ProNGF Correlates with Gleason Score and Is a Potential Driver of Nerve Infiltration in Prostate Cancer

Abstract

Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of nerve growth factor (proNGF) is overexpressed in prostate cancer and involved in the ability of prostate cancer cells to induce axonogenesis. A series of 120 prostate cancer and benign prostate hyperplasia (BPH) samples were analyzed by IHC for proNGF. ProNGF was mainly localized in the cytoplasm of epithelial cells, with marked expression in cancer compared with BPH. Importantly, the proNGF level positively correlated with the Gleason score (n = 104, τB = 0.51). A higher level of proNGF was observed in tumors with a Gleason score of ≥8 compared with a Gleason score of 7 and 6 (P < 0.001). In vitro, proNGF was detected in LNCaP, DU145, and PC-3 prostate cancer cells and BPH-1 cells but not in RWPE-1 immortalized nontumorigenic prostate epithelial cells or primary normal prostate epithelial cells. Co-culture of PC12 neuronal-like cells or 50B11 neurons with PC-3 cells resulted in neurite outgrowth in neuronal cells that was inhibited by blocking antibodies against proNGF, indicating that prostate cancer cells can induce axonogenesis via secretion of proNGF. These data reveal that ProNGF is a biomarker associated with high-risk prostate cancers and a potential driver of infiltration by nerves.

Nerve–Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression

“…ProNGF was correlated to tumor aggressiveness and low-risk tumors (Gleason score ¼ 6) contained significantly less proNGF than intermediate and high-risk tumors (Gleason score 7). Interestingly, although at this stage, there are no supporting mechanistic animal studies, prostate cancer cells in vitro were found able to stimulate neuron outgrowth through the secretion of proNGF (14). Whether or not proNGF acts directly on neurons, or is first processed into NGF, is still to be determined, but this study showed that proNGF/NGFs are involved in the neurogenic ability of prostate cancer cells.…”

“…Whether or not proNGF acts directly on neurons, or is first processed into NGF, is still to be determined, but this study showed that proNGF/NGFs are involved in the neurogenic ability of prostate cancer cells. ProNGF/NGFs have been shown to be involved in perineural invasion (5), and the study by Pundavela and colleagues (14) indicates that these growth factors also participate in tumor neoneurogenesis. Another investigation by Dobrenis and colleagues (15) has shown that the hematopoietic growth factor G-CSF constrains the growth of prostate cancer cells by supporting the survival of sympathetic nerve fibers.…”

“…However, two recently published studies in prostate cancer have shown that the attraction of nerve fibers is mediated through the production of neurotrophic growth factors by cancer cells. Pundavela and colleagues (14) have shown that proNGF, the precursor of nerve growth factor (NGF), is expressed in prostate cancer cells and a key driver of nerve infiltration. ProNGF was found to be overexpressed in prostate cancer cells compared with normal and benign hyperplastic prostate epithelial cells.…”

LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker

“…Although several studies have reported the ability of cancer cells to attract nerve fibers (40,41), very few have reported the impact of stromal cells in this process (12), especially in PDA where stromal cells compose the vast majority of the tumor cell mass. Therefore, our goal was to identify molecular targets from the PDA microenvironment that are involved in PANR, which may lead to the discovery of potent future adjuvant therapies that could prolong survival and reduce morbidity by blocking PANR.…”

NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling

“…It had already been reported (Delsite and Djakiew, 1999) that a proNGF molecule of 22 kDa is expressed by human prostatic stromal cells, as detected immunologically, but mature NGF, which would be expected to be the agent capable of attracting sympathetic and/or sensory neurites was not detected in these studies. To address whether NGF or proNGF may be involved in prostate tumor-directed neurogenesis, a cohort of 120 human prostate samples was examined by immunohistochemistry (Pundavela et al ., 2014). ProNGF was readily detected in the cytoplasm of the cancer cells but much less so in the stromal cells.…”