Growth and Survival Mechanisms Associated with Perineural Invasion in Prostate Cancer

Abstract

Perineural invasion (PNI) is the major mechanism of prostate cancer spread outside the prostate. Apoptotic and proliferation indices were determined in PNI cells using the PNI in vitro model and human PNI in tissue microarrays. RNA was extracted from the PNI model and controls and evaluated by cDNA microarray analysis. Differential expression of candidate genes was confirmed by real-time quantitative PCR, fluorescence, and immunohistochemistry using tissue microarrays. Genistein and BAY 11-7085 were added to the supernatant of cocultures and controls in microchamber cultures. The significance of nuclear factor B (NFB) nuclear translocation in human PNI was analyzed using Kaplan-Meier analysis. An increase in proliferation and a decrease in apoptosis were observed in human PNI cells and the PNI model as compared with controls. Three of 15 genes up-regulated in the cDNA microarray were involved in the apoptosis signaling pathway (NFB), and its downstream targets defender against cell death 1 and PIM-2. The increase was corroborated by real-time quantitative PCR and immunofluorescence. NFB nuclear translocation was seen in the in vitro model and human tissues, where strong nuclear expression was associated with a decrease in recurrence-free survival. Addition of genistein and BAY 11-7085 resulted in a decrease in NFB, PIM-2 and defender against cell death 1 as well as a reversal of the inhibition of apoptosis. This is the first description of a biological mechanism and functional significance of PNI. Cancer cells in a perineural location acquire a survival and growth advantage using a NFB survival pathway. Targeting PNI might help detain local spread of the tumor and influence survival.

Parameters of perineural invasion in radical prostatectomy specimens lack prognostic significance

“…26 It is also recognized that proximity of intraprostatic tumor to the resection margin in radical prostatectomy specimens is not of prognostic significance. 27 In view of this, our finding that the presence of proximity of perineural invasion to the prostatic capsule or excision margin is not associated with a higher rate of biochemical failure implies that, while infiltration of the perineural space may promote local tumor growth, it does not necessarily facilitate extraprostatic spread.…”

Determining Prostate Cancer-Specific Death through Quantification of Stromogenic Carcinoma Area in Prostatectomy Specimens

“…PNI diameter was obtained as previously described. 22,27 The point scores are obtained from each predictor (log preoperative PSA, lymph node status, SM, ECE, Gleason score, stroma percentage quantification of RSG 3 area as stroma percentage, and PNI diameter) and then manually tallied to obtain a total score before reading predicted recurrence-free probability. As the nomogram shows ( Figure 6), RSG 3 provides unique information to the model and the information provided has significant weight.…”

“…Perineural invasion (PNI), commonly found in PCa, is a hosttumor interaction between nerves and cancer cells that leads to costimulation of growth. [22][23][24][25][26] Cancer cells grow more when around the nerve and also induce neurogenesis in an autocrine loop. 27 We previously demonstrated that PNI diameter, a measure of tumor diameter around the nerve, is also a very strong biomarker for BCR-free survival.…”

“…27 We previously demonstrated that PNI diameter, a measure of tumor diameter around the nerve, is also a very strong biomarker for BCR-free survival. 22 Hence, quantification of RSG 3 area and PNI diameter provide comprehensive pathological data on the host response to tumors. These two host-response predictive biomarkers were incorporated into the clinicopathologic parameters of current use to yield a new nomogram.…”

Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

“…Twenty-seven genes were overexpressed, whereas 18 were significantly reduced in association with the acquisition of a metastatic capability during in vivo selection of LNM35 (Table 1). The 27 examples overexpressed in LNM35 included various genes previously suggested to play a functional role in metastasis such as chemokine (C-X-C motif) ligand (Heaney et al, 2000;Bernal et al, 2002), immediate early response 3 (IER3) (Goswami et al, 2004;Nicholson et al, 2004), defender against cell death 1 (DAD1) (Ayala et al, 2004;Goswami et al, 2004;Kim et al, 2006) and methionyl aminopeptidase 2 (METAP2) (Dasgupta et al, 2005;Morowitz et al, 2005). Similarly, genes with higher expression in N15 also included some previously implicated in metastasis such as cadherin 1 (E-cadherin) (Cavallaro and Christofori, 2004) and lectin galactoside-binding soluble 3 (galectin-3) (Liu and Rabinovich, 2005).…”