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Takebe N.,U.S. National Cancer Institute | Miele L.,Louisiana State University | Harris P.J.,U.S. National Cancer Institute | Jeong W.,Cancer Therapy and Research Center | And 4 more authors.
Nature Reviews Clinical Oncology

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents. © 2015 Macmillan Publishers Limited. Source

Mukai H.,National Cancer Center Hospital East
International Journal of Clinical Oncology

HER2-positive tumors account for approximately 18-20%of all breast cancers. These tumors tend to be more aggressive than HER2-negative tumors and are associated with a poorer prognosis. HER2 overexpression, as determined by either 3+ immunohistochemical staining for HER2 protein or HER2 gene amplification by fluorescence in situ hybridization, should be used to select patients for anti-HER2 therapy. Trastuzumab-containing regimens as first-line therapy should be recommended to women with HER2-positive metastatic breast cancer. The continuation of trastuzumab plus capecitabine provided a significant clinical benefit compared with capecitabine alone in women who experienced progression during trastuzumab treatment. An adjuvant trastuzumab-containing regimen should be also recommended to all intermediate- or high-risk women with HER2-positive early breast cancer. Cardiac function should be serially monitored during this treatment. Many anti- HER2 drugs against breast cancer are being developed. The basic mechanisms of their action and resistance emergence are being clarified step by step. Over the mid- or long term, clinical trials comparing these drugs will be conducted until drugs that are clinically effective and easy to use in the true sense survive. Biomarkers are being aggressively searched for concerning individual drugs under development. A position of the ''proper drug for the proper patient'' will be more firmly established. © Japan Society of Clinical Oncology 2010. Source

Tsukasaki K.,National Cancer Center Hospital East | Tobinai K.,National Cancer Center Hospital
Clinical Cancer Research

Adult T-cell leukemia-lymphoma (ATL) is a distinct malignancy of regulatory T cell (Treg)/TH2 cells caused by human T-cell lymphotropic virus type I (HTLV-1), with a high frequency of expression of CD3/CD4/CD25/CCR4 and FoxP3 in about half of the cells. However, in primary ATL cells, although expression of the virus, including the Tax oncoprotein, appears just after an in vitro culture, integration sites of the provirus into the host genome are random, and chromosomal/genetic abnormalities are complex. ATL is thus a single disease entity that is caused by HTLV-1 and possesses diverse molecular features. The clinical features and prognosis of ATL vary, and this has led to subtypes classified into four categories: acute, lymphomatous, chronic, and smoldering types, based on lactate dehydrogenase and calcium values and organ involvement. Approximately 15 to 20 million individuals are infected with HTLV-1 worldwide, 1.1 million of whom reside in Japan, and the annual incidence of ATL has been estimated to be approximately 1,000. HTLV-1 infection early in life, mainly from breast feeding, is crucial for the development of ATL. The age-specific occurrence of ATL and complex genome abnormalities that accumulate with disease progression suggest a multistep carcinogenesis model following HTLV-1 infection. Various treatment options are available for ATL and consist of watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation for aggressive ATL, and a combination of IFNα and zidovudine for ATL with leukemic manifestation. Several promising new agents, including an anti-CCR4 antibody, are currently undergoing clinical trials associated with translational research. ©2014 AACR. Source

Ikeda M.,National Cancer Center Hospital East
Japanese Journal of Clinical Oncology

In patients undergoing chemotherapy for the treatment of malignant disease, the reactivation of hepatitis B virus in hepatitis B surface antigen-positive patients has been frequently reported. However, activation has also been reported in hepatitis B surface antigen-negative patients who test positive for hepatitis B core antibody and/or hepatitis B surface antibody, who were thought to have had transient infections and to have been cured. Reactivation has often been reported in patients receiving rituximab-containing regimens and has attracted a lot of attention in recent years. In Japan, 1-3%3of patients undergoing chemotherapy are hepatitis B surface antigen-positive, and ~20-25% of patients are hepatitis B surface antigen-negative with hepatitis B core antibody and/or hepatitis B surface antibody positivity; therefore, about one out of every four patients undergoing chemotherapy may be at risk for the reactivation of hepatitis B virus. In most of the guidelines for hepatitis B virus reactivation, the prophylactic administration of an antiviral drug in hepatitis B surface antigen-positive patients is recommended, and periodic monitoring of hepatitis B virus DNA and the deferred pre-emptive administration of an antiviral drug after conversion to hepatitis B virus DNA positivity are recommended in hepatitis B surface antigen-negative patients who are hepatitis B core antibody-positive and/or hepatitis B surface antibody-positive when chemotherapy has been scheduled. However, numerous issues regarding hepatitis B virus reactivation, including the frequency, the types of anticancer drugs, the cancers that facilitate hepatitis B virus reactivation and the optimal method of management, etc., have not been fully clarified. A variety of well-designed prospective studies are currently under way in both Japan and abroad, and strong evidence of hepatitis B virus reactivation following chemotherapy is anticipated in the future. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

Saegusa M.,Kitasato University | Hashimura M.,Kitasato University | Kuwata T.,National Cancer Center Hospital East
Laboratory Investigation

Sox factors function as either activators or repressors of β-catenin/TCF transcription depending on the cellular context and associated interacting proteins. Our previous study provided evidence that alteration in β-catenin signaling is an essential event during transdifferentiation toward the morular phenotype of endometrial carcinomas (Em Cas). Here, we focused on related functional roles of Sox factors. Of eight Sox factors investigated, Sox4 could enhance β-catenin/TCF4 transcription, through upregulation of TCF4 at the transcription level, without any direct β-catenin association. Cells stably overexpressing Sox4 showed significant decreases in proliferation rate, along with increases in expression of p21 WAF1, as well as TCF4, in contrast to increased cell growth observed with knockdown. Of these factors, only Sox7 could transcriptionally upregulate Sox4 expression, but it also resulted in not only inhibition of Sox4-meditated activation of β-catenin/TCF4-driven transcription, but also repression of its own promoter activity, indicating the existence of very complex feedback loop for Sox-mediated signal cascades. Finally, Sox4 immunoreactivity was frequently pronounced in morular lesions of Em Cas, the expression being positively correlated with status of β-catenin, TCF4, and Sox7, and inversely with cell proliferation. These data therefore suggest that Sox4 may serve as a positive regulator of β-catenin signaling through alteration in TCF4 expression during morular differentiation of Em Ca cells, leading to inhibition of cell proliferation. In addition, Sox7 may also participate in the process, having complex roles in modulation of signaling. © 2012 USCAP, Inc All rights reserved. Source

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