MUC1 Enhances Tumor Progression and Contributes Toward Immunosuppression in a Mouse Model of Spontaneous Pancreatic Adenocarcinoma

Abstract

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition

“…These mice are designated PDA.MUC1 mice. This distinctive model of PDA expresses high levels of COX-2, IDO, and MUC1 and recapitulates the various stages of the human disease from preinvasive epithelial lesions (PanINs) to full blown adenocarcinoma (39). The PDA.MUC1 mice have increased circulating MUC1 and are tolerant to MUC1 immunization, making this model ideal for testing novel MUC1-based therapeutic strategies in combination with COX-2 inhibition.…”

“…Similarly, kynurenine and tryptophan serve as a measure for IDO activity because IDO converts tryptophan to kynureine. In tumor-bearing mice, IDO and COX-2 activity are high and therefore PGE 2 and kynurenine levels are high while tryptophan levels are low (39). As tumor burden decreases (with treatment), we expect that levels of PGE 2 and kynurenine would decline and tryptophan levels would increase.…”

“…39) and were maintained as heterozygotes. Genomic DNA was used to genotype the triple transgenic mice using a PCR as previously described (39). All protocols were conducted in accordance with stringent regulations laid out by the Mayo Clinic Internal Animal Care and Use Committee (IACUC).…”

“…Autologous irradiated DCs pulsed with immunizing peptides (20 g/ml) were used as stimulator cells and coincubated with the effector cells at a ratio of 10:1 for 18 h. Effector cells were incubated with 51 Cr-labeled tumor target cells at a ratio of 50:1 (5 ϫ 10 6 /ml effectors and 1 ϫ 10 5 /ml targets). Target cells used were B16 melanoma cells expressing full-length human MUC1 (39,43,45,46), and B16 melanoma cell line that does not express MUC1 as an irrelevant target. Radioactive 51 Cr released at the end of 6 h was determined using the Topcount Microscintillation Counter (Packard Biosciences).…”

“…We have recently generated a triple transgenic (Tg) mouse model of pancreatic ductal adenocarcinoma (PDA) that expresses human MUC1 as a self molecule (39). We have crossed the LSL-KRAS G12D ϫ P48 Cre mouse developed by Hingorani et al (40) with the human MUC1.…”