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.