Growth and survival mechanisms associated with perineural invasion in prostate cancer.
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 kappaB (NFkappaB) 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 (NFkappaB), and its downstream targets defender against cell death 1 and PIM-2. The increase was corroborated by real-time quantitative PCR and immunofluorescence. NFkappaB 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 NFkappaB, 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 NFkappaB survival pathway. Targeting PNI might help detain local spread of the tumor and influence survival.
Ayala
Gustavo E
GE
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA. gayala@bcm.tmc.edu
Dai
Hong
H
Ittmann
Michael
M
Li
Rile
R
Powell
Michael
M
Frolov
Anna
A
Wheeler
Thomas M
TM
Thompson
Timothy C
TC
Rowley
David
D
D000890:Anti-Infective Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009570:Nitriles; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000294:innervation*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D013450:Sulfones; D015854:Up-Regulation
D000890:Anti-Infective Agents; D051017:Apoptosis Regulatory Proteins; C416282:BAY 11-7085; C083331:DAD1 protein, human; C489987:Dad1 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D009570:Nitriles; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D019833:Genistein; D017346:Protein Serine-Threonine Kinases