Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer.
Neural alterations and aberrantly expressed nerve-specific factors promoting tumor progression are known to contribute to pancreatic cancer's extremely poor prognosis. Despite hints that axon guidance factor semaphorin 3A (SEMA3A) may function as a tumor inhibitor, its clinical importance and therapeutic potential have not yet been explored. The present study investigated the role of SEMA3A and its receptors-plexins A1-A4 (PLXNA1-A4) and neuropilin-1 (NRP1)-in pancreatic cancer. QRT-PCR and immunohistochemical analyses revealed overexpression of SEMA3A, NRP1 and PLXNA1 in metaplastic ducts, malignant cells and nerves of cancerous specimens, and showed that elevated levels of corresponding mRNA (6.8-fold, 2.0-fold and 1.5-fold, respectively) clearly correlated with negative clinicopathological manifestations such as shorter survival (SEMA3A and PLXNA1) and a lesser degree of tumor differentiation (NRP1) in Stages I-III patients. High SEMA3A expression in pancreata of Stage IV M1 patients and in peritoneal metastases, and consequent functional studies indicated that poor clinical outcome might be related to the ability of SEMA3A to promote dissemination and invasiveness of pancreatic cancer cells through activation of multiple pathways involving Rac1, GSK3b or p42/p44 MAPK, but not E- to N-cadherin switch, MMP-9 or VEGF induction. Thus, this study is the first to quantify expression of the SEMA3A system in human malignancy and to show that overexpression of SEMA3A by nerves and transformed cells leads to a SEMA3A-rich environment which may favor malignant activities of tumor cells. Furthermore, negative clinicopathological correlations suggest that SEMA3A might represent a novel intervention target but not a treatment option for pancreatic cancer patients.
Müller
Michael W
MW
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Giese
Nathalia A
NA
Swiercz
Jakub M
JM
Ceyhan
Güralp O
GO
Esposito
Irene
I
Hinz
Ulf
U
Büchler
Peter
P
Giese
Thomas
T
Büchler
Markus W
MW
Offermanns
Stefan
S
Friess
Helmut
H
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002454:Cell Differentiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000556:secondary; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000378:metabolism*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; C515995:PLXNA2 protein, human; C097871:PLXNA3 protein, human; C524474:Plxna4 protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1