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Fei Xing,
Aya Kobayashi,
Hiroshi Okuda,
Misako Watabe,
Sudha K Pai,
Puspa R Pandey,
Shigeru Hirota,
Andrew Wilber,
Yin-Yuan Mo,
Brian E Moore,
Wen Liu, Koji Fukuda,
Megumi Iiizumi,
Sambad Sharma,
Yin Liu,
Kerui Wu,
Elizabeth Peralta,
Kounosuke Watabe
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ABSTRACT: Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then 'activated' surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.
EMBO Molecular Medicine 03/2013; 5(3):384-396. · 10.33 Impact Factor
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ABSTRACT: Persistent foramen tympanicum (Huschke) is an anatomical variation located in the anteroinferior portion of the external auditory canal. We present a case of symptomatic temporomandibular joint (TMJ) herniation into the external auditory canal though an enlarged osseous defect. The herniated retrodiscal TMJ tissue moved backward when the patient's mouth was closed, and forward, when opened. Magnetic resonance imaging findings were useful for differentiating TMJ herniation from salivary fistula caused by an ectopic salivary gland.
Journal of computer assisted tomography 01/2013; 37(1):111-3. · 1.38 Impact Factor
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ABSTRACT: Fatty acid synthase (FAS) is a key enzyme of the fatty acid biosynthetic pathway which catalyzes de novo lipid synthesis. FAS expression in normal adult tissues is generally very low or undetectable as majority of fatty acids obtained are from dietary sources, whereas it is significantly upregulated in cancer cells despite adequate nutritional lipid supply. Activation of FAS provides rapidly proliferating tumor cells sufficient amount of lipids for membrane biogenesis and confers growth and survival advantage possibly acting as a metabolic oncogene. Importantly, inhibition of FAS in cancer cells using the pharmacological FAS inhibitors results in tumor cell death by apoptosis whereas normal cells are resistant. Due to this differential expression of FAS, the inhibitors of this enzyme are selectively toxic to tumor cells and therefore FAS is considered an attractive therapeutic target for cancer. Several FAS inhibitors are already patented and commercially available; however, the potential toxicity of these FAS inhibitors remains to be tested in clinical trials. In this review, we discuss some of the potent FAS inhibitors along with their patent information, the mechanism of anti-cancer effects and the development of more specific and potent FAS inhibitors with lower side effects that are expected to emerge as anti-cancer treatment in the near future.
Recent patents on anti-cancer drug discovery. 02/2012; 7(2):185-97.
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Wen Liu,
Fei Xing,
Megumi Iiizumi-Gairani,
Hiroshi Okuda,
Misako Watabe,
Sudha K Pai,
Puspa R Pandey,
Shigeru Hirota,
Aya Kobayashi,
Yin-Yuan Mo, Koji Fukuda,
Yi Li,
Kounosuke Watabe
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ABSTRACT: Wnt signalling has pivotal roles in tumour progression and metastasis; however, the exact molecular mechanism of Wnt signalling in the metastatic process is as yet poorly defined. Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG-/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients. Collectively, we have identified NDRG1 as a novel negative master regulator of Wnt signalling during the metastatic progression, which opens an opportunity to define a potential therapeutic target for metastatic disease.
EMBO Molecular Medicine 02/2012; 4(2):93-108. · 10.33 Impact Factor
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ABSTRACT: The tumor progression is not only regulated by metastasis promoting and suppressing genes in cancer cells but it is also strongly influenced by the interaction between cancer cells and the stromal cells. An abundance of inflammatory mediators and leukocytes has been known to promote cancer metastasis, and tumor associated macrophages (TAM) are the key players in the link between inflammation and cancer. TAM are derived from peripheral blood monocytes that are recruited into the tumor by inflammatory chemokines. Upon activation by cancer cells, TAM gain the ability of pro-tumoral functions including expression of various growth factors, promotion of angiogenesis and suppression of adaptive immunity, and many of these factors also play critical roles in cancer metastasis. In this review, we will summarize the recent information about the function of TAM in the inflammatory micro-environment of solid tumors and discuss the potential targets for future therapeutic approaches.
Frontiers in bioscience (Scholar edition) 01/2012; 4:787-98.
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Aya Kobayashi,
Hiroshi Okuda,
Fei Xing,
Puspa R Pandey,
Misako Watabe,
Shigeru Hirota,
Sudha K Pai,
Wen Liu, Koji Fukuda,
Christopher Chambers,
Andrew Wilber,
Kounosuke Watabe
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ABSTRACT: Metastatic disease is the major cause of cancer deaths, and recurrent tumors at distant organs are a critical issue. However, how metastatic tumor cells become dormant and how and why tumors recur in target organs are not well understood. In this study, we demonstrate that BMP7 (bone morphogenetic protein 7) secreted from bone stromal cells induces senescence in prostate cancer stem-like cells (CSCs) by activating p38 mitogen-activated protein kinase and increasing expression of the cell cycle inhibitor, p21, and the metastasis suppressor gene, NDRG1 (N-myc downstream-regulated gene 1). This effect of BMP7 depended on BMPR2 (BMP receptor 2), and BMPR2 expression inversely correlated with recurrence and bone metastasis in prostate cancer patients. Importantly, this BMP7-induced senescence in CSCs was reversible upon withdrawal of BMP7. Furthermore, treatment of mice with BMP7 significantly suppressed the growth of CSCs in bone, whereas the withdrawal of BMP7 restarted growth of these cells. These results suggest that the BMP7-BMPR2-p38-NDRG1 axis plays a critical role in dormancy and recurrence of prostate CSCs in bone and suggest a potential therapeutic utility of BMP7 for recurrent metastatic disease.
Journal of Experimental Medicine 11/2011; 208(13):2641-55. · 13.85 Impact Factor
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Hiroshi Okuda,
Aya Kobayashi,
Bo Xia,
Misako Watabe,
Sudha K Pai,
Shigeru Hirota,
Fei Xing,
Wen Liu,
Puspa R Pandey, Koji Fukuda,
Vishnu Modur,
Arnab Ghosh,
Andrew Wilber,
Kounosuke Watabe
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ABSTRACT: The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here, we report that upregulation of hyaluronan synthase 2 (HAS2) occurs in highly metastatic breast cancer stem-like cells (CSC) defined by CD44(+)/CD24(-)/ESA(+) phenotype, where it plays a critical role in the generation of a prometastatic microenvironment in breast cancer. HAS2 was critical for the interaction of CSCs with tumor-associated macrophages (TAM), leading to enhanced secretion of platelet-derived growth factor-BB from TAMs, which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone, an inhibitor of HAS, which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings show a critical role of HAS2 in the development of a prometastatic microenvironment and suggest that HAS2 inhibitors can act as antimetastatic agents that disrupt a paracrine growth factor loop within this microenvironment.
Cancer Research 11/2011; 72(2):537-47. · 7.86 Impact Factor
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ABSTRACT: The effect of proton pump inhibitors (PPIs) on the health-related quality of life (HRQoL) of patients with laryngopharyngeal reflux disease (LPRD) is not well known. Our aim was to assess the HRQoL before and after administration of a PPI in patients with LPRD.
A total of 27 LPRD patients (14 women, 13 men; mean age 54 years) were enrolled. We determined the HRQoL using three different inquiry systems: 1) Frequency Scale for the Symptoms of GERD (FSSG); 2) the 36 item short form of the Medical Outcome Study Questionnaire (SF-36); and 3) the Gastrointestinal Symptom Rating Scale (GSRS). The HRQoL was determined at baseline and after eight weeks of treatment with lansoprazole at a dose of 30mg once daily or rabeprazole at a dose of 10mg once daily.
After administration of the PPI, the FSSG, the SF-36 general health scale and mental health scale, GSRS reflux syndrome score, abdominal pain syndrome score and the indigestion syndrome score were significantly improved compared to baseline pretreatment scores (p<0.05).
PPI therapy would be useful for the treatment of LPRD.
Hepato-gastroenterology 07/2011; 58(110-111):1580-2. · 0.66 Impact Factor
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Wen Liu,
Eiji Furuta,
Kazutoshi Shindo,
Misako Watabe,
Fei Xing,
Puspa R Pandey,
Hiroshi Okuda,
Sudha K Pai,
Laura L Murphy,
Deliang Cao,
Yin-Yuan Mo,
Aya Kobayashi,
Megumi Iiizumi, Koji Fukuda,
Bo Xia,
Kounosuke Watabe
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ABSTRACT: We previously isolated cacalol as a free radical-scavenging compound from Cacalia delphiniifolia which is a traditional Asian herbal plant and is believed to have medicinal effects on cancer. In this report, we demonstrated that cacalol has strong anti-proliferation effect on breast cancer cells and induces apoptosis by activating a pro-apoptotic pathway. We also found that a combination of cacalol and other chemotherapeutic drugs (Taxol and cyclophosphamide) synergistically induced apoptosis and partially overcame chemo-resistance. To further gain a mechanistic insight, we tested a potential inhibitory effect of cacalol on fatty acid synthase gene (FAS) in breast cancer cells, and found that cacalol significantly modulated the expression of the FAS gene, which resulted in apoptosis through activation of DAPK2 and caspase 3. We have also shown that cacalol significantly suppressed the Akt-sterol regulatory element-binding proteins (SREBP) signaling pathway and concomitant transcriptional activation of FAS. In a xenograft model of nude mouse, when cacalol was administered intraperitoneally, tumor growth was significantly suppressed. Importantly, oral administration of cacalol before implanting tumors showed significant preventive effect on tumor growth in the same animal model. Furthermore, the treatment of mice with a combination of low dose of Taxol and cacalol significantly suppressed the tumor growth. Taken together, our results indicate that cacalol induces apoptosis in breast cancer cells and impairs mammary tumor growth in vivo by blocking the expression of the FAS gene through modulation of Akt-SREBP pathway, suggesting that cacalol has potential utility as a chemopreventive and chemotherapeutic agent for breast cancer.
Breast Cancer Research and Treatment 07/2011; 128(1):57-68. · 4.43 Impact Factor
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Wen Liu,
Megumi Iiizumi-Gairani,
Hiroshi Okuda,
Aya Kobayashi,
Misako Watabe,
Sudha K Pai,
Puspa R Pandey,
Fei Xing, Koji Fukuda,
Vishnu Modur,
Shigeru Hirota,
Kazuyuki Suzuki,
Toshimi Chiba,
Masaki Endo,
Tamotsu Sugai,
Kounosuke Watabe
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ABSTRACT: NDRG1 and KAI1 belong to metastasis suppressor genes, which impede the dissemination of tumor cells from primary tumors to distant organs. Previously, we identified the metastasis promoting transcription factor, ATF3, as a downstream target of NDRG1. Further analysis revealed that the KAI1 promoter contained a consensus binding motif of ATF3, suggesting a possibility that NDRG1 suppresses metastasis through inhibition of ATF3 expression followed by activation of the KAI1 gene. In this report, we found that ectopic expression of NDRG1 was able to augment endogenous KAI1 gene expression in prostate cancer cell lines, whereas silencing NDRG1 was accompanied with significant decrease in KAI1 expression in vitro and in vivo. In addition, our results of ChIP analysis indicate that ATF3 indeed bound to the promoter of the KAI1 gene. Importantly, our promoter-based analysis revealed that ATF3 modulated KAI1 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NFκB). Moreover, loss of KAI1 expression significantly abrogated NDRG1-mediated metastatic suppression in vitro as well as in a spontaneous metastasis animal model, indicating that KA11 is a functional downstream target of the NDRG1 pathway. Our result of immunohistochemical analysis showed that loss of NDRG1 and KAI1 occurs in parallel as prostate cancer progresses. We also found that a combined expression status of these two genes serves as a strong independent prognostic marker to predict metastasis-free survival of prostate cancer patients. Taken together, our result revealed a novel regulatory network of two metastasis suppressor genes, NDRG1 and KAI1, which together concerted metastasis-suppressive activities through an intrinsic transcriptional cascade.
Journal of Biological Chemistry 03/2011; 286(21):18949-59. · 4.77 Impact Factor
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Puspa R Pandey,
Hiroshi Okuda,
Misako Watabe,
Sudha K Pai,
Wen Liu,
Aya Kobayashi,
Fei Xing, Koji Fukuda,
Shigeru Hirota,
Tamotsu Sugai, [......],
Masahiro Kashiwaba,
Kazuyuki Suzuki,
Toshimi Chiba,
Masaki Endo,
Tomoaki Fujioka,
Susumu Tanji,
Yin-Yuan Mo,
Deliang Cao,
Andrew C Wilber,
Kounosuke Watabe
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ABSTRACT: Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24(-)/CD44(+)/ESA(+)) that were isolated from both ER+ and ER- breast cancer cell lines was examined. The authors found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, the results of this study indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol.
Breast Cancer Research and Treatment 12/2010; 130(2):387-98. · 4.43 Impact Factor
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ABSTRACT: Objective: Describe the clinical course and management of a labyrinthine cyst associated with a labyrinthine fistula arising in a longstanding cavity after a canal wall down mastoidectomy.: A 71-year-old woman who underwent left radical mastoidectomy at age 7 was referred to our clinic complaining of left ear fullness. She experienced severe vertigo for several years postoperatively, but did not complain of vertigo at her initial visit. A pale cystic mass was seen in the external auditory canal. She was completely deaf in her left ear and showed no signs of a fistula. Computed tomography and magnetic resonance imaging revealed a 12-mm mass in the superior semicircular canal and the vestibule. Removal of the cyst led to perilymph leakage through a large labyrinthine fistula, which was sealed by cortical bone chips, bone dust, and temporal fascia with fibrin glue. Histological examination revealed that the cyst wall was composed of fibrous connective tissue, contained scattered calcium deposits, and lacked an inner epithelial lining. The postoperative course was uneventful, and there has been no recurrence for 45 months. Conclusion: To our knowledge, this is the first reported case of a labyrinthine cyst associated with a labyrinthine fistula. This delayed labyrinthine fistula is a unique complication in a longstanding cavity after a canal wall down mastoidectomy.
