Spontaneous Cancer-Stromal Cell Fusion as a Mechanism of Prostate Cancer Androgen-Independent Progression

Abstract

We have previously shown that human prostate cancer cells are capable of acquiring malignant attributes through interaction with stromal cells in the tumor microenvironment, while the interacting stromal cells can also become affected with both phenotypic and genotypic alterations. This study used a co-culture model to investigate the mechanism underlying the co-evolution of cancer and stromal cells. Red fluorescent androgen-dependent LNCaP prostate cancer cells were cultured with a matched pair of normal and cancer-associated prostate myofibroblast cells to simulate cancer-stromal interaction, and cellular changes in the co-culture were documented by tracking the red fluorescence. We found frequent spontaneous fusions between cancer and stromal cells throughout the co-culture. In colony formation assays assessing the fate of the hybrid cells, most of the cancer-stromal fusion hybrids remained growth-arrested and eventually perished. However, some of the hybrids survived to form colonies from the co-culture with cancer-associated stromal cells. These derivative clones showed genomic alterations together with androgen-independent phenotype. The results from this study reveal that prostate cancer cells are fusogenic, and cancer-stromal interaction can lead to spontaneous fusion between the two cell types. While a cancer-stromal fusion strategy may allow the stromal compartment to annihilate invading cancer cells, certain cancer-stromal hybrids with increased survival capability may escape annihilation to form a derivative cancer cell population with an altered genotype and increased malignancy. Cancer-stromal fusion thus lays a foundation for an incessant co-evolution between cancer and the cancer-associated stromal cells in the tumor microenvironment.

Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery

“…Growing in vitro (Busund et al 2002, 2003; Shabo et al 2015; Wei et al 2014), in vivo (Powell et al 2011; Silk et al 2013), and clinical (LaBerge et al 2017; Lazova et al 2013; Yilmaz et al 2005) data indicate that this process occurs in solid tumors and may play a significant role in clinical tumor progression. Moreover, this process generates malignant cell clones (hybrids) with reduced susceptibility to oncological treatments (Carloni et al 2013; Nagler et al 2011; Wang et al 2012; Yang et al 2010). …”

Acquired Expression of NFATc1 Downregulates E-Cadherin and Promotes Cancer Cell Invasion

“…Fusion of tumor cells with hematopoietic or myeloid cells has been detected both in vitro and in vivo (19,20). More recently, myofibroblasts have emerged as a new fusion partner for osteosarcoma or prostate cancer cells (16,21). In addition, we detected CD68-positive tumor cells in the NFATc1-positive breast tumor specimens ( Fig.…”

“…Some cells might experience growth arrest and cell death (38)(39)(40), whereas others might exhibit increased malignancy (9,16), depending on their parental cell types and the tumor microenvironment. Identification and analysis of bona fide fused cells positive for NFATc1 expression in vivo will be necessary to validate a role for NFATc1 in tumor progression.…”

“…The consequences of this acquisition on tumor cell activities such as invasion and metastasis are unclear. Only recently, however, studies have begun to characterize the properties of tumor cell hybrids (7,9,(15)(16)(17).…”

Dissociated Primary Human Prostate Cancer Cells Coinjected with the Immortalized Hs5 Bone Marrow Stromal Cells Generate Undifferentiated Tumors in NOD/SCID-γ Mice

“…In addition, MSCs were able to home to C4-2B xenograft tumors and enhance Wnt signaling activity [68]. Using a co-culture model, Wang et al found that some of the cancer-stromal hybrids could survive and led to colony formation in the co-culture, and these colonies featured with androgen-independent phenotypes [69]. It has been reported that coinjection of tumorigenic rat prostatic fibroblasts enhanced tumor formation of otherwise non-tumorigenic adjacent prostatic epithelial cells via paracrine signaling, leading to the formation of carcinosarcoma [70].…”