Cancer-related axonogenesis and neurogenesis in prostate cancer.
OBJECTIVE
Perineural invasion is the only interaction between cancer cells and nerves studied to date. It is a symbiotic relationship between cancer and nerves that results in growth advantage for both. In this article, we present data on a novel biological phenomenon, cancer-related axonogenesis and neurogenesis.


METHODS
We identify spatial and temporal associations between increased nerve density and preneoplastic and neoplastic lesions of the human prostate.


RESULTS
Nerve density was increased in cancer areas as well as in preneoplastic lesions compared with controls. Two- and three-dimensional reconstructions of entire prostates confirmed axonogenesis in human tumors. Furthermore, patients with prostate cancer had increased numbers of neurons in their prostatic ganglia compared with controls, corroborating neurogenesis. Finally, two in vitro models confirmed that cancer cells, particularly when interacting with nerves in perineural invasion, induce neurite outgrowth in prostate cancer. Neurogenesis is correlated with features of aggressive prostate cancer and with recurrence in prostate cancer. We also present a putative regulatory mechanism based on semaphorin 4F (S4F). S4F is overexpressed in cancers cells in the perineural in vitro model. Overexpression of S4F in prostate cancer cells induces neurogenesis in the N1E-115 neurogenesis assay and S4F inhibition by small interfering RNA blocks this effect.


CONCLUSIONS
This is the first description of cancer-related neurogenesis and its putative regulatory mechanism.
Ayala
Gustavo E
GE
Department of Pathology, Baylor College of Medicine, Houston, Texas 77401, USA. gayala@bcm.tmc.edu
Dai
Hong
H
Powell
Michael
M
Li
Rile
R
Ding
Yi
Y
Wheeler
Thomas M
TM
Shine
David
D
Kadmon
Dov
D
Thompson
Timothy
T
Miles
Brian J
BJ
Ittmann
Michael M
MM
Rowley
David
D
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology*; D055495:Neurogenesis / Q000502:physiology*; D010525:Peripheral Nerves / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D011467:Prostate / Q000294:innervation; D019048:Prostatic Intraepithelial Neoplasia / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000378:metabolism; D046888:Tissue Array Analysis
D039961:Semaphorins