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Study Highlights the Role of Migratory Neural Progenitor Cells in Prostate Cancer Development

Review of “Progenitors from the central nervous system drive neurogenesis in cancer” from Nature by Stuart P. Atkinson

The increase in the number of tumor-associated neurons during prostate cancer development raises the possibility that neurogenesis supports tumor initiation, maintenance, and progression [1]. The outgrowth of newly formed autonomic nerve fibers into the tumor contributes to the initiation and progression of cancer [2, 3], denervation decreases prostate cancer spread [2]; however, we still know little regarding the mechanisms controlling nerve emergence during tumor progression.

Now, a fascinating new study led by Claire Magnon (Institut de Biologie François Jacob, Paris, France) reveals that neural progenitor cells (NPCs) from the subventricular zone of the brain migrate through the blood to target primary tumors or metastatic tissues where the initiate neurogenesis and support the early stages of the development of prostate cancer [4]. Can these fascinating findings lead to the construction of novel strategies for the treatment of prostate cancer?

Mauffrey et al. employed an engineered mouse model of prostate cancer; the mice expressed MYC in prostate epithelial cells [2], to induce tumor formation, and yellow fluorescent protein from the doublecortin (DCX) promoter to allow NPC tracking, as DCX marks NPCs resident in developing and adult neurogenic regions of the central nervous system [5]. Fascinatingly, the study discovered that oscillations of subventricular zone-resident DCX-positive NPCs and the disruption of the blood-brain barrier permitted NPCs to exit their niche, enter the circulation, migrate to the tumor site, and subsequently infiltrate prostate tumors and generate new adrenergic neurons. Furthermore, the specific depletion of NPCs in this model system inhibited early prostate tumor growth, while NPC transplantation further promoted tumor growth and fostered metastasis.

The authors finally sought to assess the role of DCX+ NPCs in humans by assessing benign prostate hyperplasia from a cohort of 15 patients and samples from low- and high-risk prostate cancer patients. Overall, NPC density correlated well with aggressiveness and recurrence of prostate adenocarcinoma, thereby suggesting that DCX-positive cells may play a crucial role in regulating the development and progression of prostate tumors in humans.

While this fascinating study suggests that NPCs may represent treatment targets for prostate cancer, these findings also provide additional evidence for the ongoing nature of neurogenesis in human adults. The authors now point to the next steps required to further expand this area of research, which include the characterization of the cellular and molecular events controlling how NPCs exit their neurogenic niches in the brain and migrate to tumors and metastases in rodents and humans.

For more on the fallout from this fascinating new advance, stay tuned to the Stem Cells Portal!

References 

  1. Ayala GE, Dai H, Powell M, et al., Cancer-Related Axonogenesis and Neurogenesis in Prostate Cancer. Clinical Cancer Research 2008;14:7593.
  2. Magnon C, Hall SJ, Lin J, et al., Autonomic Nerve Development Contributes to Prostate Cancer Progression. Science 2013;341:1236361.
  3. Dobrenis K, Gauthier LR, Barroca V, et al., Granulocyte colony-stimulating factor off-target effect on nerve outgrowth promotes prostate cancer development. International Journal of Cancer 2015;136:982-988.
  4. Mauffrey P, Tchitchek N, Barroca V, et al., Progenitors from the central nervous system drive neurogenesis in cancer. Nature 2019;569:672-678.
  5. Francis F, Koulakoff A, Boucher D, et al., Doublecortin Is a Developmentally Regulated, Microtubule-Associated Protein Expressed in Migrating and Differentiating Neurons. Neuron 1999;23:247-256.