Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

Abstract

Poorly understood interactions with nonmalignant cells within the tumor microenvironment play an important role in cancer progression. Here, we explored interactions between prostate cancer and muscle cells that surround the prostate. We found that coculturing of prostate cancer cells with skeletal or smooth muscle cells expands the subpopulations of cancer cells with features characteristic of cancer stem-like cells, including anchorage-independent growth, elevated CD133 expression, and drug resistance. These changes in the properties of cancer cells depend on: (i) the muscle cell-induced increases in the concentrations of interleukins 4 and 13; (ii) the cytokine-induced upregula-tion of the expression of syncytin 1 and annexin A5; and (iii) cancer cell fusion. In human prostate cancer tissues, expression of syncytin 1 and annexin A5, proteins that we found to be required for the cell fusion, positively correlated with the cancer development suggesting that these proteins can be used as biomarkers to evaluate cancer progression and potential therapeutic targets. Implications:The discovered effects of muscle cells on prostate cancer cells reveal a novel and specific pathway by which muscle cells in the microenvironment of prostate cancer cells promote cell fusion and cancer progression.

How cells fuse

“…Since then, many studies have substantiated the hypothesis that fusion among cancer cells and between cancer cells and nonmalignant cells can contribute to initiation and progression of cancer and, specifically, aneuploidy, drug resistance, and metastatic potential characteristic of malignant cells. Indeed, cancer cells do fuse with each other (Noubissi and Ogle, 2016; Uygur et al, 2019). Different cancer cells also spontaneously fuse with nonmalignant cells.…”

“…Fusion between cancer cells was found to expand the subpopulations of the cells with cancer stem cell features, suggesting that this fusion reaction promotes cancer progression. This novel system obtains a relatively high efficiency of cancer cell fusion with 10–20% of cell nuclei located in fusion-generated multinucleated cells, facilitating the analysis of the underlying mechanisms (Uygur et al, 2019). Cancer cell fusion in prostate cancer/muscle cell cocultures involves a placental fusogen Syn1 (implicated in cancer cell fusion [Noubissi and Ogle, 2016]) and AnxA5 (Uygur et al, 2019).…”

“…This novel system obtains a relatively high efficiency of cancer cell fusion with 10–20% of cell nuclei located in fusion-generated multinucleated cells, facilitating the analysis of the underlying mechanisms (Uygur et al, 2019). Cancer cell fusion in prostate cancer/muscle cell cocultures involves a placental fusogen Syn1 (implicated in cancer cell fusion [Noubissi and Ogle, 2016]) and AnxA5 (Uygur et al, 2019). Fusion is associated with up-regulation of these proteins and is inhibited by blocking their expression.…”

“…Human prostate cancer cells have higher levels of Syn1 and AnxA5 expression than nonmalignant tissues. The case for the direct involvement in cancer cell fusion is especially strong for Syn1 as blocking fusogenic refolding of Syn1 with a peptide inhibitor abolishes fusion (Uygur et al, 2019). Interestingly, ASCT2, a Syn1 receptor, also has a role in cancer cell fusion, as evidenced by the finding that knocking down ASCT2 or Syn1 inhibits fusion between breast cancer cells and endothelial cells (Bjerregaard et al, 2006).…”

Syncytin 1 dependent horizontal transfer of marker genes from retrovirally transduced cells

“…During our research related to prostate cancer cell fusion 9 , 48 hours after co-plating PC3 human prostate cancer cells transduced using lentiviral vector to express RFP (RFP-lenti) with PC3 cells transduced using pMIGR1-GFP retroviral construct to express GFP (GFP-retro) almost 60% of RFP expressing cells also expressed GFP (Fig. 1A).…”