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Cytoskeleton‐associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1–CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti‐CKAP4 antibodies were generated based on an original mouse antibody (3F11‐2B10) and inhibited DKK1–CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11‐2B10. From the 3F11‐2B10 nucleotide sequence, humanized anti‐CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11‐2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11‐2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti‐tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti‐cancer therapy. [ABSTRACT FROM AUTHOR]

This study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate‐risk stage I and II or high‐risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel‐epirubicin‐carboplatin (TEC), paclitaxel‐anthracycline (doxorubicin)‐carboplatin (TAC), or dose‐dense paclitaxel‐carboplatin (ddTC). The primary end‐point was the completion rate (CRate) of six cycles of treatment. The secondary end‐points were progression‐free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P =.005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2‐year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911). [ABSTRACT FROM AUTHOR]

Wnt5b is a member of the same family of proteins as Wnt5a, the overexpression of which is associated with cancer aggressiveness. Wnt5b is also suggested to be involved in cancer progression, however, details remain unclarified. We analyzed the biochemical properties of purified Wnt5b and the mode of secretion of Wnt5b by cancer cells. Wnt5b was glycosylated at three asparagine residues and lipidated at one serine residue, and these post-translational modifications of Wnt5b were essential for secretion. Purified Wnt5b showed Dvl2 phosphorylation and Rac activation abilities to a similar extent as Wnt5a. In cultured-cell conditioned medium, Wnt5b was detected in supernatant or precipitation fractions that were separated by centrifugation at 100 000 g. In PANC-1 pancreatic cancer cells, 55% of secreted endogenous Wnt5b was associated with exosomes. Exosomes from wild-type PANC-1 cells, but not those from Wnt5b-knockout PANC-1 cells, activated Wnt5b signaling in CHO cells and stimulated migration and proliferation of A549 lung adenocarcinoma cells, suggesting that endogenous, Wnt5b-associated exosomes are active. The exosomes were taken up by CHO cells and immunoelectron microscopy revealed that Wnt5b is indeed associated with exosomes. In Caco-2 colon cancer cells, most Wnt5b was recovered in precipitation fractions when Wnt5b was ectopically expressed (Caco-2/Wnt5b cells). Knockdown of TSG101, an exosome marker, decreased the secretion of Wnt5b-associated exosomes from Caco-2/Wnt5b cells and inhibited Wnt5b-dependent cell proliferation. Exosomes secreted from Caco-2/Wnt5b cells stimulated migration and proliferation of A549 cells. These results suggest that Wnt5b-associated exosomes promote cancer cell migration and proliferation in a paracrine manner. [ABSTRACT FROM AUTHOR]

This article has been retracted at the request of Editor-in-Chief & Author. The following article from Cancer Science: Mariko Tomita, Zahidunnabi Dewan, Naoki Yamamoto, Akira Kikuchi and Naoki Mori. Epstein-Barr virus-encoded latent membrane protein 1 activates β-catenin signaling in B lymphocytes, Cancer Science 2009; : 807-812, (doi: ), published online on 20 March 2009 on Wiley Interscience (), now Wiley Online Library (), has been retracted by agreement between the authors, the journal Editor-in-Chief, Yusuke Nakamura, and Blackwell Publishing Asia Pty Ltd. All authors wish to retract this paper due to repeated use of images in the same gel in two figures within the article. Yusuke Nakamura Editor-in-Chief Cancer Science [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus-encoded latent membrane protein 1 is considered the Epstein-Barr virus oncogene based on its importance in Epstein-Barr virus-induced B-lymphocyte transformation. Beta-catenin is a potential oncogene, and its accumulation has been implicated in a variety of human cancers. Here, we found that beta-catenin protein was highly expressed in Epstein-Barr virus-immortalized B-cell lines compared with peripheral blood mononuclear cells from healthy donors. Beta-catenin expression in Epstein-Barr virus-immortalized B-cell line decreased following treatment with LY294002, an inhibitor of phosphatidylinositol 3-kinase. Treatment with LY294002 or knockdown of beta-catenin by small interfering RNA reduced the growth of Epstein-Barr virus-immortalized B-cell line. Transient transfection of latent membrane protein 1 expression plasmid increased beta-catenin protein expression and beta-catenin-dependent transcription. Latent membrane protein 1 deletions mutants lacking the carboxyl-terminal activating region 1 domain failed to enhance beta-catenin protein expression and beta-catenin-dependent transcriptional activity. They also failed to increase phosphorylated AKT expression. Dominant-negative AKT suppressed latent membrane protein 1-induced beta-catenin-dependent transcriptional activity. These results suggest that latent membrane protein 1 activates beta-catenin through the phosphatidylinositol 3-kinase/AKT signaling pathway. Activation of the beta-catenin pathway by Epstein-Barr virus may contribute to the lymphoproliferation characteristic of Epstein-Barr virus-infected B-cells.

Wnt signaling is a complex pathway in which beta-catenin is typically viewed as a central mediator in regulating cell proliferation and differentiation. The significance of Wnt signaling in human cancer has been elucidated by the identification of mutations in genes coding for the beta-catenin-dependent pathway components, adenomatous polyposis coli gene product, beta-catenin, and Axin. Within the past 15 years, evidence has been growing of a beta-catenin-independent pathway in Wnt signaling. It is likely that this pathway activates several intracellular signaling systems to regulate cell migration, adhesion, and polarity. The beta-catenin-independent pathway has also been shown to play an important role in tumor biology. In contrast to the beta-catenin-dependent pathway, which is upregulated in many cancers and serves as a tumor promoter, the role of the beta-catenin-independent pathway is still controversial. Here we review recent developments in both the functions and mechanisms of the beta-catenin-independent pathway, with an emphasis on its functional contribution to human tumor progression.