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Page 2 of 9 Salleh et al. J Cancer Metastasis Treat 2020;6:31 I http://dx.doi.org/10.20517/2394-4722.2020.70
[4,5]
migrated from their local environment to distant sites . Importantly, this cancer type remains a hard-
to-treat malignancy mostly due to the development of tumour resistance mechanisms to the conventional
[4,5]
therapeutic approaches, which have been correlated with overall decreased survival rates . Despite these
ongoing challenges, in recent years, incremental improvements were observed in the overall survival
[6,7]
rate due to the emergence of combination chemotherapy regimens . For example, gemcitabine plus
nab-paclitaxel, and FOLFIRINOX [a combination of 5-fluorouracil (5-FU), leucovorin, irinotecan, and
oxaliplatin] show clinically meaningful improvements compared with gemcitabine monotherapy for PDAC
[6,7]
patients .

In the last decade, different biomarkers have been explored to identify a simpler tool for pancreatic cancer
[8,9]
diagnosis and prognosis . The development of tumour biomarkers are essential to precisely detect patients
at their early stage of tumour growth, as well as to evaluate the treatment responses so that the current
therapeutic strategies can be further improved [8-11] . Among various validated tools, alcohol dehydrogenase
(ADH) isoenzymes, aldehyde dehydrogenase (ALDH) enzyme as well as carbohydrate antigen 19-9 (CA
19-9) have been explored as the most common tumour markers for pancreatic cancer [8-14] . ADH and
ALDH enzymes catalyse alcohol metabolism via the oxidative pathway, which eventually results in the
[12]
generation of carcinogenic acetaldehyde. Given the importance of these biomarkers, studies by Jelski et al.
compared the activities of ADH isozymes and ALDH in pancreatic cancer vs. normal tissues, as well
as their differences between drinkers and non-drinkers. The authors observed that the class III ADH
isoenzyme activity was significantly increased in pancreatic cancer tissue (14.03 mU/L) compared to the
healthy tissue (11.45 mU/L). However, no significant differences were noticed in the activities of other
[12]
ADH isoenzymes and ALDH between pancreatic cancer and normal cells . Overall, these findings
indicated that ADH and ALDH mediated oxidative pathways of ethanol metabolism are not critical
[12]
players in pancreatic carcinogenesis . However, considering the fact of increased ADH class III enzyme
activity in pancreatic cancer, the same group analysed ADH isozymes and ALDH activities in the serum
[13]
samples of pancreatic cancer patients . The authors observed a significant increase in ADH class III
isoenzyme activity (13.52 mU/L) in pancreatic cancer patients compared to the control group (11.08
[13]
mU/L) . While total ADH activity was also significantly higher in cancer patients, no changes were
[13]
noticed in other ADH isozymes as well as ALDH activities . Notably, a similar analysis in a large cohort
of pancreatic cancer patients also demonstrated significantly increased activity of serum ADH class III
[14]
isozyme (14.03 mU/L) compared to healthy controls (11.45 mU/L), respectively . Moreover, total serum
[14]
ADH activity was also found to be increased compared to healthy controls . Overall, these studies
suggested a potential role for ADH, particularly the class III isoenzyme as a biomarker of pancreatic cancer.

In recent years, CA 19-9, also known as Sialylated Lewis antigen (Sla) has emerged as one of the most-
studied biomarkers for PDAC, which was characterized by a monoclonal antibody produced by hybridoma
technology [8-11] . As some mucins could contribute to cancer progression via mechanisms including the
induction of T cell apoptosis, which later affects the anti-cancer immune response [10,11] , the human colorectal
[11]
carcinoma cell line SW1116 was immunized with spleen cells of a mouse as a mucin-like product .
The authors of this study characterized that CA 19-9 works by detecting an antigen of a carbohydrate on
numerous protein carriers. Proteins that carry CA 19-9 were then identified by immunoprecipitating CA 19-9
from the pooled sera. In addition, mass spectrometry was also used to identify CA 19-9 associated proteins.
Notably, various assays such as antibody arrays, western blot, kininogen, and apolipoprotein E by antibody
arrays confirmed the presence of CA 19-9 antigen on apolipoprotein B-100 [10,11] .

Mechanism of CA 19-9 biogenesis
CA 19-9 is generated by deregulated glycosylation, a process that enzymatically links glycan sugars to
cellular lipids and proteins [15-17] . In the normal pancreas, glycosylated proteins play various crucial functions
including protecting and lubricating the pancreatic ducts [15-17] . However, during cancer progression