Cancer Science

A murine (mAHM) and a humanized (AHM) monoclonal antibody against CD317 (also called tetherin, BST2, or HM1.24 antigen), expressed preferentially in neoplastic B cells such as multiple myeloma, exhibited antitumor effects as a result of antibody‐dependent cellular cytotoxicity (ADCC). The putative interferon (IFN) response elements IRF‐1/2 and ISGF3 are present in the promoter of the CD317 gene, and IFN has been used for the treatment of not only myeloproliferative diseases but also solid tumors such as renal cell carcinoma (RCC) and melanoma. Therefore, we examined the effects of IFN on the expression of CD317 and on the antitumor activity of AHM and mAHM in RCC and melanoma. Flow cytometry and in vitro ADCC assays with human or mouse effector cells demonstrated that IFN‐α markedly increased the amount of cell surface CD317 and augmented the ADCC activity of mAHM and AHM in RCC cells and to a lesser extent in melanoma cells. Administration of IFN‐α to mice bearing RCC xenografts also increased the expression of CD317 in tumor cells. When coadministered with IFN‐α, mAHM exhibited more profound antitumor activity in both IFN‐α‐sensitive and ‐insensitive RCC xenograft models. Thus, AHM in combination with IFN‐α may be an effective therapy for the treatment of RCC. (Cancer Sci 2008; 99: 2461–2466)

Animal models provide researchers with powerful tools to elucidate multistage mechanisms for cancer development and to gain further insights into the biological roles of various cancer‐related genes in in vivo situations. As for colon cancer models in rodents, Apc‐disrupted mice, including Apc^Min, have been one of the most widely utilized animal models to dissect the molecular events implicated in the development of intestinal tumors. In rats, several models have been established using chemical carcinogens, including azoxymethane and 2‐amino‐1‐methyl‐6‐phenylimidazo‐ [4,5‐b]pyridine (PhIP). The former is a representative colon carcinogenic alkylating agent, and the latter a heterocyclic amine produced while cooking meat and fish, which people are exposed to in ordinary life. It is of great importance to note that PhIP preferentially targets the colon and prostate gland in male rats, and the mammary glands in female rats. Cancers in these three organs are common in Western countries and are currently increasing in Japan, where modern dietary habits are rapidly becoming more like those of the West. In the present article, the history of PhIP‐induced colon cancer models in rodents, activation/detoxification mechanisms of PhIP with regard to the formation of PhIP‐DNA adducts, mechanistic approaches to dissect the molecular events involved in the development of colon cancer by PhIP, and epidemiological evidence of human exposure to PhIP are overviewed. The induction of Paneth cell maturation/differentiation in PhIP‐induced colon cancers, genetic traits affecting susceptibility to colon carcinogenesis, and the biological relevance of colon cancer models in rodents to studying human colon carcinogenesis are also discussed. (Cancer Sci 2005; 96: 627 – 633)

Stearoyl‐CoA desaturase‐1 (SCD1) is an endoplasmic reticulum anchored enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly palmytoleyl‐CoA and oleyl‐CoA. Recent studies have revealed a function for SCD1 in the modulation of signaling processes related to cell proliferation, survival and transformation to cancer. We used MCF7 and MDA‐MB‐231 cells to analyze the role of SCD1 in the metastatic acquisition of breast cancer cells. Silencing SCD1 expression in breast cancer cells has no effect on cell viability but the levels of cell proliferation, cell cycle genes' expressions and the phosphorylation state of ERK1/2 MAPK are significantly reduced. Decreasing SCD1 expression also reduces the level of GSK3 phosphorylation, indicating higher activity of the kinase. Using cells fractionation, immunofluorescence and a β‐catenin/TCF‐responsive reporter construct, we demonstrate that lowering SCD1 expression leads to a decrease of β‐catenin amounts within the nucleus and to inhibition of its transactivation capacity. Moreover, MDA‐MB‐231 cells transfected with the SCD1 siRNA show a lower invasive potential than the control cells. Taken together, our data demonstrate that low SCD1 expression is associated with a decrease in the proliferation rate of breast cancer cells associated with a decrease in ERK1/2 activation. SCD1 silencing also inhibits GSK3 phosphorylation, lowering β‐catenin translocation to the nucleus, and, subsequently, its transactivation capacity and the expression of its target genes. Finally, we show that silencing SCD1 impairs the epithelial to mesenchymal transition‐like behavior of the cells, a characteristic of metastatic breast cancer. (Cancer Sci 2013; 104: 36–42)

The genetics of development and cancer have converged in the identification of intra‐ and extra‐cellular signaling pathways that are aberrantly regulated in cancer, and are also central to embryonic patterning. The Wnt signaling pathway has provided an outstanding example of this. The genes for β‐catenin, ARC, and Axin in the Wnt signaling pathway are often mutated in human cancers. In all such cases, the common denominator is the activation of gene transcription by β‐catenin. The resulting gene expression profile should provide a significant clue to the developmental mechanisms of cancers carrying defects in the Wnt signaling pathway. In this review, the functions of β‐catenin, APC and Axin, and the alterations of the three genes in human cancers are described. (Cancer Sci 2003; 94: 225–229)

The association between schizophrenia and cancer risk is contentious in the clinical and epidemiological literature. Studies from different populations, tumor sites, or health care systems have provided inconsistent findings. In the present study, we examined a less well‐investigated hypothesis that age plays a crucial role in cancer risk in schizophrenia. We conducted a nationwide cohort study using Taiwan's National Health Insurance Research Database (NHIRD) between 1995 and 2007. Overall, gender‐, and age‐stratified standardized incidence ratios (SIR) were used to investigate the pattern of cancer risk by age. Of the 102 202 schizophrenic patients, 1738 developed cancer after a diagnosis of schizophrenia (SIR = 0.92; 95% confidence interval [CI] 0.90–0.96). However, the age‐stratified SIR declined with age (e.g. SIR [95% CI] = 1.97 [1.85–2.33], 0.68 [0.65–0.78], and 0.36 [0.34–0.45] for those aged 20–29, 60–69, and ≥70 years, respectively) in both genders and for major cancers. Cancer risks in schizophrenic patients were lower for cancers that are more likely to develop at an older age in the general population (e.g. stomach cancer [SIR = 0.62; 95% CI 0.57–0.80], pancreatic cancer [SIR = 0.49; 95% CI 0.39–0.84], and prostate cancer [SIR = 0.35; 95% CI 0.29–0.58]). In contrast, cancer risks were higher for cancers that have a younger age of onset, such as cancers of the nasopharynx (SIR = 1.18; 95% CI 1.08–1.49), breast (SIR = 1.50; 95% CI 1.44–1.66) and uterine corpus (SIR = 2.15; 95% CI 1.98–2.74). The unique age structures and early aging potential of schizophrenia populations may contribute to the observed inverse relationship between age and cancer risk. Higher cancer comorbidity in young schizophrenic patients deserves more attention.

DNA‐targeting agents, including cisplatin, bleomycin and mitomycin C, are used routinely in cancer treatments. However, these drugs are extremely toxic, attacking normal cells and causing severe side effects. One important question to consider in designing anticancer agents is whether the introduction of sequence selectivity to DNA‐targeting agents can improve their efficacy as anticancer agents. In the present study, the growth inhibition activities of an indole‐seco 1,2,9,9a‐tetrahydrocyclopropa[1,2‐c]benz[1,2‐e]indol‐4‐one (CBI) (1) and five conjugates with hairpin pyrrole‐imidazole polyamides (2–6), which have different sequence specificities for DNA alkylation, were compared using 10 different cell lines. The average values of – log GI₅₀ (50% growth inhibition concentration) for compounds 1–6 against the 10 cell lines were 8.33, 8.56, 8.29, 8.04, 8.23 and 8.83, showing that all of these compounds strongly inhibit cell growth. Interestingly, each alkylating agent caused significantly different growth inhibition patterns with each cell line. In particular, the correlation coefficients between the – log GI₅₀ of compound 1 and its conjugates 2–6 showed extremely low values (R < 0). These results suggest that differences in the sequence specificity of DNA alkylation lead to marked differences in biological activity. Comparison of the correlation coefficients between compounds 6 and 7, with the same sequence specificity as 6, and MS‐247, with sequence specificity different from 6, when used against a panel of 37 human cancer cell lines further confirmed the above hypothesis. (Cancer Sci 2006; 97: 219–225)

Transforming growth factor (TGF)‐β signaling facilitates tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF‐β signaling may thus be a novel strategy for the treatment of patients with such cancer. In this study, we synthesized and characterized a small molecule inhibitor, A‐83‐01, which is structurally similar to previously reported ALK‐5 inhibitors developed by Sawyer et al. (2003) and blocks signaling of type I serine/threonine kinase receptors for cytokines of the TGF‐β superfamily (known as activin receptor‐like kinases; ALKs). Using a TGF‐β‐responsive reporter construct in mammalian cells, we found that A‐83‐01 inhibited the transcriptional activity induced by TGF‐β type I receptor ALK‐5 and that by activin type IB receptor ALK‐4 and nodal type I receptor ALK‐7, the kinase domains of which are structurally highly related to those of ALK‐5. A‐83‐01 was found to be more potent in the inhibition of ALK5 than a previously described ALK‐5 inhibitor, SB‐431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF‐β. In contrast, A‐83‐01 had little or no effect on bone morphogenetic protein type I receptors, p38 mitogen‐activated protein kinase, or extracellular regulated kinase. Consistent with these findings, A‐83‐01 inhibited the epithelial‐to‐mesenchymal transition induced by TGF‐β, suggesting that A‐83–01 and related molecules may be useful for preventing the progression of advanced cancers. (Cancer Sci 2005; 96: 791–800)

Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non‐coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA‐21 (miR‐21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR‐21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti‐miR‐21 oligonucleotide (AMO‐miR‐21) to sensitize K562 cells to ATO by degradation of miR‐21. The results showed that both AMO‐miR‐21 and ATO caused growth inhibition, apoptosis, and G1‐phase arrest in K562 cells. Meanwhile, AMO‐miR‐21 significantly promoted ATO‐mediated growth inhibition and apotosis without affecting the G1 phase. Apoptotic cells were confirmed morphologically with Giemsa’s staining. Furthermore, dual‐luciferase reporter vector, containing two tandem miR‐21 binding sites from PDCD4 3′UTR, validated that PDCD4 was directly regulated by miR‐21. Therefore, AMO‐miR‐21 sensitized leukemic K562 cells to ATO by inducing apoptosis partially due to its up‐regulation of PDCD4 protein level. The combination of ATO and AMO‐miR‐21 present therapeutic potential for CML.

(Cancer Sci 2010; 101: 948–954)

Reactive oxygen species (ROS), a class of highly bioactive molecules, have been widely studied in various types of cancers. ROS are considered to be normal byproducts of numerous cellular processes. Typically, cancer cells exhibit higher basal levels of ROS compared with normal cells as a result of an imbalance between oxidants and antioxidants. ROS have a dual role in cell metabolism: At low to moderate levels, ROS act as signal transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death. Extensive studies have revealed that anticancer therapies that manipulate ROS levels, including immunotherapies, show promising in vitro as well as in vivo results. In this review, we summarize molecular mechanisms and oncogenic functions that modulate ROS levels and are useful for the development of cancer therapeutic strategies. This review also provides insights into the future development of effective agents that regulate the redox system for cancer treatment.

Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is the T315I mutation against which neither nilotinib nor dasatinib show significant activity. In the present study, we investigated the activity of a novel Aurora kinase inhibitor, VE‐465, against leukemia cells expressing wild‐type BCR‐ABL or the T315I mutant form of BCR‐ABL. We observed a dose‐dependent reduction in the level of BCR‐ABL autophosphorylation in VE‐465‐treated cells. Exposure to the combination of VE‐465 and imatinib exerted an enhanced apoptotic effect in K562 cells. Combined treatment with VE‐465 and imatinib caused more attenuation of the levels of phospho‐AKT and c‐Myc in K562 cells. Further, the isobologram indicated the synergistic effect of simultaneous exposure to VE‐465 and imatinib in K562 cells. To assess the in vivo efficacy of VE‐465, athymic nude mice were injected intravenously with BaF3 cells expressing wild‐type BCR‐ABL or the T315I mutant form. The vehicle‐treated mice died of a condition resembling acute leukemia by 28 days; however, nearly all mice treated with VE‐465 (75 mg/kg, twice daily; intraperitoneally for 14 days) survived for more than 56 days. Histopathological analysis of vehicle‐treated mice revealed infiltration of the spleen. In contrast, histopathological analysis of organs from VE‐465‐treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE‐465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild‐type BCR‐ABL‐expressing cells in an efficacious manner. (Cancer Sci 2008; 99: 1251–1257)