Details of a Researcher - Saya, Hideyuki

Papers - Saya, Hideyuki

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Development of Highly Selective Fluorescent Probe Enabling Flow-Cytometric Isolation of ALDH3A1-Positive Viable Cells

Yagishita Atsushi, Ueno Tasuku, Esumi Hiroyasu, Saya Hideyuki, Kaneko Kazuhiro, Tsuchihara Katsuya, Urano Yasuteru

Bioconjugate Chemistry 28 ( 2 ) 302 - 306 2017.02

ISSN 1043-1802

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Simvastatin-induced apoptosis in osteosarcoma cells

Kamel Walied A., Sugihara Eiji, Nobusue Hiroyuki, Yamaguchi-Iwai Sayaka, Onishi Nobuyuki, Maki Kenta, Fukuchi Yumi, Matsuo Koichi, Muto Akihiro, Saya Hideyuki, Shimizu Takatsune

Molecular Cancer Therapeutics 16 ( 1 ) 182 - 192 2017.01

ISSN 1535-7163

Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro. Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 MAPK, with AMPK functioning upstream of p38 MAPK. Inhibitors of AMPK or p38 MAPK attenuated the induction of apoptosis by simvastatin, whereas metformin enhanced this effect of simvastatin by further activation of AMPK. Although treatment with simvastatin alone did not inhibit osteosarcoma tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was enhanced further by metformin administration. Our findings suggest that simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK, and that, in combination with other approaches, it holds therapeutic potential for osteosarcoma.

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Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer

Otsubo Kohei, Nosaki Kaname, Imamura Chiyo K., Ogata Hiroaki, Fujita Akitaka, Sakata Shinya, Hirai Fumihiko, Toyokawa Gouji, Iwama Eiji, Harada Taishi, Seto Takashi, Takenoyama Mitsuhiro, Ozeki Takeshi, Mushiroda Taisei, Inada Mieko, Kishimoto Junji, Tsuchihashi Kenji, Suina Kentaro, Nagano Osamu, Saya Hideyuki, Nakanishi Yoichi, Okamoto Isamu

Cancer Science 2017

ISSN 1347-9032

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.

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Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis

Jeong Sangho, Choi Eunyoung, Petersen Christine P., Roland Joseph T., Federico Alessandro, Ippolito Rossana, D'Armiento Francesco P., Nardone Gerardo, Nagano Osamu, Saya Hideyuki, Romano Marco, Goldenring James R.

United European Gastroenterology Journal 5 ( 1 ) 37 - 44 2017

ISSN 2050-6406

Background: Autoimmune gastritis (AIG) and adenocarcinoma-associated chronic atrophic gastritis (CAG) are both associated with oxyntic atrophy, but AIG patients demonstrate an increased risk of carcinoid tumors rather than the elevated risk of adenocarcinoma observed with CAG. We therefore sought to compare the characteristics of the metaplastic mucosa in AIG and CAG patients. Methods: We examined markers for metaplasia (spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia) as well as proliferation (Ki67) and immune cell populations (neutrophils, macrophages, and eosinophils) in gastric sections from 16 female patients with autoimmune thyroiditis and AIG and 17 patients with CAG associated with gastric adenocarcinoma. Results: Both AIG and CAG patients demonstrated prominent SPEM and intestinal metaplasia. However, AIG patients displayed significantly lower numbers of infiltrating macrophages and significantly reduced mucosal cell proliferation as compared to CAG patients. Conclusions: These findings indicate that, while both AIG and CAG patients display prominent oxyntic atrophy and metaplasia, the AIG patients do not show proliferative metaplastic lineages that would predispose to adenocarcinoma.

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RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

Sato Ryo, Nakano Teppei, Hosonaga Mari, Sampetrean Oltea, Harigai Ritsuko, Sasaki Takashi, Koya Ikuko, Okano Hideyuki, Kudoh Jun, Saya Hideyuki, Arima Yoshimi

BioMed Research International 2017 2017

ISSN 2314-6133

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

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The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer

Tayama Shingo, Motohara Takeshi, Narantuya Dashdemberel, Li Chenyan, Fujimoto Koichi, Sakaguchi Isao, Tashiro Hironori, Saya Hideyuki, Nagano Osamu, Katabuchi Hidetaka

Oncotarget 8 ( 27 ) 44312 - 44325 2017

ISSN 1949-2553

Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved. Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAMpositive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapyinduced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients. Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.

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ALK ^R1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN

Ueda T., Nakata Y., Yamasaki N., Oda H., Sentani K., Kanai A., Onishi N., Ikeda K., Sera Y., Honda Z. I., Tanaka K., Sata M., Ogawa S., Yasui W., Saya H., Takita J., Honda H.

Oncogene 35 ( 34 ) 4447 - 4458 2016.08

ISSN 0950-9232

Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK R1275Q, an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK R1275Q knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK R1275Q globally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK R1275Q /MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK R1275Q -expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK R1275Q /MYCN mice. These results collectively indicate that ALK R1275Q confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK R1275Q /MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK R1275Q -positive tumors.

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Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells

Tominaga K., Shimamura T., Kimura N., Murayama T., Matsubara D., Kanauchi H., Niida A., Shimizu S., Nishioka K., Tsuji E. I., Yano M., Sugano S., Shimono Y., Ishii H., Saya H., Mori M., Akashi K., Tada K. I., Ogawa T., Tojo A., Miyano S., Gotoh N.

Oncogene 2016.08

ISSN 0950-9232

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1R^high CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles’ heels of CSCs, it will be critical to break them for eradication of CSCs.Oncogene advance online publication, 22 August 2016; doi:10.1038/onc.2016.293.

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Isolation of all CD44 transcripts in human epidermis and regulation of their expression by various agents

Teye Kwesi, Numata Sanae, Ishii Norito, Krol Rafal P., Tsuchisaka Atsunari, Hamada Takahiro, Koga Hiroshi, Karashima Tadashi, Ohata Chika, Tsuruta Daisuke, Saya Hideyuki, Haftek Marek, Hashimoto Takashi

PLoS One 11 ( 8 ) 2016.08

ISSN 1932-6203

CD44, a cell surface proteoglycan, is involved in many biological events. CD44 transcripts undergo complex alternative splicing, resulting in many functionally distinct isoforms. To date, however, the nature of these isoforms in human epidermis has not been adequately determined. In this study, we isolated all CD44 transcripts from normal human epidermis, and studied how their expressions are regulated. By RT-PCR, we found that a number of different CD44 transcripts were expressed in human epidermis, and we obtained all these transcripts from DNA bands in agarose and acrylamide gels by cloning. Detailed sequence analysis revealed 18 CD44 transcripts, 3 of which were novel. Next, we examined effects of 10 different agents on the expression of CD44 transcripts in cultured human keratinocytes, and found that several agents, particularly epidermal growth factor, hydrogen peroxide, phorbol 12-myristate 13-acetate, retinoic acid, calcium and fetal calf serum differently regulated their expressions in various patterns. Furthermore, normal and malignant keratinocytes were found to produce different CD44 transcripts upon serum stimulation and subsequent starvation, suggesting that specific CD44 isoforms are involved in tumorigenesis via different CD44-mediated biological pathways.

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Concise Review: Stem cells and epithelial-mesenchymal transition (EMT) in cancer: biological implications and therapeutic targets.

Sato Ryo, Semba Takashi, Saya Hideyuki, Arima Yoshimi

Stem Cells 34 ( 8 ) 1997 - 2007 2016.08

ISSN 1066-5099

Cancer stem cells (CSCs) constitute a small subpopulation of cancer cells with stem-like properties that are able to self-renew, generate differentiated daughter cells, and give rise to heterogeneous tumor tissue. Tumor heterogeneity is a hallmark of cancer and underlies resistance to anticancer therapies and disease progression. The epithelial-mesenchymal transition (EMT) is a reversible phenomenon that is mediated by EMT-inducing transcription factors (EMT-TFs) and plays an important role in normal organ development, wound healing, and the invasiveness of cancer cells. Recent evidence showing that overexpression of several EMT-TFs is associated with stemness in cancer cells has suggested the existence of a link between EMT and CSCs. In this review, we focus on the roles of CSCs and EMT signaling in driving tumor heterogeneity. A better understanding of the dynamics of both CSCs and EMT-TFs in the generation of tumor heterogeneity may provide a basis for the development of new treatment options for cancer patients. Stem Cells 2016;34:1997–2007.

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CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma

Thanee Malinee, Loilome Watcharin, Techasen Anchalee, Sugihara Eiji, Okazaki Shogo, Abe Shinya, Ueda Shiho, Masuko Takashi, Namwat Nisana, Khuntikeo Narong, Titapun Attapol, Pairojkul Chawalit, Saya Hideyuki, Yongvanit Puangrat

Cancer Science 107 ( 7 ) 991 - 1000 2016.07

ISSN 1347-9032

Expression of CD44, especially the variant isoforms (CD44v) of this major cancer stem cell marker, contributes to reactive oxygen species (ROS) defense through stabilizing xCT (a cystine–glutamate transporter) and promoting glutathione synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of CD44v in the regulation of the ROS defense system in cholangiocarcinoma (CCA). Immunohistochemical staining of CD44v and p38^MAPK (a major ROS target) expression in Opisthorchis viverrini-induced hamster CCA tissues (at 60, 90, 120, and 180 days) reveals a decreased phospho-p38^MAPK signal, whereas the CD44v signal was increased during bile duct transformation. Patients with CCA showed CD44v overexpression and negative-phospho-p38^MAPK patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38^MAPK patients (P = 0.030). Knockdown of CD44 showed that xCT and glutathione levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v cancer stem cell therapy using sulfasalazine. Glutathione decreased and ROS increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of CD44v leads to the suppression of p38^MAPK in transforming bile duct cells. The redox status regulation of CCA cells depends on the expression of CD44v to contribute the xCT function and is a link to the poor prognosis of patients. Thus, an xCT inhibitor could inhibit cell growth and activate cell death. This suggests that an xCT-targeting drug may improve CCA therapy by sensitization to the available drug (e.g. gemcitabine) by blocking the mechanism of the cell's ROS defensive system.

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LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development

Lee Da Hye, Park Jae Oh, Kim Tae Shin, Kim Sang Kyum, Kim Tack Hoon, Kim Min Chul, Park Gun Soo, Kim Jeong Hwan, Kuninaka Shinji, Olson Eric N., Saya Hideyuki, Kim Seon Young, Lee Ho, Lim Dae Sik

Nature Communications 7 2016.06

ISSN 2041-1723

The Hippo pathway regulates the self-renewal and differentiation of various adult stem cells, but its role in cell fate determination and differentiation during liver development remains unclear. Here we report that the Hippo pathway controls liver cell lineage specification and proliferation separately from Notch signalling, using mice and primary hepatoblasts with liver-specific knockout of Lats1 and Lats2 kinase, the direct upstream regulators of YAP and TAZ. During and after liver development, the activation of YAP/TAZ induced by loss of Lats1/2 forces hepatoblasts or hepatocytes to commit to the biliary epithelial cell (BEC) lineage. It increases BEC and fibroblast proliferation by up-regulating TGFβ signalling, but suppresses hepatoblast to hepatocyte differentiation by repressing Hnf4α expression. Notably, oncogenic YAP/TAZ activation in hepatocytes induces massive p53-dependent cell senescence/death. Together, our results reveal that YAP/TAZ activity levels govern liver cell differentiation and proliferation in a context-dependent manner.

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CD44 splice variant v8-10 as a marker of serous ovarian cancer prognosis

Sosulski Amanda, Horn Heiko, Zhang Lihua, Coletti Caroline, Vathipadiekal Vinod, Castro Cesar M., Birrer Michael J., Nagano Osamu, Saya Hideyuki, Lage Kasper, Donahoe Patricia K., Pépin David

PLoS One 11 ( 6 ) 2016.06

ISSN 1932-6203

CD44 is a transmembrane hyaluronic acid receptor gene that encodes over 100 different tissue-specific protein isoforms. The most ubiquitous, CD44 standard, has been used as a cancer stem cell marker in ovarian and other cancers. Expression of the epithelial CD44 variant containing exons v8-10 (CD44v8-10) has been associated with more chemoresistant and metastatic tumors in gastrointestinal and breast cancers, but its role in ovarian cancer is unknown; we therefore investigated its use as a prognostic marker in this disease. The gene expression profiles of 254 tumor samples from The Cancer Genome Atlas RNAseqV2 were analyzed for the presence of CD44 isoforms. A trend for longer survival was observed in patients with high expression of CD44 isoforms that include exons v8-10. Immunohistochemical (IHC) analysis of tumors for presence of CD44v8-10 was performed on an independent cohort of 210 patients with high-grade serous ovarian cancer using a tumor tissue microarray. Patient stratification based on software analysis of staining revealed a statistically significant increase in survival in patients with the highest levels of transmembrane protein expression (top 10 or 20%) compared to those with the lowest expression (bottom 10 and 20%) (p = 0.0181, p = 0.0262 respectively). Expression of CD44v8-10 in primary ovarian cancer cell lines was correlated with a predominantly epithelial phenotype characterized by high expression of epithelial markers and low expression of mesenchymal markers by qPCR, Western blot, and IHC. Conversely, detection of proteolytically cleaved and soluble extracellular domain of CD44v8-10 in patient ascites samples was correlated with significantly worse prognosis (p

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Eradication of CD44-variant positive population in head and neck tumors through controlled intracellular navigation of cisplatin-loaded nanomedicines

Wang Ming, Miura Yutaka, Tsuchihashi Kenji, Miyano Kazuki, Nagano Osamu, Yoshikawa Momoko, Tanabe Ami, Makino Jun, Mochida Yuki, Nishiyama Nobuhiro, Saya Hideyuki, Cabral Horacio, Kataoka Kazunori

Journal of Controlled Release 230 26 - 33 2016.05

ISSN 0168-3659

Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth.

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The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-)

Tsuchihashi Kenji, Okazaki Shogo, Ohmura Mitsuyo, Ishikawa Miyuki, Sampetrean Oltea, Onishi Nobuyuki, Wakimoto Hiroaki, Yoshikawa Momoko, Seishima Ryo, Iwasaki Yoshimi, Morikawa Takayuki, Abe Shinya, Takao Ayumi, Shimizu Misato, Masuko Takashi, Nagane Motoo, Furnari Frank B., Akiyama Tetsu, Suematsu Makoto, Baba Eishi, Akashi Koichi, Saya Hideyuki, Nagano Osamu

Cancer Research 76 ( 10 ) 2954 - 2963 2016.05

ISSN 0008-5472

Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here, we show that the EGFR interacts with xCT and thereby promotes its cell surface expression and function inhumanglioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake, as well as increased glutamate, which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells, as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface.

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Tumour resistance in induced pluripotent stem cells derived from naked mole-rats

Miyawaki Shingo, Kawamura Yoshimi, Oiwa Yuki, Shimizu Atsushi, Hachiya Tsuyoshi, Bono Hidemasa, Koya Ikuko, Okada Yohei, Kimura Tokuhiro, Tsuchiya Yoshihiro, Suzuki Sadafumi, Onishi Nobuyuki, Kuzumaki Naoko, Matsuzaki Yumi, Narita Minoru, Ikeda Eiji, Okanoya Kazuo, Seino Ken Ichiro, Saya Hideyuki, Okano Hideyuki, Miura Kyoko

Nature Communications 7 2016.05

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype - ARF suppression-induced senescence (ASIS) - that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR.

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MIF maintains the tumorigenic capacity of brain tumor-initiating cells by directly inhibiting p53

Fukaya Raita, Ohta Shigeki, Yaguchi Tomonori, Matsuzaki Yumi, Sugihara Eiji, Okano Hideyuki, Saya Hideyuki, Kawakami Yutaka, Kawase Takeshi, Yoshida Kazunari, Toda Masahiro

Cancer Research 76 ( 9 ) 2813 - 2823 2016.05

ISSN 0008-5472

Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphereforming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro. However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells.

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Potential of sulfasalazine as a therapeutic sensitizer for CD44 splice variant 9-positive urogenital cancer

Takayama Tatsuya, Kubo Taro, Morikawa Ai, Morita Tatsuo, Nagano Osamu, Saya Hideyuki

Medical Oncology 33 ( 5 ) 2016.05

ISSN 1357-0560

Cancer stem-like cells (CSCs) with high expression of CD44 splice variant (CD44v) have an enhanced capacity for intracellular reduced glutathione synthesis and defense against reactive oxygen species, resulting in resistance to various therapeutic stresses. Sulfasalazine (SSZ), a drug used in the treatment of rheumatoid arthritis (RA), inhibits glutamate–cystine transport, and suppressed CD44v-dependent tumor growth and increased sensitivity to cytotoxic drugs in an in vivo study. Here, we present two cases of CD44v9-positive urogenital cancer with concomitant treatment with SSZ for RA. Patient 1 was a 62-year-old man who had received SSZ for RA beginning 2 months before the diagnosis of urinary bladder cancer. Although he had multiple metastases to the bladder, abdominal, left cervical and left axillary lymph nodes, and brain, complete response with multidisciplinary therapy was maintained for more than 2 years. Patient 2 was a 74-year-old man with castration-resistant prostate cancer who was diagnosed with RA during chemotherapy and a gradual increase in prostate-specific antigen (PSA) level. When SSZ was added, his PSA value (ng/mL) decreased from 12.93 to 5.58 in only 2 weeks and then quickly rebounded, whereas levels of neuron-specific enolase, a neuroendocrine differentiator and CSC marker, remained almost unchanged. We therefore speculate that SSZ treatment may represent a new adjuvant treatment option for patients with CD44v9-positive urogenital cancer.

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Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts

Umeyama Kazuhiro, Watanabe Kota, Watanabe Masahito, Horiuchi Keisuke, Nakano Kazuaki, Kitashiro Masateru, Matsunari Hitomi, Kimura Tokuhiro, Arima Yoshimi, Sampetrean Oltea, Nagaya Masaki, Saito Masahiro, Saya Hideyuki, Kosaki Kenjiro, Nagashima Hiroshi, Matsumoto Morio

Scientific Reports 6 2016.04

Marfan syndrome (MFS) is an autosomal dominant genetic disease caused by abnormal formation of the extracellular matrix with an incidence of 1 in 3, 000 to 5, 000. Patients with Marfan syndrome experience poor quality of life caused by skeletal disorders such as scoliosis, and they are at high risk of sudden death from cardiovascular impairment. Suitable animal models of MFS are essential for conquering this intractable disease. In particular, studies employing pig models will likely provide valuable information that can be extrapolated to humans because of the physiological and anatomical similarities between the two species. Here we describe the generation of heterozygous fibrillin-1 (FBN1) mutant cloned pigs (+/Glu433AsnfsX98) using genome editing and somatic cell nuclear transfer technologies. The FBN1 mutant pigs exhibited phenotypes resembling those of humans with MFS, such as scoliosis, pectus excavatum, delayed mineralization of the epiphysis and disrupted structure of elastic fibres of the aortic medial tissue. These findings indicate the value of FBN1 mutant pigs as a model for understanding the pathogenesis of MFS and for developing treatments.

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Dose-escalation study for the targeting of CD44v⁺ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)

Shitara Kohei, Doi Toshihiko, Nagano Osamu, Imamura Chiyo K., Ozeki Takeshi, Ishii Yuya, Tsuchihashi Kenji, Takahashi Shunji, Nakajima Takako E., Hironaka Shuichi, Fukutani Miki, Hasegawa Hiromi, Nomura Shogo, Sato Akihiro, Einaga Yasuaki, Kuwata Takeshi, Saya Hideyuki, Ohtsu Atsushi

Gastric Cancer 1 - 9 2016.04

ISSN 1436-3291

Background: Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine–glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted. Methods: SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH. Results: Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater. Conclusions: This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.

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