Abstract
Advanced and therapy-resistant prostate tumors often display neural or neuroendocrine behavior. We assessed the consequences of prostate cancer cell interaction with neural cells, which are rich in the human prostate and resident of the prostate tumor. In 3-dimensional co-culture with neurospheres, red fluorescent human LNCaP cells formed agglomerates on the neurosphere surface. Upon induced neural differentiation, some red fluorescent cells showed morphology of fully differentiated neural cells, indicating fusion between the cancer and neural stem cells. These fusion hybrids survived for extended times in a quiescent state. A few eventually restarted cell division and propagated to form derivative hybrid progenies. Clones of the hybrid progenies were highly heterogeneous; most had lost prostatic and epithelial markers while some had acquired neural marker expression. These results indicate that cancer cells can fuse with bystander neural cells in the tumor microenvironment; and cancer cell fusion is a direct route to tumor cell heterogeneity.
Highlights
Advanced and therapy-resistant prostate tumors often display neural or neuroendocrine behavior
The peripheral nervous system may serve as a route for cancer infiltration, since Prostate cancer (PCa) cells have high affinity to neural cells[9] and perineuronal spaces are a thoroughfare for spreading tumor cells[10]
We have demonstrated that PCa progression and metastasis is driven by cancer cell interaction with bystander resident cells in the tumor microenvironment[21,22,23]
Summary
Advanced and therapy-resistant prostate tumors often display neural or neuroendocrine behavior. Clones of the hybrid progenies were highly heterogeneous; most had lost prostatic and epithelial markers while some had acquired neural marker expression These results indicate that cancer cells can fuse with bystander neural cells in the tumor microenvironment; and cancer cell fusion is a direct route to tumor cell heterogeneity. We hypothesized that, like the fusion with bystander stromal cells of the tumor microenvironment, PCa cells may fuse with neural cells upon direct contact. We assessed the consequences of interaction between PCa and neural cells, by placing LNCaP cells in direct contact with rat neural stem cells (NSCs) under 3-D spheroid co-culture conditions[15,27]. Results revealed that PCa cells could fuse with NSCs. Upon neural differentiation, most cancer-neural hybrids perished but some survived to display phenotypic heterogeneity, some even acquiring neural cell marker expression. This study revealed a previously unrecognized aspect of cancer-neural cell interaction
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