Cancer-associated stromal fibroblasts (CAFs) are the main cellular constituents of reactive stroma in primary and metastatic cancer. We analyzed phenotypical characteristics of CAFs from human colorectal liver metastases (CLMs) and their role in inflammation and cancer progression. CAFs displayed a vimentin ؉ , ␣-smoothmuscle actin ؉ , and Thy-1 ؉ phenotype similar to resident portal-located liver fibroblasts (LFs). We demon-

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human tumors, with radical surgical resection as the only curative treatment option. However, resection is only possible in a small fraction of patients, and about 80% of the patients develop recurrencies. PDAC development is facilitated by the cytokine interleukin-6 (IL-6), which acts via classic and transsignaling. Both pathways are inhibited by the anti-IL-6-receptor antibody tocilizumab, whereas the fusion protein sgp130Fc specifically blocks trans-signaling. Here, we show that conservative or adjuvant therapy with both inhibitors reduces tumor growth in an orthotopic model of human Colo357 cells in SCID/bg mice. In the conservative setting, median primary tumor weight was reduced 2.4-fold for tocilizumab and 4.4-fold for sgp130Fc. sgp130Fc additionally led to a decrease in microvessel density, which was not observed with tocilizumab. In the adjuvant therapeutic setting after surgical resection of the primary tumor, treatment with tocilizumab or sgp130Fc decreased the local recurrence rate from 87.5% in the control group to 62.5 or 50%, respectively. Furthermore, the median weight of the local recurrent tumors was clearly diminished, and both inhibitors reduced the number of distant metastases. A significant reduction of tumor weight and metastases-comparable to gemcitabine treatment-was also observed with both inhibitors in another model using the poorly differentiated PancTuI cells. Our findings demonstrate the inhibition of IL-6 as a new treatment option in PDAC.

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Green tea catechins are considered as possible cancer preventive agents for several cancer types but little is known regarding their effects on pancreatic cancer cells. The best studied catechin and the major polyphenol present in green tea is epigallocatechin gallate (EGCG). In the present study, we investigated the in vitro anti-tumoral properties of EGCG on human pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in comparison with the effects of two minor components of green tea catechins, catechin gallate (CG) and epicatechin gallate (ECG). We found that all three catechins inhibited proliferation of PDAC cells in a dose-and time-dependent manner. Interestingly, CG and ECG exerted much stronger anti-proliferative effects than EGCG. Western blot analyses performed with PancTu-I cells revealed catechin-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases [CDK], CDK inhibitors). Again, these effects were clearly more pronounced in CG or ECG than in EGCG-treated cells. Importantly, catechins, in particular ECG, inhibited TNFa-induced activation of NF-jB and consequently secretion of pro-inflammatory and invasion promoting proteins like IL-8 and uPA. Overall, our data show that green tea catechins ECG and CG exhibit potent and much stronger anti-proliferative and anti-inflammatory activities on PDAC cells than the most studied catechin EGCG. (Cancer Sci 2011; 102: 728-734) P ancreatic ductal adenocarcinoma (PDAC) is the 10th most commonly diagnosed cancer, but it has the fourth highest mortality rate among all cancer-related deaths in the US. Since 1975 long-term survival rates have improved only marginally and are currently around 5%.(1) The poor prognosis of PDAC is attributed to an aggressive cancer progression with a high invasive and metastatic potential. Conventional chemotherapy and radiotherapy are still largely ineffective in improving pancreatic cancer and surgical resection has only limited benefits because of a high rate of recurrent disease.(2) Recently, we have shown in a murine orthotopic xenotransplantation model that tumor recurrence and metastasis after surgical resection of PDAC is substantially driven by tumor cell-derived, tumor necrosis factor a (TNFa).(3) Furthermore, we showed a significant contribution of endogenous TNFa to the growth and invasiveness of primary PDAC tumors. We proposed that TNF-inhibiting drugs, infliximab and etanercept, which are broadly used for the treatment of chronic inflammatory diseases, will also be beneficial in PDAC treatment, especially after subtotal pancreaticoduodenectomy.Plant phytochemicals like quercetin, resveratrol and catechins are some examples of alternative chemotherapeutics being extensively tested for their anti-tumoral and anti-inflammatory potential. (4,5) Catechins are polyphenols present in green and black tea, red wine and chocolate. Catechins, which mainly occur in green tea, comprise epigallocatechin gallate (EGCG), epicatechin (EC), gallocatechin (GC), epigallocatechin ...