MUC4-expressing pancreatic adenocarcinomas show elevated levels of both T1 and T2 cytokines: potential pathobiologic implications.
OBJECTIVE
The human MUC4 mucin plays an important role in the pathogenesis of pancreatic cancer. Recently, we have demonstrated that MUC4 expression in pancreatic tumor cells is regulated by interferon-gamma (IFNgamma) and by retinoic acid via transforming growth factor beta 2 (TGFbeta-2). In the present study, we established the pathobiological association of various cytokines and MUC4 in pancreatic tumor tissues and tumor cell lines.


METHODS
Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and/or immunohistochemical analyses, we examined the expression of MUC4, IFNgamma, TGFbetas, and several immunologically relevant cytokines in a panel of 11 pancreatic adenocarcinomas (PA), three normal pancreatic (NP) tissue specimens, and 11 pancreatic tumor cell lines.


RESULTS
Our data revealed that both MUC4 and IFNgamma were expressed at moderate to high levels in the majority of PA, while being undetectable in NP. Moreover, transcript for interleukin 2 (IL-2), a known marker of activated T helper 1 (TH1) lymphocytes, exhibited an expression profile similar to IFNgamma, suggesting a role of these immune effector cells as a potential source of IFNgamma in PA. Of note, IFNgamma protein was detected in the inflamed tissues neighboring tumor areas. Furthermore, TGFbetas were expressed by most cell lines and frequently upregulated in PA compared with NP. Interestingly, both IL-12 and IL-10, two key cytokines of the TH1 and TH2 pathways, respectively, were expressed at higher levels in PA relative to NP.


CONCLUSIONS
These observations support the potential implication of IFNgamma and TGFbetas in MUC4 regulation in vivo and suggest a complex interaction of TH1 and TH2 signaling in the pancreatic tumor microenvironment. These findings may provide useful insights into the pathobiology of pancreatic cancer.
Andrianifahanana
Mahefatiana
M
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA.
Chauhan
Subhash C
SC
Choudhury
Amit
A
Moniaux
Nicolas
N
Brand
Randall E
RE
Sasson
Aaron A
AA
Pour
Parviz M
PM
Batra
Surinder K
SK
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D055264:Mucin-4; D009077:Mucins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D007378:Interleukins; C524658:MUC4 protein, human; D055264:Mucin-4; D009077:Mucins; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma