic resistance, and distant metastasis. In this study, we co-cultured prostate cancer cells with stromal cells to study the process of cancer-bystander cell interaction. Compared to primary stromal cells, spontaneously transformed stromal cells had significantly enhanced activity in inducing heterogeneity in cancer cells. By tracking the individual cancer-stromal interactions, we found that the transformed stromal sublines had a high tendency to fuse with cancer cells, forming cancer-stromal fusion hybrids that had the ability to proliferate. Hybridization between individual cancer cells and stromal cells resulted in genotypic and phenotypic diversification. This study indicates that the pathophysiologic status of the bystander cell compartment is crucial to the progression of tumor cell heterogeneity.Abstract Tumor cells gain advantages in growth and survival by acquiring genotypic and phenotypic heterogeneity. Interactions with bystander cells in the tumor microenvironment contribute to the progression of heterogeneity. We have shown that fusion between tumor and bystander cells is one form of interaction, and that tumor-bystander cell fusion has contrasting effects. By trapping fusion hybrids in the heterokaryon or synkaryon state, tumor-bystander cell fusion prevents the progression of heterogeneity. However, if trapping fails, fusion hybrids will resume replication to form derivative clones with diverse genomic makeups and behavioral phenotypes. To determine the characteristics of bystander cells that influence the fate of fusion hybrids, we co-cultured prostate mesenchymal stromal cell lines and their spontaneously transformed sublines with LNCaP as well as HPE-15 prostate cancer cells. Subclones derived from cancer-stromal fusion hybrids were examined for genotypic and phenotypic diversifications. Both stromal cell lines were capable of fusing with cancer cells, but only fusion hybrids with the transformed stromal subline generated large numbers of derivative subclones. Each subclone had distinct cell morphologies and growth behaviors and was detected with complete genomic hybridization. The health conditions of the bystander cell compartment play a crucial role in the progression of tumor cell heterogeneity.