Pancreatic ductal adenocarcinoma is among the top 10 causes of death from cancer in industrialized countries. In comparison with other gastrointestinal malignancies, pancreatic cancer is one of the tumors most resistant to chemotherapy. An important mechanism of tumor multidrug resistance is increased drug efflux mediated by several transporters of the ABC superfamily. Especially BCRP (ABCG2), MDR1 P-glycoprotein (ABCB1) and members of the MRP (ABCC) family are important in mediating drug resistance. The MRP family consists of 9 members (MRP1-MRP9) with MRP1-MRP6 being best characterized with respect to protein localization and substrate selectivity. Here, we quantified the mRNA expression of BCRP and of all MRP family members in normal human pancreas and pancreatic carcinoma and analyzed the mRNA level of the transporters most abundantly expressed in pancreatic tissue, BCRP, MRP1, MRP3, MRP4 and MRP5, in 37 tissue samples. In addition, we determined the localization of the 4 MRP proteins in normal human pancreas and in pancreatic carcinoma. The expression of BCRP, MRP1 and MRP4 mRNA did not correlate with tumor stage or grading. On the other hand, the expression of MRP3 mRNA was upregulated in pancreatic carcinoma samples and was correlated with tumor grading. The MRP5 mRNA level was significantly higher in pancreatic carcinoma tissue compared to normal pancreatic tissue. These data suggest that MRP3 and MRP5 are involved in drug resistance of pancreatic tumors and that quantitative analysis of their expression may contribute to predict the benefit of chemotherapy in patients with pancreatic cancer. ' 2005 Wiley-Liss, Inc.Key words: multidrug resistance protein; pancreatic carcinoma; ABCC family; MRP Pancreatic cancer is the 4th to 5th leading cause of cancerrelated death in most Western industrialized countries 1 with an average survival after diagnosis of 3 to 6 months. In Europe, it is the 8th most common cancer with approximately 74,000 newly diagnosed cases per year. 2 In spite of impressive advances in the field of diagnostic imaging of the pancreas, the availability of numerous tumor markers and an aggressive therapeutic approach, the prognosis of pancreatic carcinoma continues to be poor, with less than 5% surviving beyond 5 years. Surgical resection is possible in up to 40% of the patients with localized disease, but even in this group of patients, prognosis is relatively poor. 3,4 Most treatment failures are due to local recurrence, hepatic metastases or both and occur within 1 to 2 years after surgery. 5,6 Adjuvant therapy may improve long-term survival 7-10 but its routine use is not universal 9 because the results of randomized trials have been inconclusive. 8 In case of nonresectable pancreatic carcinomas infiltrating the retroperitoneal plexi or the superior mesenteric artery, chemotherapy might be the option of choice for the treatment. Until now, much impact on survival has not been achieved regarding the different chemotherapies, with maximum median survival times lying between 4 and 9 months ...

Background:The protumor activities of cancer-associated fibroblasts (CAFs) suggest that they are potential therapeutic targets for the treatment of cancer. The mechanism of CAF heterogeneity in gastric cancer (GC) remains unclear and has slowed translational advances in targeting CAFs. Therefore, a comprehensive understanding of the classification, function, activation stage, and spatial distribution of the CAF subsets in GC is urgently needed. Methods: In this study, the characteristics of the CAF subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by the CAF subsets were analyzed by performing single-cell RNA sequencing of eight pairs of GC and adjacent mucosal (AM) samples. The spatial distribution of the CAF subsets in different Lauren subtypes of GC, as well as the neighborhood relations between these CAF subsets and the protumor immune cell subsets were evaluated by performing multistaining registration. Results: Tumor epithelial cells exhibited significant intratumor and intertumor variabilities, while CAFs mainly exhibited intratumor variability. Moreover, we identified four CAF subsets with different properties in GC. These four CAF subsets shared similar properties with their resident fibroblast counterparts in the adjacent mucosa but also exhibited enhanced protumor activities. Additionally, two CAF subsets, inflammatory CAFs (iCAFs) and extracellular matrix CAFs (eCAFs), communicated with adjacent immune cell subsets in the GC TME. iCAFs interacted with T cells by secreting interleukin (IL)-6 and C-X-C motif chemokine ligand 12 (CXCL12), while eCAFs correlated with M2 macrophages via the expression of periostin (POSTN). eCAFs, which function as a pro-invasive CAF subset, decreased the overall survival time of patients with GC. Conclusions: iCAFs and eCAFs not only exhibited enhanced pro-invasive activities but also mobilized the surrounding immune cells to construct a tumor-favorable microenvironment. Therefore, inhibiting their activation restrains the GC 'seed' and simultaneously improves the 'GC' soil, suggesting that it represents a promising therapeutic strategy for the treatment of GC.

SUMMARY:Notwithstanding the importance of understanding how pancreatic ductal adenocarcinoma develops, the process remains controversial. A key question is whether the cells of origin of the tubular complexes that constitute precursor lesions are derived from a single cell type or from multiple types. Suggestions that they arise solely from centroacinar cells or ductal cells have been based on inference due to their morphologic appearance in tissue from patients or investigation of limited numbers of tubular complexes in animal models later in the carcinogenic process. The present study establishes clearly that two steps are involved; rapid transdifferentiation to produce tubular complexes followed later by transformation of the component cells. Animals were killed at intervals beginning 1 day after implantation of the carcinogen dimethylbenzanthracene. Transdifferentiation of acinar cells to ductal cells does not require cell division. Transition of lobules to tubular complexes begins by 2 days after implantation of carcinogen. Within 4 days after implantation well-developed tubular complexes are present. Islets participate in the process. Ductal adenocarcinoma is observed by 1 month after implantation of carcinogen. Chymotrypsin and cytokeratin localized by immunocytochemistry indicate acinar and ductal cell characteristics. Acino-ductal transdifferentiation persists in carcinogen-implanted animals, but not in controls implanted with sodium chloride crystals or subjected to sham implantation. The precursor lesions (tubular complexes) are formed by the transdifferentiation of acinar cells and to a lesser extent islet cells, with the incorporation of the duct cells pre-existing in the lobules. Therefore, cells that at one time were acinar cells, islet cells, and duct cells, provide the precursor cells for the ductal adenocarcinoma that develops from tubular complexes. The results raise the question whether the transdifferentiated cells in the tubular complexes of patients with chronic pancreatitis are more susceptible to carcinogenic influences, resulting in the increased rate of pancreatic cancer. (Lab Invest 2003, 83:853-859).

No abstract