PDAC is a disease with a dismal prognosis and ranks 9th in the incidence of solid
cancers and 4th for cancer-related deaths, with an overall median survival of
around 4–6 months. The only cure is surgery; however, this option is available
only to a maximum of 20% of the patients diagnosed with the disease. Even for
these patients, median survival is less than 2 years, and only few patients survive
significantly longer.
ALCAM - a cell adhesion molecule expressed by epithelial cells in several organs.
It is expressed at sites of cell– cell contact and is associated intimately with
adhesive structures that maintain the structural integrity of the epithelium in
various organs, its expression and function has been evaluated in some
desmoplasia including melanoma, prostate carcinoma, breast cancer, colorectal
carcinoma, bladder cancer, and esophageal squamous cell carcinoma.
Using our microarray analyses, we demonstrate that the expression of activated
leukocyte cell adhesion molecule (ALCAM, CD166) is altered in pancreatic ductal
adenocarcinoma (PDAC). Furthermore, ALCAM was found to be increased in the
sera of patients suffering from pancreatic cancer suggesting a role in pancreatic
carcinogenesis.
We hypothesized that – due to its physiological function as a cell-cell contact
protein – ALCAM might be involved in oncogenic transformation in both PNET and
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PDAC and we propose ALCAM as a novel serum biomarker in human pancreatic
cancer which is associated with cell adhesion, growth and chemoresistance.
Interestingly, the majority of the pancreatic cancer tissue samples tested showed
low or no immunoreactivity for ALCAM which is in contrast to the findings in the
patient sera. Immunohistochemical analysis revealing weak ALCAM positivity in
ductal cells in the normal pancreas while on islet cells, a strong membrane
staining was found. In cancer cells, different staining patterns were observed:
while some cancer cells showed various intensities of ALCAM positivity in the
cytoplasm, we found cancer cell membrane staining in a minority of slides. In the
functional experiments, there were striking differences in tumor cell behaviour
comparing PDAC cells to PNET cells following ALCAM RNAi. The observed
differences in chemoresistance induction might be attributable to the tested
chemotherapeutic substances (i.e. gemcitabine vs. rapamycin) and suggest that
ALCAM might have a specific role in relation to gemcitabine. This is of particular
importance since gemcitabine is the “standard of care” both in the palliative and
adjuvant treatment of pancreatic cancer. Interestingly, ALCAM silencing had no
effect on pancreatic cancer growth which is indicative of a minor importance of
cell-cell contacts for in vitro pancreatic cancer cell growth; since the epithelial
integrity is disturbed in cell culture in any way, these findings might be a reflection
of the model system used in our study. However, the role of ALCAM in cancer is
generally controversially discussed, these equivocal results suggest that ALCAM
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function might be dependent on a) the malignant cell type analyzed, b) the
different tumor-stroma interactions present in various tumor entities and c)
potentially also different (unknown) levels of proteases which might cleave
ALCAM and could thus be ‘responsible’ for the observed differences in ALCAM
functions. In addition, de-regulations of the protein sorting machinery could be the
cause for the differences in ALCAM localization between different cancers but
also for differences within one particular tumor entitiy (i.e. in this case PDAC). In
our study, we propose ALCAM as a novel serum biomarker in human pancreatic
cancer which is associated with cell adhesion, growth and chemoresistance.
In conclusion, we demonstrate in this study that ALCAM expression is
de-regulated in pancreatic cancer and in pancreatic neuroendocrine tumors, that it
is a serum biomarker in PDAC and that it is associated with neuroendocrine tumor
growth and exocrine cancer chemoresistance. These findings lay the basis for in
depth analyses of ALCAM protein processing, signaling and of ALCAM-mediated
cell-cell and cell-matrix interactions in PDAC and PNET. Clearly, additional
research is needed to evaluate the role of ALCAM in each tumor type, to
determine its interaction with other cellular intermediates, and to determine
whether ALCAM is a therapeutic target to treat primary or metastatic tumors.
«
PDAC is a disease with a dismal prognosis and ranks 9th in the incidence of solid
cancers and 4th for cancer-related deaths, with an overall median survival of
around 4–6 months. The only cure is surgery; however, this option is available
only to a maximum of 20% of the patients diagnosed with the disease. Even for
these patients, median survival is less than 2 years, and only few patients survive
significantly longer.
ALCAM - a cell adhesion molecule expressed by epithelial cells in seve...
»
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