MUC1 is expressed at the apical surface of ductal epithelia of tissues, including breast, pancreas, airway, and the gastrointestinal tract, where its functions include lubrication and protection of the epithelia. In addition, roles for MUC1 have been suggested in both adhesive and antiadhesive properties of tumor cells, and extensive O-glycosylation of the MUC1 tandem repeat domain may contribute to these functions. Little information is available on the specific O-glycosylation of MUC1. One problem in identifying different MUC1 glycoforms has been that monoclonal antibodies raised against the MUC1 core protein recognize epitopes in the tandem repeat domain, which is often glycosylated to an extent that obscures these epitopes. We developed an epitope-tagged form of MUC1 that allowed the detection of multiple MUC1 glycoforms and established the presence of a number of important blood group and tumorassociated carbohydrate antigens on MUC1 expressed by two pancreatic tumor cell lines (Panc-1 and S2-013) and two colon tumor cell lines (Caco-2 and HT-29). Antigens detected include sialyl-Lewis a , sialyl-Lewis c , sialyl-Lewis x , and sialyl-Tn.The human epithelial mucin MUC1 (1-4) is a type 1 membrane-bound glycoprotein expressed by ductal epithelia of a number of organs including breast, pancreas, airway, and gastrointestinal tract (reviewed by Gum (5)). Its functions in these tissues include lubrication and protection of the epithelia, and roles in cell adhesion have been suggested (6 -8). There is great diversity in the post-translational processing of MUC1 by epithelial cells in different organs. Moreover, MUC1 is aberrantly expressed by tumors (9) with patterns of post-translational modifications that are different from corresponding normal cell types (10); several different glycoforms of MUC1 were originally described as "tumor-associated antigens." Although MUC1 has been the subject of a number of lines of research, little is known about the mechanisms that direct its diverse post-translational processing.Until recently, there has been little precise information available on the O-glycosylation of MUC1 with respect to blood group antigens. One report demonstrated sLe a 1 and sLe x epitopes on MUC1 core protein expressed in a pancreatic tumor cell line (11), and two reports showed that MUC1 was one of the proteins associated with SLEX antigen secreted by colon carcinoma cells (12,13). In addition, the glycosylation of MUC1 purified from a human mammary tumor cell line (T47D), solid tumor, and human breast milk has been described (14). A major problem in detecting and purifying different glycoforms of the MUC1 core protein is that monoclonal antibodies raised against the core protein bind epitopes in the tandem repeat domain. Many forms of MUC1 that are secreted by different adenocarcinomas are heavily glycosylated in this domain, which obscures the protein epitopes recognized by these anti-MUC1 antibodies. Polyclonal antibodies generated against the cytoplasmic tail (15) do not bind the secreted forms of the...

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Background: Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro.

Matrix metalloproteinases (MMPs) are believed to contribute to the complex process of cancer progression. They also exhibit an alpha1-proteinase inhibitor (alphaPI)-degrading activity generating a carboxyl-terminal fragment of approximately 5 kd (alphaPI-C). This study reports that overexpression of alphaPI-C in S2-020, a cloned subline derived from the human pancreas adenocarcinoma cell line SUIT-2, potentiates the growth capability of the cells in nude mice. After stable transfection of a vector containing a chimeric cDNA encoding a signal peptide sequence of tissue inhibitor of metalloproteinase-1 followed by cDNA for alphaPI-C into S2-020 cells, three clones that stably secrete alphaPI-C were obtained. The ectopic expression of alphaPI-C did not alter in vitro cellular growth. However, subcutaneous injection of the alphaPI-C-secreting clones resulted in tumors that were 1.5 to 3-fold larger than those of control clones with an increased tendency to invasiveness and lymph node metastasis. These effects could be a result of modulation of natural killer (NK) cell-mediated control of tumor growth in nude mice, as the growth advantage of alphaPI-C-secreting clones was not observed in NK-depleted mice, and alphaPI-C-secreting clones showed decreased NK sensitivity in vitro. In addition, production of alphaPI and generation of the cleaved form of alphaPI by MMP were observed in various human tumor cell lines and in a highly metastatic subline of SUIT-2 in vitro. These results provide experimental evidence that the alphaPI-degrading activity of MMPs may play a role in tumor progression not only via the inactivation of alphaPI but also via the generation of alphaPI-C.

Pancreatic cancer has an abysmal prognosis because of late diagnosis and lack of effective therapeutics. New drugs are desperately needed. The present study determined the effect of the LTB4 receptor antagonist, LY293111, on tumor growth and metastases in a fluorescent orthotopic model of pancreatic cancer. Pancreatic cancer cells (S2-013) with stable expression of enhanced green fluorescent protein were implanted into the duodenal pancreatic lobe of athymic mice. Animals were allocated to four groups (eight mice per group): control (no treatment); LY293111; gemcitabine; and LY293111 + gemcitabine. Monitoring of the surgical procedure and follow-up examinations at 2, 3, and 4 weeks after implantation to monitor tumor growth and metastases were performed using a fluorescence microscope and the reversible skin-flap technique. A staging and scoring system was developed to evaluate tumor progression, based on the TNM classification. Control animals developed end-stage disease with invasive cancer, metastases, and cachexia. Tumor growth and incidence of metastases were significantly reduced in all treated mice. However, combined treatment with LY293111 and gemcitabine was most effective. LY293111 is a novel therapeutic agent for pancreatic cancer, which improves the efficacy of gemcitabine. It is well tolerated and can be administered orally and, therefore, provides a new hope for patients suffering from pancreatic adenocarcinoma.

Situs solitus refers to the normal arrangement of body organs. Situs inversus totalis is a complete mirror image or reverse isomeric form of the thoracic and abdominal viscera. Any arrangement of organs between these two extremes is designated by heterotaxia. Several patterns of vascular and visceral abnormalities are associated with heterotaxia, and two loosely defined syndromes of splenic anomalies (asplenia and polysplenia) are most common. We present the case of a 71-year-old woman with situs inversus totalis and polysplenia syndrome who developed synchronous double cancer originating from the stomach and rectum. Abdominal manifestations were situs inversus totalis combined with multiple lobulated spleen, azygous continuation of the interrupted inferior vena cava, direct drainage of hepatic vein to left atrium, preduodenal portal vein, short pancreas, incomplete rotation of the colon, and malrotation of the intestine. Histologically, gastric cancer was diagnosed as papillary adenocarcinoma and rectal cancer, as moderately differentiated adenocarcinoma. The patient was successfully treated with total gastrectomy for gastric cancer and low-anterior resection of the rectum for rectal cancer.

A human pancreatic cancer cell line (SUIT-2) and four sublines cloned in vitro (S2-007, S2-013, S2-020 and S2-028) were inoculated into nude mice for assessment of metastatic potentials. After 16 weeks of subcutaneous injection, the parent SUIT-2 line metastasized to the lungs and lymph nodes in three of six mice. S2-007 cells presented the highest metastatic potential in pulmonary (5/6) and lymph node (2/6) metastases among the four sublines. No metastasis was found in S2-028. The incidence of spontaneous pulmonary metastasis was correlated with that of pulmonary colonization after intravenous (i.v.) injection of cell clusters (r = 0.87, P = 0.056). Pulmonary colonization potential using single cells, however, did not always reflect a spontaneous metastatic ability. Type I collagenolytic activity in serum-free conditioned media of these cells was correlated effectively with the incidence of spontaneous pulmonary metastasis (r = 0.92, P = 0.026) and pulmonary colonization after i.v. injection of cell clusters (r = 0.95, P = 0.013). Thus, type I collagenolytic activity may possibly be essential to spontaneous cancer metastasis.