Abstract
Neural progenitors cross the blood–brain barrier and infiltrate prostate tumors to drive neurogenesis.
Major finding: Neural progenitors cross the blood–brain barrier and infiltrate prostate tumors to drive neurogenesis.
Concept: Differentiation of DCX+ cells into adrenergic neurons enhances tumor development and metastasis.
Impact: These data define cross-talk between the CNS and tumor cells and suggest potential therapeutic targets.
Innervation of the tumor microenvironment is critical for tumor development and metastasis in many solid cancers. However, whether this process involves outgrowth of already-established nerves or requires de novo neurogenesis remains unclear. Mauffrey and colleagues show that, in prostate cancer, neural progenitors from the central nervous system (CNS) cross the blood–brain barrier and seed areas of local and metastasized tumors to initiate neurogenesis. The stroma of human prostate tumors contained cells expressing doublecortin (DCX), a marker of neural progenitors, and the density of DCX+ cells was associated with tumor aggressiveness and recurrence. In a murine model of prostate cancer, DCX+ cells were indeed found in neurogenic areas of the CNS, including the subventricular zone (SVZ), and also in the tumor stroma, but not in the prostates of healthy mice. These cells expressed additional markers of neural progenitors as well as genes associated with neuron differentiation and projection. Moreover, lineage tracing of these progenitor cells revealed that adrenergic neo-neurons can develop in situ within the prostate tumor microenvironment. During tumor development, DCX+ neural progenitors exited the SVZ and crossed the breached blood–brain barrier, migrated through the blood, and infiltrated prostate tumors, where they could differentiate into neurons. Selective depletion of DCX+ cells, either from the entire mouse or specifically from the SVZ, reduced the number of neoplastic lesions and impaired orthotopic engraftment of tumor cells. Conversely, transplantation of DCX+ neural progenitors purified from prostate tumors or the SVZ into established tumor xenografts enhanced tumor growth and metastasis. Taken together, these data demonstrate the role of neural progenitors in prostate tumor development and highlight DCX+ cells as potential targets to suppress primary tumors and metastases.
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