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Despite radical extension of surgical procedures, the cure rate of pancreatic head carcinoma patients still remains low. A cause of this concerns unsuccessful locoregional control, which may originate from a positive surgical margin near the superior mesenteric artery (SMA). However, no studies have examined invasion of pancreatic carcinoma around the SMA. En bloc resection of the head of the pancreas and the superior mesenteric vessels was performed on 6 patients who had pancreatic head carcinoma invading the superior mesenteric vein. The specimens were cut perpendicular to the SMA and consecutive serial sections were made. The slices were stained with hematoxylin and eosin or immunohistochemistry for cytokeratin 19 to easily detect carcinoma tissue under a microscope. Nodal metastasis around the SMAs was found in all of the cases. There were no characteristics of the arrangement of the metastatic nodes along the SMA. Lymphatic emboli were often observed close to the metastatic nodes. Neural invasions were detected around the tumors in every case and were continuously connected with the extrapancreatic nerve plexus. The nerve plexus covering the SMA were involved in 4 cases. Involvement was observed mainly behind the SMA, reaching as far as the left side of the SMA in 3 cases. The invasion extended further upwards along the right side of SMA for the celiac nerve plexus. The lymphatics and the nerve plexus in the area around the SMA were frequently involved by pancreatic head carcinoma. This involvement would have been left behind unless the SMA was resected.

Tumor cells escape immunologic rejection through diverse mechanisms. Fas and its ligand represent one such mechanism. Recently we reported that pancreatic cancer cell lines express Fas-ligand and kill lymphoid cells by Fas-mediated apoptosis in vitro. This study was designed to determine whether human pancreatic tumors express Fas-ligand in vivo, as a potential mediator of counterattacking the host immune cells, and to determine if Fas-ligand expression correlates with clinicopathologic characteristics and patient survival. Fas-ligand expression in 45 primary pancreatic ductal cancers and two hepatic metastases was determined using immunohistochemistry. Apoptotic cells within the tumor were assessed by immunohistochemistry for the presence of single stranded DNA. Immunohistochemistry showed that 37 (82%) of the primary tumors and both of the hepatic metastases expressed Fas-ligand. Tumor infiltrating lymphoid cells were frequently apoptotic, but the cancer cells were rarely apoptotic. Patients with Fas-ligand-positive tumor had significantly shorter survival times than Fas-ligand-negative. A multivariate analysis indicated that Fas-ligand expression and the histologic margin status were significant prognostic factors. These results suggest that the expression of Fas-ligand in human pancreatic cancers and the induction of apoptosis in the infiltrating lymphoid cells may be required to counterattack the host cytotoxic T-lymphocytic and natural killer cellular responses.

Pancreatic ductal cancer has higher angiotensin II concentrations compared with normal pancreas or other solid tumors. This study examined angiotensin II type 1 (AT1) receptor expression and the role of angiotensin II in proliferation and survival of human pancreatic cancer cells. All three pancreatic cancer cell lines studied, from well to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed strong expression of AT1 receptor. In contrast, HT-29 human colon cancer cells showed extremely weak expression. Angiotensin II stimulated the growth of pancreatic cancer cells through MAP kinase activation but had no significant effect on proliferation of HT-29 colon cancer cells. In addition, angiotensin II significantly prevented cisplatin (CDDP)-induced apoptosis through NF-kappaB activation and the subsequent production of anti-apoptotic molecules, including survivin and Bcl-XL, in pancreatic cancer cells. These findings suggest that angiotensin II plays a role in the growth and chemoresistance of AT1-positive pancreatic cancer cells through its action as a potent mitogen and anti-apoptotic molecule.

Protease-activated receptor (PAR)-2 is a G protein-coupled receptor that is activated by trypsin. The purpose of this study was to examine PAR-2 expression and the role of trypsin in cell proliferation in human pancreatic cancer cells. All four pancreatic cancer cell lines studied, from well to undifferentiated types, AsPC-1, BxPC-3, Panc-1, and MIAPaCa-2, had significant levels of PAR-2 mRNA detected by reverse transcription-polymerase chain reaction, and showed a band of about 55 kDa corresponding to the known molecular weight of PAR-2: AsPC-1, BxPC-3 and Panc-1 showed a strong band, and MIAPaCa-2 showed a weak one. Immunocytochemically, AsPC-1, BxPC-3, and Panc-1 showed intense immunostaining for PAR-2, predominantly in the plasma membrane, while in MIAPaCa-2, immunostaining was weak. Proliferative activity of AsPC-1 cells was increased by concentrations of trypsin as low as 10 nM, and activity peaked at a concentration of 100 nM, representing almost 60% of that induced by 10% fetal bovine serum. In contrast, trypsin had no significant effect on proliferation of MIAPaCa-2 cells. These findings suggest that trypsin plays a role in the growth of PAR-2-positive pancreatic cancer cells and serves as a potent mitogen in vitro, functioning as a growth factor.

A 77-year-old man with advanced esophageal cancer with tracheal and esophageal obstruction underwent continuous low-dose FP chemotherapy for a total of seven weeks, resulting in a complete response (CR) and disappearance of the esophago-tracheal fistula. Since discharge from the hospital, he has maintained a stable good condition for about two years while receiving biweekly low dose FP chemotherapy and oral UFT. Eight patients who had post-operative recurrence and underwent noncurative operation for esophageal cancer were given low-dose FP chemotherapy. The results of this chemotherapy for those 8 patients and the present patient, for a total of 9 patients were 2 CR, 2 PR, 3 NC and 2 PD, with an overall response rate of 44%, and overall one-year and two-year survival rates of 44% and 22%, respectively.

Laminin-5 (LN5), which consists of laminin alpha3, beta3 and gamma2 chains, is a laminin isoform produced by various kinds of normal epithelial cells and tumor cells. Strong activity of LN5 in adhesion, migration and scattering of cells in vitro and its frequent detection in human tumor tissues have suggested a possible role of LN5 in the malignant growth of tumor cells. To examine whether LN5 affects the malignant potential of tumor cells, we prepared human fibrosarcoma HT1080 cell lines producing LN5 by transfecting a cDNA of laminin alpha3 chain into the parent cell line, which constitutively expressed the laminin beta3 and gamma2 chains. The exogenous alpha3 chain associated with the endogenous beta3 and gamma2 chains to secrete the LN5 heterotrimer that has strong cell-scattering and cell adhesion activities. The HT1080 transfectants expressing LN5 efficiently adhered to culture dishes in a serum-free condition as compared with control HT1080 cells, which secreted the monomers and heterodimer of the beta3 and gamma2 chains. When injected into nude mice subcutaneously, the HT1080 transfectants expressing LN5 grew faster and formed much larger tumors than the control cells. This suggests that LN5 promotes tumor growth in vivo.