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Since the first report in 1976, accumulated clinical evidence has supported intravesical Bacillus Calmette-Guerin (BCG) therapy as one of the standard methods of management of intermediateand high-risk non-muscle invasive bladder cancer. Despite its efficacy, intravesical BCG therapy is associated with a variety of adverse events (AEs), most of which are tolerable or controllable with supportive care. However, some patients receiving intravesical BCG therapy may experience uncommon but severe AEs, leading to cessation of BCG therapy. Not all, but most severe AEs result from either local or systemic infection with live BCG. Intravesical instillation of BCG elicits multiple immune reactions, although the precise immunological mechanism of BCG therapy is not clear. It is convenient to separate the complex reactions into the following three categories: infection of urothelial cells or bladder cancer cells, induction of immune reactions, and induction of antitumor effects. Recently, our knowledge about each category has increased. Based on this understanding, predictors of the efficacy of intravesical BCG therapy, such as urinary cytokine measurement and cytokine gene polymorphism, have been investigated. Recently, preclinical studies using a novel engineered mycobacterium vaccine have been conducted to overcome the limitations of BCG therapy. One approach is Th1 cytokineexpressing recombinant forms of BCG; another approach is development of non-live bacterial agents to avoid AEs due to live BCG infection. We also briefly describe our approach using an octaarginine-modified liposome-incorporating BCG cell wall component to develop future substitutes for live BCG. (Cancer Sci 2013; 104: 22-27) I ntravesical Bacillus Calmette-Guerin (BCG) therapy is undoubtedly the most successful immunotherapy for cancer.(1) In 1976, Morales et al.(2) reported the prophylactic effect of topical application of live BCG to the bladder to prevent bladder cancer recurrence. In the original protocol, 120 mg BCG diluted with 50 mL saline was instilled into the bladder via a urethral catheter with an indwelling time of 2 h and was repeated once a week for 6 weeks. Since then, intravesical BCG therapy has been widely used and is recognized as a standard method of management of intermediate-and high-risk non-muscle invasive bladder cancer, although the optimal schedule and duration are still being tested. Despite its efficacy, intravesical BCG therapy is not free from severe and possibly fatal complications due to the use of live BCG. However, the precise immunological mechanism of BCG therapy is not clear, and understanding the immune responses induced by BCG is needed to develop a more active and less toxic immunotherapy. In this review, we summarize basic and clinical information about intravesical BCG therapy, and also describe the prospect of an engineered mycobacterium vaccine. Current clinical use of intravesical BCG therapyAt initial diagnosis, approximately 70% of bladder cancer patients are diagnosed with non-muscle invasive blad...

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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