| dc.description.abstract | Introduction: Polymeric immunoglobulin receptor (pIgR) traffics
Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither
are expressed in the normal pancreas. Recent work has demonstrated pIgR to be
upregulated in hepatocellular carcinoma, even though it is not expressed in normal
liver cells. High pIgR levels are associated with poor survival and distant metastases
for a number of cancers such as nasopharyngeal cancers, lung and oesophageal
cancers.
Recent work from our laboratory suggested pIgR may be upregulated in
pancreatic ductal adenocarcinoma (PDAC). My aim was to assess pIgR’s role in
PDAC by interrogating human PDAC tissue samples as well using cell biology
experimental tools.
Methods: pIgR expression was manipulated (siRNA and shRNA) in cell lines to
evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D
organotypics models. Tissue Microarrays of patients with PDAC were analysed after
pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a
combined bio-marker panel.
Results: Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα)
could not modulate pIgR expression in PDAC cell lines despite this effect being seen
in other studies using colorectal and nasopharyngeal cancer cell lines. Downregulation
in pIgR expression in Capan1 cell line resulted in reduction of cellular
proliferation (n= 3, P<0.05, Friedman test), adhesion (n= 3, P<0.05, Kruskal-Wallis)
and migration (n= 3, P<0.05, Kruskal-Wallis). In 3D organotypic models, pIgR
downregulation resulted in reduced cancer cell invasion (n= 9, P<0.05, Kruskal-
Wallis) and diminished contraction of gels (n= 9, P<0.05, Kruskal-Wallis).
In human PDAC, decreased E-cadherin expression correlates with increased pIgR
expression through pancreatic intra-epithelial neoplasia (PanIN) progression. There
was no IgA expression in PDAC. pIgR expression had no clinical correlation with
routine prognostic measures such as differentiation, lymph node metastasis (n= 88,
P=0.5012, Kruskal-Wallis). Even in combination with stromal indices (α-smooth
muscle action (SMA) and Picrosirius red), low pIgR scores had no statistically
significant impact on prognosis but had a trend towards better survival (n= 88,
P=0.2791, Mann-Whitney U test).
Conclusion: pIgR may be involved in progression from pre-neoplastic lesions such
as PanIN to PDAC. pIgR may have a biological impact on cellular motility and
invasion due to yet to be deciphered signalling cascades with marked effect on
cellular phenotype. Careful analysis is required to study the impact of pIgR on
prognostic impact bearing in mind the histological sub-types of pancreatic cancer. | en_US |
