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Sample records for helps stem-like carcinoma

  1. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    SciTech Connect

    Barbieri, Federica; Wurth, Roberto; Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina; Thellung, Stefano; Daga, Antonio; Cilli, Michele; Ferrari, Angelo; Florio, Tullio

    2012-04-15

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell-like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-{alpha} and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: Black-Right-Pointing-Pointer Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 Black-Right-Pointing-Pointer These grow as spheres in serum-free medium and self-renew Black-Right-Pointing-Pointer Isolated stem-like cancer cells initiate tumor in immunodeficient mice Black-Right-Pointing-Pointer Xenografted tumors are phenotypically similar to the original tumor Black

  2. Hepatocellular carcinoma: thyroid hormone promotes tumorigenicity through inducing cancer stem-like cell self-renewal

    PubMed Central

    Wang, Tao; Xia, Lei; Ma, Sicong; Qi, Xingxing; Li, Qigen; Xia, Yun; Tang, Xiaoyin; Cui, Dan; Wang, Zhi; Chi, Jiachang; Li, Ping; Feng, Yu-xiong; Xia, Qiang; Zhai, Bo

    2016-01-01

    Cancer stem-like cells (CSCs) play a key role in maintaining the aggressiveness of hepatocellular carcinoma (HCC), but the cell-biological regulation of CSCs is unclear. In the study, we report that thyroid hormone (TH) promotes cell self-renewal in HCC cells. TH also increases the percentage of CD90 + HCC cells and promotes drug resistance of HCC cells. By analyzing primary human HCC samples, we found that TRα transcript level is significantly elevated in primary liver cancer and portal vein metastatic tumor, compared to that of adjacent normal liver tissue. Knocking down TRα not only inhibits HCC self-renewal in vitro but also suppresses HCC tumor growth in vivo. Interestingly, treatment of TH leads to activation of NF-κB, which is required for the function of TH on inducing HCC cell self-renewal. We also found TRα and p65 cooperatively drive the expression of BMI1 by co-binding to the promoter region of BMI1 gene. In summary, our study uncovers a novel function of TH signaling in regulating the CSCs of HCC, and these findings might be useful for developing novel therapies by targeting TH function in HCC cells. PMID:27174710

  3. DC120, a novel AKT inhibitor, preferentially suppresses nasopharyngeal carcinoma cancer stem-like cells by downregulating Sox2

    PubMed Central

    Tang, Jun; Yang, Fen; Feng, Gong-Kan; Chen, Wen-Dan; Wu, Xiao-Qi; Qian, Xiao-Jun; Ding, Ke; Zhu, Xiao-Feng

    2015-01-01

    Side population (SP) contains cancer stem-like cells (CSLCs). In this study, we characterized SP cells from nasopharyngeal carcinoma (NPC) cell lines and found that SP cells had a higher self-renewal ability in vitro and greater tumorigenicity in vivo. The AKT pathway was activated in NPC SP cells. DC120, a 2-pyrimidyl-5-amidothiazole inhibitor of the ATP binding site of AKT, inhibited phosphorylation of FKHRL1 and GSK-3β. DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts’ tumor recurrence. This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a. A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo. Clinical evaluation of DC120 is warranted. PMID:25749514

  4. Association between ALDH1+/CD133+ stem-like cells and tumor angiogenesis in invasive ductal breast carcinoma

    PubMed Central

    LV, XINQUAN; WANG, YINGZI; SONG, YIMIN; PANG, XIA; LI, HUIXIANG

    2016-01-01

    The growth and metastasis of tumors is dependent on angiogenesis; however, the association between tumor stem cells (TSCs) and tumor angiogenesis remains to be elucidated. The present study aimed to investigate the expression of the TSC markers aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 133 (CD133) in invasive ductal breast carcinoma, and identify their correlation with tumor angiogenesis. Stem-like cells from the breast tissue of 120 patients, who were diagnosed with invasive ductal breast carcinoma at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, Henan, China) between January 2009 and December 2010, were collected by surgical resection and analyzed using immunohistochemical double staining. The expression of the vascular markers CD34, CD105 and vascular endothelial growth factor (VEGF) were determined using single staining. Overall, 25.83% (31/120) of the specimens contained a large number of ALDH1+/CD133+ stem-like cells (ALDH1+/CD133+ tumor). ALDH1+/CD133+ expression is associated with microvessel density, VEGF-positive rate and estrogen receptor expression (P<0.05); however, ALDH1+/CD133+ expression was not associated with age, tumor diameter, lymph node metastasis, histological classification, progesterone receptor expression or human epidermal growth factor receptor 2 expression (P>0.05). The ALDH1+/CD133+ tumor phenotype and expression of VEGF were identified to be correlated in the present study (P=0.020). The present study revealed a close association between breast cancer TSC markers, including ALDH1 and CD133, and tumor angiogenesis. The results of the present study may provide a novel target and treatment strategy for future studies investigating tumor growth and metastasis. PMID:26998072

  5. CD133+ cancer stem-like cells promote migration and invasion of salivary adenoid cystic carcinoma by inducing vasculogenic mimicry formation

    PubMed Central

    Wang, Sha-sha; Gao, Xiao-lei; Liu, Xin; Gao, Shi-yu; Fan, Yun-long; Jiang, Ya-ping; Ma, Xiang-rui; Jiang, Jian; Feng, Hao; Chen, Qian-ming; Tang, Ya-jie; Tang, Ya-ling; Liang, Xin-hua

    2016-01-01

    Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133− ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133− cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation. PMID:27074560

  6. Side population in hepatocellular carcinoma HCCLM3 cells is enriched with stem-like cancer cells

    PubMed Central

    GUO, ZHE; JIANG, JING-HANG; ZHANG, JUN; YANG, HAO-JIE; ZHONG, YAN-PING; SU, JIE; YANG, RI-RONG; LI, LE-QUN; XIANG, BANG-DE

    2016-01-01

    Substantial evidence implicates that low-abundance cancer stem cells (CSCs) are responsible for tumor metastasis and recurrence in hepatocellular carcinoma (HCC). Side population (SP) cells possess typical CSCs-like features, and are frequently considered as a special subpopulation in which CSCs are enriched and in studies may be considered as a substitute for CSCs. The aim of the present study was to examine the abundance of SP cells in human HCC cell lines with different metastatic potentials and compare their CSC-like, tumorigenic and invasive properties with those of the main population (MP) cells. An experimental system is described for identifying SP cells and analyzing their CSC-like properties. The relative abundance of SP cells correlated directly with the metastatic potential of the HCC cell line: HCCLM3, 16.3±2.2%; MHCC97-H, 8.4±0.7%; MHCC97-L, 4.7±0.5%; and Huh7, 1.0±0.3% (P<0.05). SP cells isolated from HCCLM3 cultures showed significantly higher proliferation rates and clonogenicity than the corresponding MP cells, in addition to higher migration and invasive abilities in vitro and greater tumorigenicity in mice. Expression levels of all CSC-associated genes tested, except EpCAM and Oct4, were significantly higher in SP cells. The findings revealed that the proportion of SP cells correlates with metastatic potential, and SP cells demonstrated the characteristics expected of CSCs, implicating them in HCC metastasis. Further studies on the identification and characterization of SP cells using clinical HCC specimens will contribute to the understanding of how SP cells are involved in these disease processes. PMID:27123080

  7. Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo.

    PubMed

    Lotti, Roberta; Palazzo, Elisabetta; Petrachi, Tiziana; Dallaglio, Katiuscia; Saltari, Annalisa; Truzzi, Francesca; Quadri, Marika; Puviani, Mario; Maiorana, Antonino; Marconi, Alessandra; Pincelli, Carlo

    2016-01-01

    Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β₁-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in Ras(G12V)-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development.

  8. Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo

    PubMed Central

    Lotti, Roberta; Palazzo, Elisabetta; Petrachi, Tiziana; Dallaglio, Katiuscia; Saltari, Annalisa; Truzzi, Francesca; Quadri, Marika; Puviani, Mario; Maiorana, Antonino; Marconi, Alessandra; Pincelli, Carlo

    2016-01-01

    Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β1-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in RasG12V-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development. PMID:26771605

  9. IMMUNOREGULATORY PROPERTIES OF CD44+ CANCER STEM-LIKE CELLS IN SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

    PubMed Central

    Chikamatsu, Kazuaki; Takahashi, Goro; Sakakura, Koichi; Ferrone, Soldano; Masuyama, Keisuke

    2012-01-01

    Background CD44 was found as a surface marker in cancer stem cell (CSC) of squamous cell carcinoma of the head and neck (SCCHN); however, the immunologic properties of such CSCs have not yet been elucidated. Methods The immunologic properties of CD44+ cancer stem-like cells were compared with those of CD44− cells using flow cytometry and enzyme-linked immunosorbent assay. Results CD44+ cells exhibited weak HLA-A2 and class II expression. Interestingly, downregulation of transporter antigen processing (TAP)2 was found in CD44+ cells. The CD44+ cell population produced significantly higher levels of interleukin (IL)-8, granulocyte colony-stimulating factor (G-CSF), and transforming growth factor (TGF)-β than the CD44− cell population. Moreover, CD44+ cells have been shown to not only more strongly inhibit T-cell proliferation, but also to more efficiently inhibit regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSC) as compared with CD44− cells. Additionally, CD44+ cells suppressed Th1 responses and enhanced regulatory T cell responses. Conclusion CSCs might have higher malignant potential with numerous escape strategies from immune attack. PMID:20848440

  10. MicroRNA-452 promotes stem-like cells of hepatocellular carcinoma by inhibiting Sox7 involving Wnt/β-catenin signaling pathway

    PubMed Central

    Zheng, Zhiyun; Liu, Jimin; Yang, Zhe; Wu, Limin; Xie, Haiyang; Jiang, Chaozhe; Lin, Binyi; Chen, Tianchi; Xing, Chunyang; Liu, Zhikun; Song, Penghong; Yin, Shengyong; Zheng, Shusen; Zhou, Lin

    2016-01-01

    The decrease of microRNA-452 (miR-452) in gliomas promoted stem-like features and tumorigenesis. However, the role of miR-452, especially in regulating cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) remains ambiguous. We enriched stem-like HCC cells by serial passages of hepatospheres with chemotherapeutic agents. Stem-like characteristics including the capabilities of chemo-resistance, stemness-related gene expression profiling, self-renewal, tumorigenicity and metastasis formation were detected. MiR-452 was markedly increased in the chemo-resistant hepatospheres and human HCC tissues. and the overexpression of miR-452 in HCC patients predicted poor overall survival. MiR-452 significantly promoted stem-like characteristics in vitro and in vivo. Further, Sox7 was identified as the direct target of miR-452, which could physically bind with β-catenin and TCF4 in the nucleus and then inhibit the activity of Wnt/β-catenin signaling pathway. Finally, the combined chemotherapy of doxorubicin and all-trans retinoic acid (ATRA) showed dramatically efficiency in suppressing HCC metastasis. These data suggested that miR-452 promoted stem-like traits of HCC, which might be a potential therapeutic target for HCC. The combination of doxorubicin and ATRA might be a promising therapy in HCC management. PMID:27058905

  11. Cell-surface Vimentin: A mislocalized protein for isolating csVimentin(+) CD133(-) novel stem-like hepatocellular carcinoma cells expressing EMT markers.

    PubMed

    Mitra, Abhisek; Satelli, Arun; Xia, Xueqing; Cutrera, Jeffrey; Mishra, Lopa; Li, Shulin

    2015-07-15

    Recent advances in cancer stem cell biology have shown that cancer stem-like cells with epithelial-mesenchymal transition (EMT) phenotypes are more aggressive and cause relapse; however, absence of a specific marker to isolate these EMT stem-like cells hampers research in this direction. Cell surface markers have been identified for isolating cancer stem-like cells, but none has been identified for isolating cancer stem-like cells with EMT phenotype. Recently, we discovered that Vimentin, an intracellular EMT tumor cell marker, is present on the surface of colon metastatic tumor nodules in the liver. In our study, we examined the potential of targeting cell surface Vimentin (CSV) to isolate stem-like cancer cells with EMT phenotype, by using a specific CSV-binding antibody, 84-1. Using this antibody, we purified the CSV-positive, CD133-negative (csVim(+) CD133(-) ) cell population from primary liver tumor cell suspensions and characterized for stem cell properties. The results of sphere assays and staining for the stem cell markers Sox2 and Oct4A demonstrated that csVim(+) CD133(-) cells have stem-like properties similar to csVim(-) CD133(+) population. Our investigation further revealed that the csVim(+) CD133(-) cells had EMT phenotypes, as evidenced by the presence of Twist and Slug in the nucleus, the absence of EpCAM on the cell surface and basal level of expression of epithelial marker E-cadherin. The csVimentin-negative CD133-positive stem cells do not have any EMT phenotypes. csVim(+) CD133(-) cells exhibited more aggressively metastatic in livers than csVim(-) CD133(+) cells. Our findings indicate that csVim(+) CD133(-) cells are promising targets for treatment and prevention of metastatic hepatocellular carcinoma.

  12. p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma.

    PubMed

    Zhu, Y; Liu, H; Xu, L; An, H; Liu, W; Liu, Y; Lin, Z; Xu, J

    2015-02-12

    The p21-activated kinase 1 (PAK1), a serine/threonine kinase that orchestrates cytoskeletal remodeling and cell motility, has been shown to function as downstream node for various oncogenic signaling pathways to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, resulting in tumor formation and invasiveness. Although alterations in PAK1 expression and activity have been detected in various human malignancies, its potential biological and clinical significance in renal cell carcinoma (RCC) remains obscure. In this study, we found increased PAK1 and phosphorylated PAK1 levels in tumor tissues according to TNM stage progression. Elevated phosphorylated PAK1 levels associated with progressive features and indicated unfavorable overall survival (OS) as an independent adverse prognosticator for patients with RCC. Moreover, PAK1 kinase activation with constitutive active PAK1 mutant T423E promoted growth, colony formation, migration, invasion and stem-like phenotype of RCC cells, and vice versa, in PAK1 inhibition by PAK1 kinase inactivation with specific PAK1 shRNA, dead kinase PAK1 mutant K299R or allosteric inhibitor IPA3. Stem-like phenotype due to sunitinib administration via increased PAK1 kinase activation could be ameliorated by PAK1 shRNA, PAK1 mutant K299R and IPA3. Furthermore, nuclear factor-κB (NF-κB)/interleukin-6 (IL-6) activation was found to be responsible for PAK1-mediated stem-like phenotype following sunitinib treatment. Both IL-6 neutralizing antibody and IPA3 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that oncogenic activation of PAK1 defines an important mechanism for maintaining stem-like phenotype and sunitinib resistance through NF-κB/IL-6 activation in RCC, lending PAK1-mediated NF-κB/IL-6 activation considerable appeal as novel pharmacological therapeutic targets against sunitinib resistance.

  13. RBP2 induces stem-like cancer cells by promoting EMT and is a prognostic marker for renal cell carcinoma

    PubMed Central

    Zhou, Dahai; Kannappan, Vinodh; Chen, Xiang; Li, Jingqin; Leng, Xuefeng; Zhang, Jinping; Xuan, Shiying

    2016-01-01

    Renal cell carcinoma (RCC), one of the most common kidney cancers, has a poor prognosis. Epithelial to mesenchymal transition (EMT) is a hallmark of carcinoma invasion and metastasis. Several studies have examined the molecular regulation of EMT, but the relationship between histone demethylases and EMT is little understood. In this study, we investigated the role of retinoblastoma-binding protein-2 (RBP2), a histone demethylase that is highly expressed in RCC and is positively correlated with poor RCC prognosis in the regulation of EMT. We found that ectopic overexpression of RBP2 can induce cancer stem cell-like (CSC) phenotypes through EMT in RCC cells by converting them to a more mesenchymal phenotype. This results in increased resistance to apoptosis, which leads to enhanced tumor growth in xenograft models. Together, our data show that RBP2 is an epigenetic regulator that has an important role in the initiation of CSC phenotypes through EMT, leading to tumor progression. RBP2 is also a novel biomolecule for RCC diagnosis, and prognosis and may be a therapeutic target. PMID:27282106

  14. RBP2 induces stem-like cancer cells by promoting EMT and is a prognostic marker for renal cell carcinoma.

    PubMed

    Zhou, Dahai; Kannappan, Vinodh; Chen, Xiang; Li, Jingqin; Leng, Xuefeng; Zhang, Jinping; Xuan, Shiying

    2016-01-01

    Renal cell carcinoma (RCC), one of the most common kidney cancers, has a poor prognosis. Epithelial to mesenchymal transition (EMT) is a hallmark of carcinoma invasion and metastasis. Several studies have examined the molecular regulation of EMT, but the relationship between histone demethylases and EMT is little understood. In this study, we investigated the role of retinoblastoma-binding protein-2 (RBP2), a histone demethylase that is highly expressed in RCC and is positively correlated with poor RCC prognosis in the regulation of EMT. We found that ectopic overexpression of RBP2 can induce cancer stem cell-like (CSC) phenotypes through EMT in RCC cells by converting them to a more mesenchymal phenotype. This results in increased resistance to apoptosis, which leads to enhanced tumor growth in xenograft models. Together, our data show that RBP2 is an epigenetic regulator that has an important role in the initiation of CSC phenotypes through EMT, leading to tumor progression. RBP2 is also a novel biomolecule for RCC diagnosis, and prognosis and may be a therapeutic target. PMID:27282106

  15. Characterization of cancer stem-like cells derived from a side population of a human gallbladder carcinoma cell line, SGC-996

    SciTech Connect

    Li, Xin-xing; Wang, Jian; Wang, Hao-lu; Wang, Wei; Yin, Xiao-bin; Li, Qi-wei; Chen, Yu-ying; Yi, Jing

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer We sorted SP cells from a human gallbladder carcinoma cell lines, SGC-996. Black-Right-Pointing-Pointer SP cells displayed higher proliferation and stronger clonal-generating capability. Black-Right-Pointing-Pointer SP cells showed more migratory and invasive abilities. Black-Right-Pointing-Pointer SP cells were more resistant and tumorigenic than non-SP counterparts. Black-Right-Pointing-Pointer ABCG2 might be a candidate as a marker for SP cells. -- Abstract: The cancer stem cell (CSC) hypothesis proposes that CSCs, which can renew themselves proliferate infinitely, and escape chemotherapy, become the root of recurrence and metastasis. Previous studies have verified that side population (SP) cells, characterized by their ability to efflux lipophilic substrate Hoechst 33342, to share many characteristics of CSCs in multiplying solid tumors. The purpose of this study was to sort SP cells from a human gallbladder carcinoma cell line, SGC-996 and to preliminarily identify the biological characteristics of SP cells from the cell line. Using flow cytometry we effectively sorted SP cells from the cell line SGC-996. SP cells not only displayed higher proliferative, stronger clonal-generating, more migratory and more invasive capacities, but showed stronger resistance. Furthermore, our experiments demonstrated that SP cells were more tumorigenic than non-SP counterparts in vivo. Real-time PCR analysis and immunocytochemistry showed that the expression of ATP-binding cassette subfamily G member 2 (ABCG2) was significantly higher in SP cells. Hence, these results collectively suggest that SP cells are progenitor/stem-like cells and ABCG2 might be a candidate marker for SP cells in human gallbladder cancer.

  16. EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition.

    PubMed

    Sato, Fumiyuki; Kubota, Yoshimasa; Natsuizaka, Mitsuteru; Maehara, Osamu; Hatanaka, Yutaka; Marukawa, Katsuji; Terashita, Katsumi; Suda, Goki; Ohnishi, Shunsuke; Shimizu, Yuichi; Komatsu, Yoshito; Ohashi, Shinya; Kagawa, Shingo; Kinugasa, Hideaki; Whelan, Kelly A; Nakagawa, Hiroshi; Sakamoto, Naoya

    2015-01-01

    There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF-β in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-β1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC.

  17. EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition

    PubMed Central

    Sato, Fumiyuki; Kubota, Yoshimasa; Natsuizaka, Mitsuteru; Maehara, Osamu; Hatanaka, Yutaka; Marukawa, Katsuji; Terashita, Katsumi; Suda, Goki; Ohnishi, Shunsuke; Shimizu, Yuichi; Komatsu, Yoshito; Ohashi, Shinya; Kagawa, Shingo; Kinugasa, Hideaki; Whelan, Kelly A; Nakagawa, Hiroshi; Sakamoto, Naoya

    2015-01-01

    There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF-β in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-β1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC. PMID:25897987

  18. EZH2 is overexpressed in laryngeal squamous cell carcinoma and enhances the stem-like properties of AMC-HN-8 cells

    PubMed Central

    Huang, Jiameng; Zhou, Liang; Chen, Hui; Wu, Chunping; Duo, Zhang; Zhang, Yanping

    2016-01-01

    The enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) histone methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which is important for epigenetic regulation. EZH2 is highly expressed in various types of tumors, and its high-level expression promotes the progression and invasion of certain tumors. However, the expression level of EZH2 and its functions in laryngeal squamous cell carcinomas are unknown. In the present study, the level of EZH2 expression in laryngeal squamous cell carcinomas was evaluated using immunochemical staining and reverse transcription-quantitative polymerase chain reaction. EZH2 was overexpressed in AMC-HN-8 cells with lentiviral transfection. Cell proliferation, apoptosis, cell-cycle, chemotherapy-sensitivity and in vivo tumorigenic assays were performed. The results indicated that EZH2 was highly expressed in laryngeal squamous cell carcinomas. Additionally, EZH2 overexpression promoted proliferation, accelerated cell-cycle progression and enhanced the tumorigenicity in laryngeal squamous cancer cells. More importantly, EZH2 enhanced the chemotherapy resistance of these cells. Overall, the results indicated that EZH2 promotes the progression of laryngeal squamous cell cancer and could be a potential chemotherapeutic target for the treatment of such cancer. PMID:27446358

  19. Oncogenic signaling pathways and origins of tumor-initiating stem-like cells of hepatocellular carcinomas induced by hepatitis C virus, alcohol and/or obesity.

    PubMed

    Chen, Chia-Lin; Tsukamoto, Hidekazu; Machida, Keigo

    2014-07-01

    This review article discusses the importance and oncogenic signaling pathways of tumor-initiating cells (TICs) in several etiologies of hepatocellular carcinomas (HCCs) induced by hepatitis C virus (HCV), alcohol, obesity and/or chemicals. Stem cells may be present in cancer tissue, and a hierarchy of cells is formed, as is the case for normal tissue. Tumor formation, growth and propagation are maintained by a small proportion of cells with stem cell-like properties. TICs are present in alcohol-fed HCV transgenic mice, diethylnitrosamine/phenobarbital-treated mice (chemical carcinogenesis) and Spnb2 +/- mice (defective TGF-β signal). Alcohol/obesity-associated endotoxemia induces the stem cell marker Nanog through TLR4 signaling to generate TICs and liver tumors in several HCC models. The oncogenic pathway (such as the STAT3 and TLR4-NANOG pathway) and mechanism of generation of TICs of HCCs associated with HCV, alcohol and obesity are discussed. Understanding the molecular stemness signaling and cellular hierarchy and defining key TIC-specific genes will accelerate the development of novel biomarkers and treatment strategies. This review highlights recent advances in understanding the pathogenesis of liver TICs and discusses unanswered questions about the concept of liver TICs. (This project was supported by NIH grants 1R01AA018857 and P50AA11999).

  20. Recognition and killing of cancer stem-like cell population in hepatocellular carcinoma cells by cytokine-induced killer cells via NKG2d-ligands recognition

    PubMed Central

    Rong, Xiao-Xiang; Wei, Fang; Lin, Xiao-Lin; Qin, Yu-Juan; Chen, Lin; Wang, Hui-Yan; Shen, Hong-Fen; Jia, Li-Ting; Xie, Rao-Ying; Lin, Tao-Yan; Hao, Wei-Chao; Yang, Jie; Yang, Sheng; Cheng, Yu-Shuang; Huang, Wen-Hua; Li, Ai-min; Sun, Yan; Luo, Rong-Cheng; Xiao, Dong

    2016-01-01

    ABSTRACT There is an urgent need for more potent and safer approaches to eradicate cancer stem cells (CSCs) for curing cancer. In this study, we investigate cancer-killing activity (CKA) of cytokine-induced killer (CIK) cells against CSCs of hepatocellular carcinoma (HCC). To visualize CSCs in vitro by fluorescence imaging, and image and quantify CSCs in tumor xenograft-bearing mice by bioluminescence imaging, HCC cells were engineered with CSC detector vector encoding GFP and luciferase controlled by Nanog promoter. We found that CIK cells have a strong CKA in vitro against putative CSCs of HCC, as shown by tumorsphere formation and time-lapse imaging. Additionally, time-lapse recording firstly revealed that putative CSCs were attacked simultaneously by many CIK cells and finally eradicated by CIK cells, indicating the necessity of achieving sufficient effector-to-target ratios. We firstly illustrated that anti-NKG2D antibody blocking partially but significantly inhibited CKA of CIK cells against putative CSCs. More importantly, intravenous infusion of CIK cells remarkably delayed tumor growth in mice with a significant decrease in putative CSC number monitored by bioluminescence imaging. Taken together, these findings demonstrate CKA of CIK cells against putative CSCs of HCC, at least in part, by NKG2D-ligands recognition. PMID:27141341

  1. Cytokine-induced killer cells efficiently kill stem-like cancer cells of nasopharyngeal carcinoma via the NKG2D-ligands recognition.

    PubMed

    Wei, Fang; Rong, Xiao-Xiang; Xie, Rao-Ying; Jia, Li-Ting; Wang, Hui-Yan; Qin, Yu-Juan; Chen, Lin; Shen, Hong-Fen; Lin, Xiao-Lin; Yang, Jie; Yang, Sheng; Hao, Wei-Chao; Chen, Yan; Xiao, Sheng-Jun; Zhou, Hui-Rong; Lin, Tao-Yan; Chen, Yu-Shuang; Sun, Yan; Yao, Kai-Tai; Xiao, Dong

    2015-10-27

    Cancer stem cells (CSCs) are considered to be the root cause for cancer treatment failure. Thus, there remains an urgent need for more potent and safer therapies against CSCs for curing cancer. In this study, the antitumor activity of cytokine-induced killer (CIK) cells against putative CSCs of nasopharyngeal carcinoma (NPC) was fully evaluated in vitro and in vivo. To visualize putative CSCs in vitro by fluorescence imaging, and image and quantify putative CSCs in tumor xenograft-bearing mice by in vivo bioluminescence imaging, NPC cells were engineered with CSC detector vector encoding GFP and luciferase (Luc) under control of Nanog promoter. Our study reported in vitro intense tumor-killing activity of CIK cells against putative CSCs of NPC, as revealed by percentage analysis of side population cells, tumorsphere formation assay and Nanog-promoter-GFP-Luc reporter gene strategy plus time-lapse recording. Additionally, time-lapse imaging firstly illustrated that GFP-labeled or PKH26-labeled putative CSCs or tumorspheres were usually attacked simultaneously by many CIK cells and finally killed by CIK cells, suggesting the necessity of achieving sufficient effector-to-target ratios. We firstly confirmed that NKG2D blockade by anti-NKG2D antibody significantly but partially abrogated CIK cell-mediated cytolysis against putative CSCs. More importantly, intravenous infusion of CIK cells significantly delayed tumor growth in NOD/SCID mice, accompanied by a remarkable reduction in putative CSC number monitored by whole-body bioluminescence imaging. Taken together, our findings suggest that CIK cells demonstrate the intense tumor-killing activity against putative CSCs of NPC, at least in part, by NKG2D-ligands recognition. These results indicate that CIK cell-based therapeutic strategy against CSCs presents a promising and safe approach for cancer treatment. PMID:26418951

  2. Therapeutic targeting of CBP/β-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin

    PubMed Central

    Chan, King Chi; Chan, Lai Sheung; Ip, Joseph Chok Yan; Lo, Carman; Yip, Timothy Tak Chun; Ngan, Roger Kai Cheong; Wong, Ricky Ngok Shun; Lo, Kwok Wai; Ng, Wai Tong; Lee, Anne Wing Mui; Tsao, George Sai Wah; Kahn, Michael; Lung, Maria Li; Mak, Nai Ki

    2015-01-01

    Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2hi/CD44hi CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC. PMID:25897700

  3. Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

    PubMed Central

    Yang, Rui; Tang, Qiusha; Miao, Fengqin; An, Yanli; Li, Mengfei; Han, Yong; Wang, Xihui; Wang, Juan; Liu, Peidang; Chen, Rong

    2015-01-01

    Purpose To explore the thermoresistance and expression of heat-shock protein 90 (HSP90) in magnetic hyperthermia-treated human liver cancer stem-like cells (LCSCs) and the effects of a heat-shock protein HSP90 inhibitor 17-allylamino-17-demethoxgeldanamycin (17-AAG) on hepatocellular carcinoma-burdened nude mice. Methods CD90+ LCSCs were isolated by magnetic-activated cell sorting from BEL-7404. Spheroid formation, proliferation, differentiation, drug resistance, and tumor formation assays were performed to identify stem cell characteristics. CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17-AAG/TMs) was prepared by reverse-phase evaporation and its characteristics were studied. Heat tolerance in CD90+ LCSCs and the effect of CD90@17-AAG/TMs-mediated heat sensitivity were examined in vitro and in vivo. Results CD90+ LCSCs showed significant stem cell-like properties. The 17-AAG/TMs were successfully prepared and were spherical in shape with an average size of 128.9±7.7 nm. When exposed to magnetic hyperthermia, HSP90 was up-regulated in CD90+ LCSCs. CD90@17-AAG/TMs inhibited the activity of HSP90 and increased the sensitivity of CD90+ LCSCs to magnetic hyperthermia. Conclusion The inhibition of HSP90 could sensitize CD90+ LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo. PMID:26677324

  4. Adult stem-like cells in kidney

    PubMed Central

    Hishikawa, Keiichi; Takase, Osamu; Yoshikawa, Masahiro; Tsujimura, Taro; Nangaku, Masaomi; Takato, Tsuyoshi

    2015-01-01

    Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration. PMID:25815133

  5. Adult stem-like cells in kidney.

    PubMed

    Hishikawa, Keiichi; Takase, Osamu; Yoshikawa, Masahiro; Tsujimura, Taro; Nangaku, Masaomi; Takato, Tsuyoshi

    2015-03-26

    Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration. PMID:25815133

  6. Carcinomas of ovary and lung with clear cell features: can immunohistochemistry help in differential diagnosis?

    PubMed

    Howell, Nicole R; Zheng, Wenxin; Cheng, Liang; Tornos, Carmen; Kane, Philip; Pearl, Michael; Chalas, Eva; Liang, Sharon X

    2007-04-01

    Metastatic lung carcinomas with clear cell morphology can be confused with primary ovarian clear cell carcinomas. We performed immunohistochemical stains in 14 cases of non-small cell lung carcinomas with clear cell features and 14 cases of ovarian clear cell carcinomas using a panel of markers, including thyroid transcription factor 1 (TTF-1), carcinoembryonic antigen (CEA), Wilms tumor gene 1, octamer-binding transcription factor 4 (OCT-4), cancer antigen 125 (CA-125), estrogen receptor, and progesterone receptor. Among non-small cell lung carcinomas with clear cell features, 87.5% of adenocarcinomas (or 50% overall frequency in lung carcinomas) were positive for TTF-1, whereas none of the ovarian clear cell carcinomas were positive (P = 0.002). All 14 ovarian clear cell carcinomas stained for CA-125 as compared with 1 non-small cell lung carcinoma (P < 0.001). On the other hand, 85% of non-small cell lung carcinomas stained for CEA, whereas none of the ovarian clear cell carcinomas did (P < 0.001). Interestingly, 4 ovarian clear cell carcinomas (28%) showed positive staining for the germ cell marker OCT-4. Either lung or ovarian carcinomas stained for Wilms tumor gene 1, estrogen receptor, or progesterone receptor very infrequently; and the difference between the 2 groups was not statistically significant. Our results suggest that an immunohistochemical panel consisting of TTF-1, CEA, CA-125, and OCT-4 is helpful in distinguishing most pulmonary and ovarian carcinomas with clear cell features.

  7. Cells susceptible to epithelial-mesenchymal transition are enriched in stem-like side population cells from prostate cancer.

    PubMed

    Luo, Yong; Cui, Xinhao; Zhao, Jiahui; Han, Yili; Li, Mingchuan; Lin, Yunhua; Jiang, Yongguang; Lan, Ling

    2014-02-01

    Accumulating evidence suggests that epithelial-mesenchymal transition (EMT) acts as an important factor for the promotion of tumor progression. Strategies for suppressing EMT remain the subject of ongoing research. In the present study, fluorescence-activated cell sorting (FACS) was used to isolate side population (SP) cells from human prostate cancer (PCa) cell lines and xenograft tissues. After identifying their molecular and functional stem-like characteristics, stem-like SP cells from a cell line and from xenograft tissue were transfected with hypoxia inducible factor-1α (HIF-1α). The potential of the prostate stem-like SP cells to undergo EMT was compared with that in their bulk counterparts after HIF-1α introduction. Stem-like SP cells acquired more complete EMT molecular features and exhibited stronger aggressive capability than the homologous bulk population cells both in vitro (proliferation and invasion) and in vivo (tumorigenesis and metastasis formation). We, therefore, concluded that EMT is closely associated with tumor heterogeneity, and that PCa cells susceptible to EMT are enriched in stem-like SP cells. These findings disclose a new approach, targeting the cellular basis of the EMT process that may help to identify effective and accurate methods for suppressing tumor growth and preventing distant dissemination.

  8. The effect of salinomycin on ovarian cancer stem-like cells

    PubMed Central

    Chung, Hyewon; Kim, Yu-Hwan; Kwon, Myoung; Shin, So-Jin; Kwon, Sang-Hoon; Cha, Soon-Do

    2016-01-01

    Objective The identification of cancer stem-like cells is a recent development in ovarian cancer. Compared to other cancer cells, cancer stem-like cells present more chemo-resistance and more aggressive characteristics. They play an important role in the recurrence and drug resistance of cancer. Therefore, the target therapy of cancer stem-like cell may become a promising and effective approach for ovarian cancer treatment. It may also help to provide novel diagnostic and therapeutic strategies. Methods The OVCAR3 cell line was cultured under serum-free conditions to produce floating spheres. The CD44+CD117+ cell line was isolated from the human ovarian cancer cell line OVCAR3 by using immune magnetic-activated cell sorting system. The expression of stemness genes such as OCT3/4, NANOG and SOX2 mRNA were determined by reverse transcription polymerase chain reaction. OVCAR3 parental and OVCAR3 CD44+CD117+ cells were grown in different doses of paclitaxel and salinomycin to evaluate the effect of salinomycin. And growth inhibition of OVCAR3 CD44+CD117+ cells by paclitaxel combined with salinomycin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results Tumor spheroids generated from the OVCAR3 cell line are shown to have highly enriched CD44 and CD117 expression. Treatment with a combination of paclitaxel and salinomycin demonstrated growth inhibition of OVCAR3 CD44+CD117+ cells. Conclusion The present study is a detailed investigation on the expression of CD44 and CD117 in cancer stem cells and evaluates their specific tumorigenic characteristics in ovarian cancer. This study also demonstrates significant growth inhibition of cancer stem-like cells by paclitaxel combined with salinomycin. Identification of these cancer stem-like cell markers and growth inhibition effect of salinomycin may be the next step to the development of novel target therapy in ovarian cancer. PMID:27462592

  9. Harnessing the apoptotic programs in cancer stem-like cells

    PubMed Central

    Wang, Ying-Hua; Scadden, David T

    2015-01-01

    Elimination of malignant cells is an unmet challenge for most human cancer types even with therapies targeting specific driver mutations. Therefore, a multi-pronged strategy to alter cancer cell biology on multiple levels is increasingly recognized as essential for cancer cure. One such aspect of cancer cell biology is the relative apoptosis resistance of tumor-initiating cells. Here, we provide an overview of the mechanisms affecting the apoptotic process in tumor cells emphasizing the differences in the tumor-initiating or stem-like cells of cancer. Further, we summarize efforts to exploit these differences to design therapies targeting that important cancer cell population. PMID:26253117

  10. Help

    ERIC Educational Resources Information Center

    Tollefson, Ann

    2009-01-01

    Planning to start or expand a K-8 critical language program? Looking for support in doing so? There "may" be help at the federal level for great ideas and strong programs. While there have been various pools of federal dollars available to support world language programs for a number of years, the federal government's interest in assuring strong…

  11. Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells.

    PubMed

    Schonberg, David L; Miller, Tyler E; Wu, Qiulian; Flavahan, William A; Das, Nupur K; Hale, James S; Hubert, Christopher G; Mack, Stephen C; Jarrar, Awad M; Karl, Robert T; Rosager, Ann Mari; Nixon, Anne M; Tesar, Paul J; Hamerlik, Petra; Kristensen, Bjarne W; Horbinski, Craig; Connor, James R; Fox, Paul L; Lathia, Justin D; Rich, Jeremy N

    2015-10-12

    Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared with tissue-specific progenitors. Direct interrogation of iron uptake demonstrated that CSCs potently extract iron from the microenvironment more effectively than other tumor cells. Systematic interrogation of iron flux determined that CSCs preferentially require transferrin receptor and ferritin, two core iron regulators, to propagate and form tumors in vivo. Depleting ferritin disrupted CSC mitotic progression, through the STAT3-FoxM1 regulatory axis, revealing an iron-regulated CSC pathway. Iron is a unique, primordial metal fundamental for earliest life forms, on which CSCs have an epigenetically programmed, targetable dependence. PMID:26461092

  12. Glioblastoma Stem-Like Cells—Biology and Therapeutic Implications

    PubMed Central

    Gürsel, Demirkan B.; Shin, Benjamin J.; Burkhardt, Jan-Karl; Kesavabhotla, Kartik; Schlaff, Cody D.; Boockvar, John A.

    2011-01-01

    The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells. PMID:21796273

  13. miR-203 inhibits the proliferation and self-renewal of esophageal cancer stem-like cells by suppressing stem renewal factor Bmi-1.

    PubMed

    Yu, Xiying; Jiang, Xingran; Li, Hongxia; Guo, Liping; Jiang, Wei; Lu, Shih-Hsin

    2014-03-15

    Cancer stem-like cells exist in many malignancies and several stem cell-related genes and microRNAs, such as Bmi-1 and miR-203, have been identified as cancer stem-like cell regulators using gene microarray or sequencing analysis. Previously, we used side population (SP) sorting to enrich cancer stem-like cells from esophageal squamous cell carcinoma (ESCC) cell line EC9706. Our results demonstrated that EC9706 SP cells shared common features of cancer stem-like cells. In this study, we examined the expression of Bmi-1 and miR-203 in ESCC SP and non-SP (NSP) cells. Our results showed that, when compared with NSP cells, Bmi-1 was up-regulated and miR-203 was down-regulated in SP cells. During the differentiation from SP to NSP cells, the expression levels of Bmi-1 were gradually decreased. Overexpression of miR-203 resulted in a significant reduction of endogenous Bmi-1 protein level in EC9706 cells. SP and NSP analyses revealed that the SP cell fraction was markedly decreased in miR-203 overexpressed cells. miR-203 overexpressed cells also showed a significant reduction in colony formation, which was resistant to chemotherapeutic drug treatment and tumorigenicity in nude mice. Rescue experiments demonstrated that ectopic expression of Bmi-1 in miR-203 overexpressed cells increased the SP fraction and restored cell proliferation. Taken together, these results indicated that stem renewal factor Bmi-1 was a direct target of miR-203. The regulation of Bmi-1 by miR-203 may play an important role in controlling cell proliferation and self-renewal of esophageal cancer stem-like cells. It may also promote the development of new therapeutic strategies and efficient drugs that target ESCC stem-like cells.

  14. Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells

    SciTech Connect

    Hyun, Kyung-Hwan; Yoon, Chang-Hwan; Kim, Rae-Kwon; Lim, Eun-Jung; An, Sungkwan; Park, Myung-Jin; Hyun, Jin-Won; Suh, Yongjoon; Kim, Min-Jung; Lee, Su-Jae

    2011-07-01

    A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in the malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133{sup +} cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.

  15. Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

    PubMed Central

    Huang, Tse-Hung; Huang, Yan-Jiun; Sue, Yu-Kai; Huynh, Thanh-Tuan; Hsiao, Michael; Liu, Tsan-Zon; Wu, Alexander TH; Lin, Chien-Min

    2016-01-01

    Clinically, serum level of folate has been negatively correlated to the stage and progression of liver cancer. Nevertheless, the functional consequence of folate deficiency (FD) in malignancy has not been fully investigated. Human hepatocellular carcinoma (HCC) cells (as study model) and other cancer types such as lung and glioma were cultured under folate deficient (FD) and folate complete (FD) conditions. Molecular characterization including intracellular ROS/RNS (reactive oxygen/nitrogen species), viability, colony formation, cancer stem-like cell (CSC) phenotype analyses were performed. In vivo tumorigenesis under FD and FC conditions were also examined. FD induced a significant increase in ROS and RNS, suppressing proliferative ability but inducing metastatic potential. Mesenchymal markers such as Snail, ZEB2, and Vimentin were significantly up-regulated while E-cadherin down-regulated. Importantly, CSC markers such as Oct4, β-catenin, CD133 were induced while PRRX1 decreased under FD condition. Furthermore, FD-conditioned HCC cells showed a decreased miR-22 level, leading to the increased expression of its target genes including HDAC4, ZEB2 and Oct4. Finally, xenograft mouse model demonstrated that FD diet promoted tumorigenesis and metastasis as compared to their FC counterparts. Our data provides rationales for the consideration of folate supplement as a metastasis preventive measure. PMID:27119349

  16. Cancer stem-like cells contribute to cisplatin resistance and progression in bladder cancer.

    PubMed

    Zhang, Yi; Wang, Zhi; Yu, Jin; Shi, Jia zhong; Wang, Chun; Fu, Wei hua; Chen, Zhi wen; Yang, Jin

    2012-09-01

    A variety of cancer stem-like cells (CSCs) have been shown to be responsible for cancer tumorigenicity, relapse and metastasis. Despite several reports demonstrating the presence of CSCs in human bladder cancer, their identities are still under debate, and few studies have examined their roles in cisplatin resistance and related tumor progression. In this study, a subpopulation of CSCs was enriched following cisplatin selection from the bladder cell line T24. The cisplatin-resistant T24 cells displayed a greater self-renewal capacity as demonstrated by higher levels of sphere formation and stem cell marker expression, contained a larger proportion of side population cells and exhibited higher tumorigenicity. They also possessed epithelial-mesenchymal transition characteristics. Furthermore, a strong correlation between the levels of Bmi1 and Nanog expression and the degree of malignancy of urothelial cell carcinomas tissues was observed. We provide the first direct evidence that CSC-like cells exist in the population of cisplatin-resistant bladder cancer cells and may play a role in the progression and drug resistance of bladder cancer. PMID:22343321

  17. CCL21/CCR7 Axis Contributed to CD133+ Pancreatic Cancer Stem-Like Cell Metastasis via EMT and Erk/NF-κB Pathway

    PubMed Central

    Zhang, Lirong; Wang, Dongqing; Li, Yumei; Liu, Yanfang; Xie, Xiaodong; Wu, Yingying; Zhou, Yuepeng; Ren, Jing; Zhang, Jianxin; Zhu, Haitao; Su, Zhaoliang

    2016-01-01

    Background Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial-mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines. This study investigated the role of CCL21/CCR7 in promoting EMT and metastasis of cluster of differentiation 133+ (CD133+) pancreatic cancer stem-like cells. Methods Panc-1, AsPC-1, and MIA PaCa-2 pancreatic cancer cells were selected because of their aggressive invasive potentials. CCR7 expression levels were examined in total, CD133+ and CD133− cell fractions by Immunofluorescence analysis and real time-quantitative polymerase chain reaction (RT-qPCR). The role of CCL21/CCR7 in mediating metastasis and survival of CD133+ pancreatic cancer stem-like cells was detected by Transwell assays and flow cytometry, respectively. EMT and lymph node metastasis related markers (E-cadherin, N- cadherin, LYVE-1) were analyzed by western blot. CCR7 expression levels were analyzed by immunohistochemical staining and RT-qPCR in resected tumor tissues, metastatic lymph nodes, normal lymph nodes and adjacent normal tissues from patients with pancreatic carcinoma. Results CCR7 expression was significantly increased in CD133+ pancreatic cancer stem-like cells, resected pancreatic cancer tissues, and metastatic lymph nodes, compared with CD133− cancer cells, adjacent normal tissues and normal lymph nodes, respectively. CCL21/CCR7 promoted metastasis and survival of CD133+ pancreatic cancer stem-like cells and regulated CD133+ pancreatic cancer stem-like cells metastasis by modulating EMT and Erk/NF-κB pathway

  18. Targeting JNK for therapeutic depletion of stem-like glioblastoma cells

    PubMed Central

    Matsuda, Ken-ichiro; Sato, Atsushi; Okada, Masashi; Shibuya, Keita; Seino, Shizuka; Suzuki, Kaori; Watanabe, Eriko; Narita, Yoshitaka; Shibui, Soichiro; Kayama, Takamasa; Kitanaka, Chifumi

    2012-01-01

    Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells. PMID:22816039

  19. [Effects of different culture system of isolating and passage of sheep embryonic stem-like cells].

    PubMed

    Bai, Changming; Liu, Chousheng; Wang, Zhigang; Wang, Xinzhuang

    2008-07-01

    In this research, we use mouse embryonic fibroblasts as feeder layers. To eliminate the influence of serum and mouse embryonic stem cells (ESCs) conditioned medium (ESCCM) on self-renewal of sheep embryonic stem-like cells, knockout serum replacement (KSR) was used to replace serum, then supplanted with ESCCM for the isolation and cloning of sheep embryonic stem-like cells. We found when inner cell masses (ICMs) cultured in the control group with medium supplanted with fetal bovine serum (FBS), sheep ES-like cells could not survive for more than 3 passages. However, sheep embryonic stem-like cells could remain undifferentiated for 5 passages when cultured in the medium that FBS was substituted by KSR. The result indicates that KSR culture system was more suitable for the isolation and cloning of sheep embryonic stem-like cells compared to FBS culture system. Finally we applied medium with 15% KSR as basic medium supplanted with 40% ESCCM as a new culture system to isolate sheep embryonic stem-like cells, we found one embryonic stem-like cell line still maintained undifferentiating for 8 passages, which characterized with a normal and stable karyotype and high expression of alkaline phosphatase. These results suggest that it is suitable to culture sheep ICM in the new culture system with 15% KSR as basic medium and supplanted with 40% ESCCM, which indicated that mouse ES cells might secrete factors playing important roles in promoting sheep ES-like cells' self-renewal. PMID:18837407

  20. Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells

    PubMed Central

    Ames, Erik; Canter, Robert J; Grossenbacher, Steven K; Mac, Stephanie; Smith, Rachel C; Monjazeb, Arta M; Chen, Mingyi; Murphy, William J

    2015-01-01

    Natural killer (NK) cells are innate lymphocytes postulated to mediate resistance against primary haematopoietic but not solid tumor malignancies. Cancer stem cells (CSCs) are a small subset of malignant cells with stem-like properties which are resistant to chemo- and radiotherapies and are able to repopulate a tumor after cytoreductive treatments. We observed increased frequencies of stem-like tumor cells after irradiation, with increased expression of stress ligands on surviving stem-like cells. Ex vivo NK cells activated by low dose IL2 in vitro and IL15 in vivo displayed an increased ability to target solid tumor stem-like cells both in vitro and in vivo after irradiation. Mechanistically, both upregulation of stress-related ligands on the stem-like cells as well as debulking of non-stem populations contributed to these effects as determined by data from cell lines, primary tumor samples, and most relevant patient derived specimens. In addition, pretreatment of tumor-bearing mice with local radiation prior to NK transfer resulted in significantly longer survival indicating that radiation therapy in conjunction with NK cell adoptive immunotherapy targeting stem-like cancer cells may offer a promising novel radio-immunotherapy approach in the clinic. PMID:26405602

  1. [Effects of different culture system of isolating and passage of sheep embryonic stem-like cells].

    PubMed

    Bai, Changming; Liu, Chousheng; Wang, Zhigang; Wang, Xinzhuang

    2008-07-01

    In this research, we use mouse embryonic fibroblasts as feeder layers. To eliminate the influence of serum and mouse embryonic stem cells (ESCs) conditioned medium (ESCCM) on self-renewal of sheep embryonic stem-like cells, knockout serum replacement (KSR) was used to replace serum, then supplanted with ESCCM for the isolation and cloning of sheep embryonic stem-like cells. We found when inner cell masses (ICMs) cultured in the control group with medium supplanted with fetal bovine serum (FBS), sheep ES-like cells could not survive for more than 3 passages. However, sheep embryonic stem-like cells could remain undifferentiated for 5 passages when cultured in the medium that FBS was substituted by KSR. The result indicates that KSR culture system was more suitable for the isolation and cloning of sheep embryonic stem-like cells compared to FBS culture system. Finally we applied medium with 15% KSR as basic medium supplanted with 40% ESCCM as a new culture system to isolate sheep embryonic stem-like cells, we found one embryonic stem-like cell line still maintained undifferentiating for 8 passages, which characterized with a normal and stable karyotype and high expression of alkaline phosphatase. These results suggest that it is suitable to culture sheep ICM in the new culture system with 15% KSR as basic medium and supplanted with 40% ESCCM, which indicated that mouse ES cells might secrete factors playing important roles in promoting sheep ES-like cells' self-renewal.

  2. Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis

    PubMed Central

    Carlisi, D; Buttitta, G; Di Fiore, R; Scerri, C; Drago-Ferrante, R; Vento, R; Tesoriere, G

    2016-01-01

    Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. In this paper, we report the production of mammospheres from three lines of TNBC cells and demonstrate that both parthenolide (PN) and its soluble analog dimethylaminoparthenolide (DMAPT) suppressed this production and induced cytotoxic effects in breast cancer stem-like cells, derived from dissociation of mammospheres. In particular, the drugs exerted a remarkable inhibitory effect on viability of stem-like cells. Such an effect was suppressed by N-acetylcysteine, suggesting a role of reactive oxygen species (ROS) generation in the cytotoxic effect. Instead z-VAD, a general inhibitor of caspase activity, was ineffective. Analysis of ROS generation, performed using fluorescent probes, showed that both the drugs stimulated in the first hours of treatment a very high production of hydrogen peroxide. This event was, at least in part, a consequence of activation of NADPH oxidases (NOXs), as it was reduced by apocynin and diphenylene iodinium, two inhibitors of NOXs. Moreover, both the drugs caused downregulation of Nrf2 (nuclear factor erythroid 2-related factor 2), which is a critical regulator of the intracellular antioxidant response. Prolonging the treatment with PN or DMAPT we observed between 12 and 24 h that the levels of both superoxide anion and hROS increased in concomitance with the downregulation of manganese superoxide dismutase and catalase. In addition, during this phase dissipation of mitochondrial membrane potential occurred together with necrosis of stem-like cells. Finally, our results suggested that the effect on ROS generation found in the first hours of treatment was, in part, responsible for the cytotoxic events observed in the successive phase. In conclusion, PN and DMAPT markedly inhibited viability of stem-like cells derived from three lines of TNBCs by inducing ROS generation, mitochondrial dysfunction and cell necrosis

  3. Transcriptional profiling of adult neural stem-like cells from the human brain.

    PubMed

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate.

  4. Transcriptional Profiling of Adult Neural Stem-Like Cells from the Human Brain

    PubMed Central

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O.; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A.

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33–60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate. PMID

  5. Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells

    PubMed Central

    Isokpehi, Raphael D; Wollenberg Valero, Katharina C; Graham, Barbara E; Pacurari, Maricica; Sims, Jennifer N; Udensi, Udensi K; Ndebele, Kenneth

    2015-01-01

    Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0–AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres. PMID:26279619

  6. Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells.

    PubMed

    Isokpehi, Raphael D; Wollenberg Valero, Katharina C; Graham, Barbara E; Pacurari, Maricica; Sims, Jennifer N; Udensi, Udensi K; Ndebele, Kenneth

    2015-01-01

    Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0-AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres.

  7. Novel anticancer activity of phloroglucinol against breast cancer stem-like cells

    SciTech Connect

    Kim, Rae-Kwon; Uddin, Nizam; Hyun, Jin-Won; Kim, Changil; Suh, Yongjoon; Lee, Su-Jae

    2015-08-01

    Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage-independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44{sup +} cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2 and β-catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse. - Highlights: • Phloroglucinol suppresses in vivo tumor formation. • Phloroglucinol sensitizes breast cancer cells to anticancer agents. • Phloroglucinol inhibits breast cancer stem-like cells. • Phloroglucinol inhibits PI3K/AKT and KRAS/RAF/ERK signaling pathways.

  8. Bruton's tyrosine kinase (Btk) inhibitor ibrutinib suppresses stem-like traits in ovarian cancer

    PubMed Central

    Zucha, Muhammad Ary; Wu, Alexander T.H.; Lee, Wei-Hwa; Wang, Liang-Shun; Lin, Wan-Wan; Yuan, Chiou-Chung; Yeh, Chi-Tai

    2015-01-01

    According to a Prognoscan database, upregulation of Bruton's tyrosine kinase (Btk) is associated with low overall survival in ovarian cancer patients. We found that spheroids-forming ovarian cancer cell, which highly expressed cancer stem-like cell (CSC) markers and Btk, were cisplatin resistant. We next treated CSCs and non-CSCs by a combination of ibrutinib and cisplatin. We found that chemoresistance was dependent on Btk and JAK2/STAT3, which maintained CSC by inducing Sox-2 and prosurvival genes. We suggest that addition of ibrutinib to cisplatin may improve treatment outcome in ovarian cancer. PMID:26036311

  9. Establishment and Analysis of Cancer Stem-Like and Non-Cancer Stem-Like Clone Cells from the Human Colon Cancer Cell Line SW480.

    PubMed

    Takaya, Akari; Hirohashi, Yoshihiko; Murai, Aiko; Morita, Rena; Saijo, Hiroshi; Yamamoto, Eri; Kubo, Terufumi; Nakatsugawa, Munehide; Kanaseki, Takayuki; Tsukahara, Tomohide; Tamura, Yasuaki; Takemasa, Ichiro; Kondo, Toru; Sato, Noriyuki; Torigoe, Toshihiko

    2016-01-01

    Human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be isolated as side population (SP) cells, aldehyde dehydrogenase high (ALDHhigh) cells or cell surface marker-positive cells including CD44+ cells and CD133+ cells. CSCs/CICs and non-CSCs/CICs are unstable in in vitro culture, and CSCs/CICs can differentiate into non-CSCs/CICs and some non-CSCs/CICs can dedifferentiate into CSCs/CICs. Therefore, experiments using a large amount of CSCs/CICs are technically very difficult. In this study, we isolated single cell clones from SP cells and main population (MP) cells derived from the human colon cancer cell line SW480. SP analysis revealed that SP clone cells had relatively high percentages of SP cells, whereas MP clone cells showed very few SP cells, and the phenotypes were sustainable for more than 2 months of in vitro culture. Xenograft transplantation revealed that SP clone cells have higher tumor-initiating ability than that of MP clone cells and SP clone cell showed higher chemo-resistance compared with MP clone cells. These results indicate that SP clone cells derived from SW480 cells are enriched with CSCs/CICs, whereas MP clone cells are pure non-CSCs/CICs. SP clone cells and MP clone cells are a very stable in vitro CSC/CIC-enriched and non-CSC/CIC model for further analysis.

  10. Establishment and Analysis of Cancer Stem-Like and Non-Cancer Stem-Like Clone Cells from the Human Colon Cancer Cell Line SW480

    PubMed Central

    Takaya, Akari; Hirohashi, Yoshihiko; Murai, Aiko; Morita, Rena; Saijo, Hiroshi; Yamamoto, Eri; Kubo, Terufumi; Nakatsugawa, Munehide; Kanaseki, Takayuki; Tsukahara, Tomohide; Tamura, Yasuaki; Takemasa, Ichiro; Kondo, Toru; Sato, Noriyuki; Torigoe, Toshihiko

    2016-01-01

    Human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be isolated as side population (SP) cells, aldehyde dehydrogenase high (ALDHhigh) cells or cell surface marker-positive cells including CD44+ cells and CD133+ cells. CSCs/CICs and non-CSCs/CICs are unstable in in vitro culture, and CSCs/CICs can differentiate into non-CSCs/CICs and some non-CSCs/CICs can dedifferentiate into CSCs/CICs. Therefore, experiments using a large amount of CSCs/CICs are technically very difficult. In this study, we isolated single cell clones from SP cells and main population (MP) cells derived from the human colon cancer cell line SW480. SP analysis revealed that SP clone cells had relatively high percentages of SP cells, whereas MP clone cells showed very few SP cells, and the phenotypes were sustainable for more than 2 months of in vitro culture. Xenograft transplantation revealed that SP clone cells have higher tumor-initiating ability than that of MP clone cells and SP clone cell showed higher chemo-resistance compared with MP clone cells. These results indicate that SP clone cells derived from SW480 cells are enriched with CSCs/CICs, whereas MP clone cells are pure non-CSCs/CICs. SP clone cells and MP clone cells are a very stable in vitro CSC/CIC-enriched and non-CSC/CIC model for further analysis. PMID:27415781

  11. Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

    SciTech Connect

    Yue, Dongli; Zhang, Zhen; Li, Jieyao; Chen, Xinfeng; Ping, Yu; Liu, Shasha; Shi, Xiaojuan; Li, Lifeng; Wang, Liping; Huang, Lan; Zhang, Bin; and others

    2015-08-01

    Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells. - Highlights: • Esophageal cancer sphere-forming cells possess cancer stem cell properties. • Sphere-forming cells enhance TGF-β1 pathway activity. • TGF-β 1 inhibitor suppresses the migration and invasion of sphere-forming cells.

  12. Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells

    PubMed Central

    Cheng, Jie; Li, Wenxin; Kang, Bo; Zhou, Yanwen; Song, Jiasheng; Dan, Songsong; Yang, Ying; Zhang, Xiaoqian; Li, Jingchao; Yin, Shengyong; Cao, Hongcui; Yao, Hangping; Zhu, Chenggang; Yi, Wen; Zhao, Qingwei; Xu, Xiaowei; Zheng, Min; Zheng, Shusen; Li, Lanjuan; Shen, Binghui; Wang, Ying-Jie

    2015-01-01

    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to environmental toxicants, is increasingly recognized as a key player in embryogenesis and tumorigenesis. Here we show that a variety of tryptophan derivatives that act as endogenous AhR ligands can affect the transcription level of the master pluripotency factor Oct4. Among them, ITE enhances the binding of the AhR to the promoter of Oct4 and suppresses its transcription. Reduction of endogenous ITE levels in cancer cells by tryptophan deprivation or hypoxia leads to Oct4 elevation, which can be reverted by administration with synthetic ITE. Consequently, synthetic ITE induces the differentiation of stem-like cancer cells and reduces their tumorigenic potential in both subcutaneous and orthotopic xenograft tumour models. Thus, our results reveal a role of tryptophan derivatives and the AhR signalling pathway in regulating cancer cell stemness and open a new therapeutic avenue to target stem-like cancer cells. PMID:26059097

  13. Enriched inhibition of cancer and stem-like cancer cells via STAT-3 modulating niclocelles

    NASA Astrophysics Data System (ADS)

    Misra, Santosh K.; Jensen, Tor W.; Pan, Dipanjan

    2015-04-01

    We describe for the first time a therapeutic strategy to target stem-like cancer cells via STAT-3 modulation using a nanomedicine approach. Niclocelle, a niclosamide loaded rigid core mixed micelle, was synthesized from a self-assembled well-defined amphiphilic diblock copolymer and an FDA-approved signal transducer and activator of transcription factor 3. Followed by a rigorous physico-chemical characterization, niclocelles were evaluated biologically for cytotoxicity and apoptosis in human melanoma (C32) and breast cancer (MDA-MB231 and MCF-7) cells. Niclocelles were found to selectively reduce the CD44+ stem cell population in C32 cells via STAT-3 modulation.We describe for the first time a therapeutic strategy to target stem-like cancer cells via STAT-3 modulation using a nanomedicine approach. Niclocelle, a niclosamide loaded rigid core mixed micelle, was synthesized from a self-assembled well-defined amphiphilic diblock copolymer and an FDA-approved signal transducer and activator of transcription factor 3. Followed by a rigorous physico-chemical characterization, niclocelles were evaluated biologically for cytotoxicity and apoptosis in human melanoma (C32) and breast cancer (MDA-MB231 and MCF-7) cells. Niclocelles were found to selectively reduce the CD44+ stem cell population in C32 cells via STAT-3 modulation. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c5nr00403a

  14. Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization.

    PubMed

    Gatti, Monica; Wurth, Roberto; Vito, Guendalina; Pattarozzi, Alessandra; Campanella, Chiara; Thellung, Stefano; Maniscalco, Lorella; De Maria, Raffaella; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Bajetto, Adriana; Ratto, Alessandra; Ferrari, Angelo; Barbieri, Federica; Florio, Tullio

    2016-05-01

    Cancer stem cells (CSCs) represent a small subpopulation of cells responsible for tumor formation and progression, drug resistance, tumor recurrence and metastasization. CSCs have been identified in many human tumors including osteosarcoma (OSA). CSC distinctive properties are the expression of stem cell markers, sustained growth, self-renewal and tumorigenicity. Here we report the isolation of stem-like cells from two canine OSA cultures, characterized by self-renewal, evaluated by sphere formation ability, differential marker expression, and in vitro proliferation when cultured in a medium containing EGF and bFGF. Current therapies for OSA increased survival time, but prognosis remains poor, due to the development of drug resistance and metastases. Chemotherapy shrinks the tumor mass but CSCs remain unaffected, leading to tumor recurrence. Metformin, a drug for type 2 diabetes, has been shown to possess antitumor properties affecting CSC survival in different human and animal cancers. Here we show that metformin has a significant antiproliferative effect on canine OSA stem-like cells, validating this in vitro model for further pre-clinical drug evaluations. In conclusion, our results demonstrate the feasibility of obtaining CSC-enriched cultures from primary canine OSA cells as a promising model for biological and pharmacological studies of canine and human OSAs.

  15. Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization.

    PubMed

    Gatti, Monica; Wurth, Roberto; Vito, Guendalina; Pattarozzi, Alessandra; Campanella, Chiara; Thellung, Stefano; Maniscalco, Lorella; De Maria, Raffaella; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Bajetto, Adriana; Ratto, Alessandra; Ferrari, Angelo; Barbieri, Federica; Florio, Tullio

    2016-05-01

    Cancer stem cells (CSCs) represent a small subpopulation of cells responsible for tumor formation and progression, drug resistance, tumor recurrence and metastasization. CSCs have been identified in many human tumors including osteosarcoma (OSA). CSC distinctive properties are the expression of stem cell markers, sustained growth, self-renewal and tumorigenicity. Here we report the isolation of stem-like cells from two canine OSA cultures, characterized by self-renewal, evaluated by sphere formation ability, differential marker expression, and in vitro proliferation when cultured in a medium containing EGF and bFGF. Current therapies for OSA increased survival time, but prognosis remains poor, due to the development of drug resistance and metastases. Chemotherapy shrinks the tumor mass but CSCs remain unaffected, leading to tumor recurrence. Metformin, a drug for type 2 diabetes, has been shown to possess antitumor properties affecting CSC survival in different human and animal cancers. Here we show that metformin has a significant antiproliferative effect on canine OSA stem-like cells, validating this in vitro model for further pre-clinical drug evaluations. In conclusion, our results demonstrate the feasibility of obtaining CSC-enriched cultures from primary canine OSA cells as a promising model for biological and pharmacological studies of canine and human OSAs. PMID:27506084

  16. The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells.

    PubMed

    Boyle, S T; Ingman, W V; Poltavets, V; Faulkner, J W; Whitfield, R J; McColl, S R; Kochetkova, M

    2016-01-01

    The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.

  17. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway.

    PubMed

    Han, Seula; Woo, Jong Kyu; Jung, Yuchae; Jeong, Dawoon; Kang, Minsook; Yoo, Young-Ji; Lee, Hani; Oh, Seung Hyun; Ryu, Jae-Ha; Kim, Woo-Young

    2016-01-22

    In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulk cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer.

  18. Semaphorin 3A Induces Mesenchymal-Stem-Like Properties in Human Periodontal Ligament Cells

    PubMed Central

    Maeda, Hidefumi; Hasegawa, Daigaku; Gronthos, Stan; Bartold, Peter Mark; Menicanin, Danijela; Fujii, Shinsuke; Yoshida, Shinichiro; Tomokiyo, Atsushi; Monnouchi, Satoshi; Akamine, Akifumi

    2014-01-01

    Periodontal ligament stem cells (PDLSCs) have recently been proposed as a novel option in periodontal regenerative therapy. However, one of the issues is the difficulty of stably generating PDLSCs because of the variation of stem cell potential between donors. Here, we show that Semaphorin 3A (Sema3A) can induce mesenchymal-stem-like properties in human periodontal ligament (PDL) cells. Sema3A expression was specifically observed in the dental follicle during tooth development and in parts of mature PDL tissue in rodent tooth and periodontal tissue. Sema3A expression levels were found to be higher in multipotential human PDL cell clones compared with low-differentiation potential clones. Sema3A-overexpressing PDL cells exhibited an enhanced capacity to differentiate into both functional osteoblasts and adipocytes. Moreover, PDL cells treated with Sema3A only at the initiation of culture stimulated osteogenesis, while Sema3A treatment throughout the culture had no effect on osteogenic differentiation. Finally, Sema3A-overexpressing PDL cells upregulated the expression of embryonic stem cell markers (NANOG, OCT4, and E-cadherin) and mesenchymal stem cell markers (CD73, CD90, CD105, CD146, and CD166), and Sema3A promoted cell division activity of PDL cells. These results suggest that Sema3A may possess the function to convert PDL cells into mesenchymal-stem-like cells. PMID:24380401

  19. Conditionally reprogrammed cells represent a stem-like state of adult epithelial cells

    PubMed Central

    Suprynowicz, Frank A.; Upadhyay, Geeta; Krawczyk, Ewa; Kramer, Sarah C.; Hebert, Jess D.; Liu, Xuefeng; Yuan, Hang; Cheluvaraju, Chaitra; Clapp, Phillip W.; Boucher, Richard C.; Kamonjoh, Christopher M.; Randell, Scott H.; Schlegel, Richard

    2012-01-01

    The combination of irradiated fibroblast feeder cells and Rho kinase inhibitor, Y-27632, conditionally induces an indefinite proliferative state in primary mammalian epithelial cells. These conditionally reprogrammed cells (CRCs) are karyotype-stable and nontumorigenic. Because self-renewal is a recognized property of stem cells, we investigated whether Y-27632 and feeder cells induced a stem-like phenotype. We found that CRCs share characteristics of adult stem cells and exhibit up-regulated expression of α6 and β1 integrins, ΔNp63α, CD44, and telomerase reverse transcriptase, as well as decreased Notch signaling and an increased level of nuclear β-catenin. The induction of CRCs is rapid (occurs within 2 d) and results from reprogramming of the entire cell population rather than the selection of a minor subpopulation. CRCs do not overexpress the transcription factor sets characteristic of embryonic or induced pluripotent stem cells (e.g., Sox2, Oct4, Nanog, or Klf4). The induction of CRCs is also reversible, and removal of Y-27632 and feeders allows the cells to differentiate normally. Thus, when CRCs from ectocervical epithelium or tracheal epithelium are placed in an air–liquid interface culture system, the cervical cells form a well differentiated stratified squamous epithelium, whereas the tracheal cells form a ciliated airway epithelium. We discuss the diagnostic and therapeutic opportunities afforded by a method that can generate adult stem-like cells in vitro without genetic manipulation. PMID:23169653

  20. Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells.

    PubMed

    Cheng, Jie; Li, Wenxin; Kang, Bo; Zhou, Yanwen; Song, Jiasheng; Dan, Songsong; Yang, Ying; Zhang, Xiaoqian; Li, Jingchao; Yin, Shengyong; Cao, Hongcui; Yao, Hangping; Zhu, Chenggang; Yi, Wen; Zhao, Qingwei; Xu, Xiaowei; Zheng, Min; Zheng, Shusen; Li, Lanjuan; Shen, Binghui; Wang, Ying-Jie

    2015-06-10

    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to environmental toxicants, is increasingly recognized as a key player in embryogenesis and tumorigenesis. Here we show that a variety of tryptophan derivatives that act as endogenous AhR ligands can affect the transcription level of the master pluripotency factor Oct4. Among them, ITE enhances the binding of the AhR to the promoter of Oct4 and suppresses its transcription. Reduction of endogenous ITE levels in cancer cells by tryptophan deprivation or hypoxia leads to Oct4 elevation, which can be reverted by administration with synthetic ITE. Consequently, synthetic ITE induces the differentiation of stem-like cancer cells and reduces their tumorigenic potential in both subcutaneous and orthotopic xenograft tumour models. Thus, our results reveal a role of tryptophan derivatives and the AhR signalling pathway in regulating cancer cell stemness and open a new therapeutic avenue to target stem-like cancer cells.

  1. Histological Characterization of the Tumorigenic “Peri-Necrotic Niche” Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma

    PubMed Central

    Ishii, Aya; Kimura, Tokuhiro; Sadahiro, Hirokazu; Kawano, Hiroo; Takubo, Keiyo; Suzuki, Michiyasu; Ikeda, Eiji

    2016-01-01

    Background Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically. Methods Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay. Results A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. Conclusions These data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas. PMID:26799577

  2. Biomarker-specific conjugated nanopolyplexes for the active coloring of stem-like cancer cells

    NASA Astrophysics Data System (ADS)

    Hong, Yoochan; Lee, Eugene; Choi, Jihye; Haam, Seungjoo; Suh, Jin-Suck; Yang, Jaemoon

    2016-06-01

    Stem-like cancer cells possess intrinsic features and their CD44 regulate redox balance in cancer cells to survive under stress conditions. Thus, we have fabricated biomarker-specific conjugated polyplexes using CD44-targetable hyaluronic acid and redox-sensible polyaniline based on a nanoemulsion method. For the most sensitive recognition of the cellular redox at a single nanoparticle scale, a nano-scattering spectrum imaging analyzer system was introduced. The conjugated polyplexes showed a specific targeting ability toward CD44-expressing cancer cells as well as a dramatic change in its color, which depended on the redox potential in the light-scattered images. Therefore, these polyaniline-based conjugated polyplexes as well as analytical processes that include light-scattering imaging and measurements of scattering spectra, clearly establish a systematic method for the detection and monitoring of cancer microenvironments.

  3. Biomarker-specific conjugated nanopolyplexes for the active coloring of stem-like cancer cells.

    PubMed

    Hong, Yoochan; Lee, Eugene; Choi, Jihye; Haam, Seungjoo; Suh, Jin-Suck; Yang, Jaemoon

    2016-06-01

    Stem-like cancer cells possess intrinsic features and their CD44 regulate redox balance in cancer cells to survive under stress conditions. Thus, we have fabricated biomarker-specific conjugated polyplexes using CD44-targetable hyaluronic acid and redox-sensible polyaniline based on a nanoemulsion method. For the most sensitive recognition of the cellular redox at a single nanoparticle scale, a nano-scattering spectrum imaging analyzer system was introduced. The conjugated polyplexes showed a specific targeting ability toward CD44-expressing cancer cells as well as a dramatic change in its color, which depended on the redox potential in the light-scattered images. Therefore, these polyaniline-based conjugated polyplexes as well as analytical processes that include light-scattering imaging and measurements of scattering spectra, clearly establish a systematic method for the detection and monitoring of cancer microenvironments. PMID:27098318

  4. A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells.

    PubMed

    Mao, Diane D; Gujar, Amit D; Mahlokozera, Tatenda; Chen, Ishita; Pan, Yanchun; Luo, Jingqin; Brost, Taylor; Thompson, Elizabeth A; Turski, Alice; Leuthardt, Eric C; Dunn, Gavin P; Chicoine, Michael R; Rich, Keith M; Dowling, Joshua L; Zipfel, Gregory J; Dacey, Ralph G; Achilefu, Samuel; Tran, David D; Yano, Hiroko; Kim, Albert H

    2015-06-23

    Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.

  5. Drug Delivery Using Nanoparticles for Cancer Stem-Like Cell Targeting

    PubMed Central

    Lu, Bing; Huang, Xiaojia; Mo, Jingxin; Zhao, Wei

    2016-01-01

    The theory of cancer stem-like cell (or cancer stem cell, CSC) has been established to explain how tumor heterogeneity arises and contributes to tumor progression in diverse cancer types. CSCs are believed to drive tumor growth and elicit resistance to conventional therapeutics. Therefore, CSCs are becoming novel target in both medical researches and clinical studies. Emerging evidences showed that nanoparticles effectively inhibit many types of CSCs by targeting various specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) and signaling pathways (Notch, Hedgehog, and TGF-β), which are critically involved in CSC function and maintenance. In this review, we briefly summarize the current status of CSC research and review a number of state-of-the-art nanomedicine approaches targeting CSC. In addition, we discuss emerging therapeutic strategies using epigenetic drugs to eliminate CSCs and inhibit cancer cell reprogramming. PMID:27148051

  6. Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

    PubMed Central

    Yang, Jian; Gao, Tian; Simões, Bruno M.; Eyre, Rachel; Guo, Weichun; Clarke, Robert B.

    2016-01-01

    Notch signaling regulates normal stem cells and is also thought to regulate cancer stem cells (CSCs). Recent data indicate that Notch signaling plays a role in the development and progression of osteosarcoma, however the regulation of Notch in chemo-resistant stem-like cells has not yet been fully elucidated. In this study we generated cisplatin-resistant osteosarcoma cells by treating them with sub-lethal dose of cisplatin, sufficient to induce DNA damage responses. Cisplatin-resistant osteosarcoma cells exhibited lower proliferation, enhanced spheroid formation and more mesenchymal characteristics than cisplatin-sensitive cells, were enriched for Stro-1+/CD117+ cells and showed increased expression of stem cell-related genes. A similar effect was observed in vivo, and in addition in vivo tumorigenicity was enhanced during serial transplantation. Using several publicly available datasets, we identified that Notch expression was closely associated with osteosarcoma stem cells and chemotherapy resistance. We confirmed that cisplatin-induced enrichment of osteosarcoma stem cells was mediated through Notch signaling in vitro, and immunohistochemistry showed that cleaved Notch1 (NICD1) positive cells were significantly increased in a relapsed xenograft which had received cisplatin treatment. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signalling inhibited cisplatin-enriched osteosarcoma stem cell activity in vitro, including Stro-1+/CD117+ double positive cells and spheroid formation capacity. The Notch inhibitor DAPT also prevented tumor recurrence in resistant xenograft tumors. Overall, our results show that cisplatin induces the enrichment of osteosarcoma stem-like cells through Notch signaling, and targeted inactivation of Notch may be useful for the elimination of CSCs and overcoming drug resistance. PMID:27102300

  7. Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties

    PubMed Central

    Ma, Yuanyuan; Liang, Dongming; Liu, Jian; Axcrona, Karol; Kvalheim, Gunnar; Stokke, Trond; Nesland, Jahn M.; Suo, Zhenhe

    2011-01-01

    Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O2), 7% O2 induced higher expressions of HIF-1α and HIF-2α, which were associated with upregulation of Oct3/4 and Nanog; 1% O2 induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O2 also extended the G0/G1 stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44bright cells. Correspondingly, the sorted CD44bright cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44dim cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44bright cells under normoxia formed significantly more colonies and spheres compared with the CD44dim cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties. PMID:22216200

  8. Ca2+/calmodulin-dependent protein kinase IIγ enhances stem-like traits and tumorigenicity of lung cancer cells

    PubMed Central

    Wang, Yongfang; Zhou, You; Zhang, Chenchen; Yang, Yiming; Yang, Ying; Xu, Haiyan; Xu, Rongzhen; Wang, Kai

    2015-01-01

    Highly tumorigenic stem-like cells, considered tumor-initiating cells (TICs), are the main cause of lung cancer initiation, relapse, and drug resistance. In this study, we identified that Ca2+/calmodulin-dependent protein kinase IIγ (CaMKIIγ) was aberrantly expressed in highly tumorigenic stem-like lung cancer cells, and was also correlated with poor prognosis in human lung cancer. Functionally, CaMKIIγ enhanced stem-like traits and the tumorigenicity of lung cancer cells in an Akt- and β-catenin-dependent manner. In addition, we found that CaMKIIγ upregulated Oct4 expression via Akt-mediated histone acetylation. Taken together, our findings reveal a critical role of CaMKIIγ in regulating the stemness and tumorigenicity of lung cancer cells and offer a promising therapeutic target for TICs. PMID:25965829

  9. Prognostic Value of 18F-FDG PET-CT in Nasopharyngeal Carcinoma: Is Dynamic Scanning Helpful?

    PubMed Central

    Huang, Bingsheng; Wong, Ching-Yee Oliver; Lai, Vincent; Kwong, Dora Lai-Wan; Khong, Pek-Lan

    2015-01-01

    Objectives. To evaluate the differences in prognostic values of static and dynamic PET-CT in nasopharyngeal carcinoma (NPC). Material and Methods. Forty-five patients who had static scan were recruited. Sixteen had dynamic scan. The primary lesions were delineated from standardized uptake value (SUV) maps from static scan and Ki maps from dynamic scan. The average follow-up lasted for 34 months. The patients who died or those with recurrence/residual disease were considered “poor outcome”; otherwise they were considered “good outcome.” Fisher's exact test and ROC analysis were used to evaluate the prognostic value of various factors. Results. Tumor volume thresholded by 40% of maximal SUV (VOLSUV40) significantly predicted treatment outcome (p = 0.024) in the whole cohort. In 16 patients with dynamic scan, all parameters by dynamic scan were insignificant in predicting the outcome. The combination of maximal SUV, maximal Ki, VOLSUV40, and VOLKi37 (the tumor volume thresholded by 37% maximal Ki) achieved the highest predicting accuracy for treatment outcome with sensitivity, specificity, and accuracy of 100% in these 16 patients; however this improvement compared to VOLSUV40 was insignificant. Conclusion. Tumor volume from static scan is useful in NPC prognosis. However, the role of dynamic scanning was not justified in this small cohort. PMID:26064927

  10. Can New Ultrasound Signs Help in Identifying Follicular Variant of Papillary Carcinoma of Thyroid? – A Pilot Study

    PubMed Central

    Anuradha, C.; Manipadam, M. T.; Asha, H. S.; Dukhabandhu, N.; Abraham, D.; Paul, M. J.

    2016-01-01

    Aim: To describe two new ultrasound signs for thyroid nodules – “nodule in nodule” and “hypoechoic internal septae” and assess their usefulness in differentiating follicular variant of papillary thyroid carcinoma (FVPTC) from benign thyroid nodules (BTN). Methodology: Ultrasound findings of 210 patients with histopathologically proven FVPTC (68 nodules, M:F=13:47 with mean age of 39.5±11.9 years) and BTN (165 nodules, (M:F=41:109 with mean age of 44±11.3 years) were retrospectively reviewed from PACS by a single radiologist blinded to the final diagnosis. Logistic regression analysis was performed to identify the best predictors of FVPTC and their diagnostic performance was assessed. Results: The “nodule in nodule” sign was seen in 80.9% of FVPTC and only 12.1% of BTN. The “hypoechoic internal septae” sign was seen in 44.1% of FVPTC and 17% of BTN. Younger patients, heterogeneous echotexture, nodule in nodule sign, thick incomplete non-uniform halo and presence of significant nodes were the best predictors of FVPTC (p<0.05). The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and relative risk for FVPTC given as odds ratio (95% CI) for heterogeneous echotexture and nodule in nodule sign which were the best 2 predictors of FVPTC were 91.2%, 81.8%, 67.3%, 95.7%, 84.5%, 46.5 (18.5–117.4) and 80.9%, 87.7%, 74.3%, 91.2%, 86.2%, 32.5 (15.04–70.2), respectively. There was improvement in the specificity (91.5%) and accuracy (86.6%) when a combined criterion of heterogeneous echotexture and nodule in nodule sign was applied to predict FVPTC. Conclusion: The “nodule in nodule” sign is common in FVPTC and when combined with heterogeneous echotexture can differentiate FVPTC and BTN with high specificity. PMID:27689170

  11. Can New Ultrasound Signs Help in Identifying Follicular Variant of Papillary Carcinoma of Thyroid? – A Pilot Study

    PubMed Central

    Anuradha, C.; Manipadam, M. T.; Asha, H. S.; Dukhabandhu, N.; Abraham, D.; Paul, M. J.

    2016-01-01

    Aim: To describe two new ultrasound signs for thyroid nodules – “nodule in nodule” and “hypoechoic internal septae” and assess their usefulness in differentiating follicular variant of papillary thyroid carcinoma (FVPTC) from benign thyroid nodules (BTN). Methodology: Ultrasound findings of 210 patients with histopathologically proven FVPTC (68 nodules, M:F=13:47 with mean age of 39.5±11.9 years) and BTN (165 nodules, (M:F=41:109 with mean age of 44±11.3 years) were retrospectively reviewed from PACS by a single radiologist blinded to the final diagnosis. Logistic regression analysis was performed to identify the best predictors of FVPTC and their diagnostic performance was assessed. Results: The “nodule in nodule” sign was seen in 80.9% of FVPTC and only 12.1% of BTN. The “hypoechoic internal septae” sign was seen in 44.1% of FVPTC and 17% of BTN. Younger patients, heterogeneous echotexture, nodule in nodule sign, thick incomplete non-uniform halo and presence of significant nodes were the best predictors of FVPTC (p<0.05). The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and relative risk for FVPTC given as odds ratio (95% CI) for heterogeneous echotexture and nodule in nodule sign which were the best 2 predictors of FVPTC were 91.2%, 81.8%, 67.3%, 95.7%, 84.5%, 46.5 (18.5–117.4) and 80.9%, 87.7%, 74.3%, 91.2%, 86.2%, 32.5 (15.04–70.2), respectively. There was improvement in the specificity (91.5%) and accuracy (86.6%) when a combined criterion of heterogeneous echotexture and nodule in nodule sign was applied to predict FVPTC. Conclusion: The “nodule in nodule” sign is common in FVPTC and when combined with heterogeneous echotexture can differentiate FVPTC and BTN with high specificity.

  12. Cancer/testis antigens trigger epithelial-mesenchymal transition and genesis of cancer stem-like cells.

    PubMed

    Yang, Ping; Huo, Zihe; Liao, Huaidong; Zhou, Quansheng

    2015-01-01

    Malignant tumors aberrantly overexpress various embryonic genes and proto-oncogenes, including a variety of cancer-testis antigens (CTAs). CTAs belong to a class of testis-derived proteins which are only expressed in germ cells in the male testis, and the expression of CTA genes is entirely silenced in the adult somatic tissues. They are, however, aberrantly overexpressed in a variety of malignant tumor tissues. Emerging evidence shows that a number of CTAs promote epithelialmesenchymal transition (EMT) and genesis of cancer stem like cells, escalating tumorigenesis, invasion, and metastasis. The can cer-testis antigens, such as SSX, MAGE-D4B, CAGE, piwil2, and CT45A1, upregulate EMT and metastatic genes, promoting EMT and tumor dissemination. In addition, certain members of CTAs, including Piwil2, DNAJB8, CT45A1, MAGE-A, GAGE, and SPANX, are implicated in the initiation or maintenance, of cancer stem-like cells, promoting tumorigenesis and malignant progression. Clinically CTAs are closely associated with poor prognosis in cancer patients. Intriguely, CTAs are strongly immunogenic and normally restricted to the male testis after birth, however, these proteins are aberrantly overexpressed in cancer stem-like cells and in a variety of cancers, suggesting their target potential for cancer immunotherapy, as diagnostic biomarkers, and as targets for novel anticancer drug discovery. Thus, the targeting of tumorigenic CTAs is a promising strategy to eradicate cancer stem-like cells and inhibit tumorigenesis for effective cancer treatment.

  13. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

    PubMed Central

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  14. Breast cancer stem-like cells: clinical implications and therapeutic strategies

    PubMed Central

    TUDORAN, OANA MIHAELA; BALACESCU, OVIDIU; BERINDAN-NEAGOE, IOANA

    2016-01-01

    Breast cancer is the most frequently diagnosed cancer in women, being also the leading cause of cancer death among female population, including in Romania. Resistance to therapy represents a major problem for cancer treatment. Current cancer treatments are both expensive and induce serious side effects; therefore ineffective therapies are both traumatic and pricy. Characterizing predictive markers that can identify high-risk patients could contribute to dedicated/personalized therapy to improve the life quality and expectancy of cancer patients. Moreover, there are some markers that govern specific tumor molecular features that can be targeted with specific therapies for those patients who are most likely to benefit. The identification of stem cells in both normal and malignant breast tissue have lead to the hypothesis that breast tumors arise from breast cancer stem-like cells (CSCs), and that these cells influence tumor’s response to therapy. CSCs have similar self-renewal properties to normal stem cells, however the balance between the signaling pathways is altered towards tumor formation In this review, we discuss the molecular aspects of breast CSCs and the controversies regarding their use in the diagnosis and treatment decision of breast cancer patients. PMID:27152067

  15. Radiotherapy diagnostic biomarkers in radioresistant human H460 lung cancer stem-like cells

    PubMed Central

    Yun, Hong Shik; Baek, Jeong-Hwa; Yim, Ji-Hye; Um, Hong-Duck; Park, Jong Kuk; Song, Jie-Young; Park, In-Chul; Kim, Jae-Sung; Lee, Su-Jae; Lee, Chang-Woo; Hwang, Sang-Gu

    2016-01-01

    ABSTRACT Tumor cell radioresistance is a major contributor to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. In this work, we established a radioresistant H460 (RR-H460) cell line from parental radiosensitive H460 lung cancer cells by exposure to fractionated radiation. The radiation-resistant, anti-apoptotic phenotype of RR-H460 cell lines was confirmed by their enhanced clonogenic survival and increased expression of the radioresistance genes Hsp90 and Her-3. RR-H460 cells displayed characteristics of cancer stem-like cells (CSCs), including induction of the surface marker CD44 and stem cell markers Nanog, Oct4, and Sox2. RR-H460 cells also exhibited sphere formation and malignant behavior, further supporting a CSC phenotype. Using proteomic analyses, we identified 8 proteins that were up-regulated in RR-H460 CSC lines and therefore potentially involved in radioresistance and CSC-related biological processes. Notably, 4 of these—PAI-2, NOMO2, KLC4, and PLOD3—have not been previously linked to radioresistance. Depletion of these individual genes sensitized RR-H460 cells to radiotoxicity and additively enhancing radiation-induced apoptosis. Our findings suggest the possibility of integrating molecular targeted therapy with radiotherapy as a strategy for resolving the radioresistance of lung tumors. PMID:26901847

  16. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

    PubMed Central

    2014-01-01

    Background Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. Case presentation We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking. We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed. Conclusions The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour. PMID:24739212

  17. Targeting cancer stem-like cells as an approach to defeating cellular heterogeneity in Ewing sarcoma.

    PubMed

    Cornaz-Buros, Sandrine; Riggi, Nicolo; DeVito, Claudio; Sarre, Alexandre; Letovanec, Igor; Provero, Paolo; Stamenkovic, Ivan

    2014-11-15

    Plasticity in cancer stem-like cells (CSC) may provide a key basis for cancer heterogeneity and therapeutic response. In this study, we assessed the effect of combining a drug that abrogates CSC properties with standard-of-care therapy in a Ewing sarcoma family tumor (ESFT). Emergence of CSC in this setting has been shown to arise from a defect in TARBP2-dependent microRNA maturation, which can be corrected by exposure to the fluoroquinolone enoxacin. In the present work, primary ESFT from four patients containing CD133(+) CSC subpopulations ranging from 3% to 17% of total tumor cells were subjected to treatment with enoxacin, doxorubicin, or both drugs. Primary ESFT CSC and bulk tumor cells displayed divergent responses to standard-of-care chemotherapy and enoxacin. Doxorubicin, which targets the tumor bulk, displayed toxicity toward primary adherent ESFT cells in culture but not to CSC-enriched ESFT spheres. Conversely, enoxacin, which enhances miRNA maturation by stimulating TARBP2 function, induced apoptosis but only in ESFT spheres. In combination, the two drugs markedly depleted CSCs and strongly reduced primary ESFTs in xenograft assays. Our results identify a potentially attractive therapeutic strategy for ESFT that combines mechanism-based targeting of CSC using a low-toxicity antibiotic with a standard-of-care cytotoxic drug, offering immediate applications for clinical evaluation.

  18. Vascular Transdifferentiation in the CNS: A Focus on Neural and Glioblastoma Stem-Like Cells

    PubMed Central

    Bauchet, Luc; Rothhut, Bernard; Hugnot, Jean-Philippe

    2016-01-01

    Glioblastomas are devastating and extensively vascularized brain tumors from which glioblastoma stem-like cells (GSCs) have been isolated by many groups. These cells have a high tumorigenic potential and the capacity to generate heterogeneous phenotypes. There is growing evidence to support the possibility that these cells are derived from the accumulation of mutations in adult neural stem cells (NSCs) as well as in oligodendrocyte progenitors. It was recently reported that GSCs could transdifferentiate into endothelial-like and pericyte-like cells both in vitro and in vivo, notably under the influence of Notch and TGFβ signaling pathways. Vascular cells derived from GBM cells were also observed directly in patient samples. These results could lead to new directions for designing original therapeutic approaches against GBM neovascularization but this specific reprogramming requires further molecular investigations. Transdifferentiation of nontumoral neural stem cells into vascular cells has also been described and conversely vascular cells may generate neural stem cells. In this review, we present and discuss these recent data. As some of them appear controversial, further validation will be needed using new technical approaches such as high throughput profiling and functional analyses to avoid experimental pitfalls and misinterpretations. PMID:27738435

  19. EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells

    PubMed Central

    Krusche, Benjamin; Ottone, Cristina; Clements, Melanie P; Johnstone, Ewan R; Goetsch, Katrin; Lieven, Huang; Mota, Silvia G; Singh, Poonam; Khadayate, Sanjay; Ashraf, Azhaar; Davies, Timothy; Pollard, Steven M; De Paola, Vincenzo; Roncaroli, Federico; Martinez-Torrecuadrada, Jorge; Bertone, Paul; Parrinello, Simona

    2016-01-01

    Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM. DOI: http://dx.doi.org/10.7554/eLife.14845.001 PMID:27350048

  20. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells.

    PubMed

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O'Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  1. ROCK Inhibition Facilitates In Vitro Expansion of Glioblastoma Stem-Like Cells

    PubMed Central

    Tilson, Samantha G.; Haley, Elizabeth M.; Triantafillu, Ursula L.; Dozier, David A.; Langford, Catherine P.; Gillespie, G. Yancey; Kim, Yonghyun

    2015-01-01

    Due to their stem-like characteristics and their resistance to existing chemo- and radiation therapies, there is a growing appreciation that cancer stem cells (CSCs) are the root cause behind cancer metastasis and recurrence. However, these cells represent a small subpopulation of cancer cells and are difficult to propagate in vitro. Glioblastoma is an extremely deadly form of brain cancer that is hypothesized to have a subpopulation of CSCs called glioblastoma stem cells (GSCs; also called brain tumor initiating cells, BTICs). We propose the use of selective Rho-kinase (ROCK) inhibitors, Y-27632 and fasudil, to promote GSC/BTIC-like cell survival and propagation in vitro. ROCK inhibitors have been implicated in suppressing apoptosis, and it was hypothesized that they would increase the number of GSC/BTIC-like cells grown in vitro and improve cloning efficiencies. Indeed, our data demonstrate that transient and continuous supplementation of non-toxic concentrations of Y-27632 and fasudil inhibited apoptosis, enhanced the cells’ ability to form spheres, and increased stem cell marker expressing GSC/BTIC-like cell subpopulation. Our data indicated that pharmacological and genetic (siRNA) inhibitions of the ROCK pathway facilitates in vitro expansion of GSC/BTIC-like cells. Thus, ROCK pathway inhibition shows promise for future optimization of CSC culture media. PMID:26167936

  2. miR-367 promotes proliferation and stem-like traits in medulloblastoma cells

    PubMed Central

    Kaid, Carolini; Silva, Patrícia B G; Cortez, Beatriz A; Rodini, Carolina O; Semedo-Kuriki, Patricia; Okamoto, Oswaldo K

    2015-01-01

    In medulloblastoma, abnormal expression of pluripotency factors such as LIN28 and OCT4 has been correlated with poor patient survival. The miR-302/367 cluster has also been shown to control self-renewal and pluripotency in human embryonic stem cells and induced pluripotent stem cells, but there is limited, mostly correlational, information about these pluripotency-related miRNA in cancer. We evaluated whether aberrant expression of such miRNA could affect tumor cell behavior and stem-like traits, thereby contributing to the aggressiveness of medulloblastoma cells. Basal expression of primary and mature forms of miR-367 were detected in four human medulloblastoma cell lines and expression of the latter was found to be upregulated upon enforced expression of OCT4A. Transient overexpression of miR-367 significantly enhanced tumor features typically correlated with poor prognosis; namely, cell proliferation, 3-D tumor spheroid cell invasion and the ability to generate neurosphere-like structures enriched in CD133 expressing cells. A concurrent downregulation of the miR-367 cancer-related targets RYR3, ITGAV and RAB23, was also detected in miR-367-overexpressing cells. Overall, these findings support the pro-oncogenic activity of miR-367 in medulloblastoma and reveal a possible mechanism contributing to tumor aggressiveness, which could be further explored to improve patient stratification and treatment of this important type of pediatric brain cancer. PMID:26250335

  3. Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells.

    PubMed

    Wahba, Amy; Rath, Barbara H; Bisht, Kheem; Camphausen, Kevin; Tofilon, Philip J

    2016-05-15

    Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F-cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line-specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. Cancer Res; 76(10); 3078-87. ©2016 AACR.

  4. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

    PubMed

    Wang, Tao; Narayanaswamy, Radhika; Ren, Huilan; Torchilin, Vladimir P

    2016-06-01

    Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types. PMID:27259361

  5. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

    PubMed

    Wang, Tao; Narayanaswamy, Radhika; Ren, Huilan; Torchilin, Vladimir P

    2016-06-01

    Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types.

  6. Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest.

    PubMed

    Long, Patrick M; Tighe, Scott W; Driscoll, Heather E; Fortner, Karen A; Viapiano, Mariano S; Jaworski, Diane M

    2015-08-01

    Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-l-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth.

  7. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

    PubMed Central

    Di Martile, Marta; Desideri, Marianna; De Luca, Teresa; Gabellini, Chiara; Buglioni, Simonetta; Eramo, Adriana; Sette, Giovanni; Milella, Michele; Rotili, Dante; Mai, Antonello; Carradori, Simone; Secci, Daniela; De Maria, Ruggero; Del Bufalo, Donatella; Trisciuoglio, Daniela

    2016-01-01

    Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC. PMID:26870991

  8. STAT3 is Overactivated in Gastric Cancer Stem-Like Cells

    PubMed Central

    Hajimoradi, Monireh; Mohammad Hassan, Zuhair; Ebrahimi, Marzieh; Soleimani, Masoud; Bakhshi, Mahdieh; Firouzi, Javad; Samani, Fazel Sahraneshin

    2016-01-01

    Objective Gastric cancer (GC) is widely associated with chronic inflammation. The pro inflammatory microenvironment provides conditions that disrupt stem/progenitor cell proliferation and differentiation. The signal transducer and activator of transcrip- tion-3 (STAT3) signaling pathway is involved in inflammation and also contributes to the maintenance of embryonic stem cell (ESCs) pluripotency. Here, we have investi- gated the activation status of STAT3 in GC stem-like cells (GCSLCs). Materials and Methods In this experimental research, CSLCs derived from the human GC cell line MKN-45 and patient specimens, through spheroid body formation, character- ized and then assayed for the STAT3 transcription factor expression in mRNA and protein level further to its activation. Results Spheroid cells showed higher potential for spheroid formation than the pa- rental cells. Furthemore, stemness genes NANOG, c-MYC and SOX-2 were over expressed in spheroids of MKN-45 and in patient samples. In MKN-45 spheroid cells, epithelial mesenchymal transition (EMT) related markers CDH2, SNAIL2, TWIST and VIMENTIN were upregulated (P<0.05), but we observed no change in expression of the E-cadherin epithelial marker. These cells exhibited more resistance to docetaxel (DTX) when compared with parental cells (P<0.05) according to the MTS assay. Al- though immunostaining and Western blotting showed expression of the STAT3 pro- tein in both spheroids and parents, the mRNA level of STAT3 in spheroids was higher than the parents. Nuclear translocation of STAT3 was accompanied by more intensive phospho-STAT3 (p-STAT3) in spheroid structures relative to the parent cells accord- ing to flow cytometry analysis (P<0.05). Conclusion The present findings point to STAT3 over activation in GCSLCs. Com- plementary experiments are required to extend the role of STAT3 in stemness fea- tures and invasion properties of GCSCs and to consider the STAT3 pathway for CSC targeted therapy. PMID:26862521

  9. Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest

    PubMed Central

    Long, Patrick M.; Tighe, Scott W.; Driscoll, Heather E.; Fortner, Karen A.; Viapiano, Mariano S.; Jaworski, Diane M.

    2015-01-01

    Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-L-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth. PMID:25573156

  10. Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells.

    PubMed

    Wahba, Amy; Rath, Barbara H; Bisht, Kheem; Camphausen, Kevin; Tofilon, Philip J

    2016-05-15

    Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F-cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line-specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. Cancer Res; 76(10); 3078-87. ©2016 AACR. PMID:27005284

  11. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.

    PubMed

    Schroeder, Anne; Herrmann, Andreas; Cherryholmes, Gregory; Kowolik, Claudia; Buettner, Ralf; Pal, Sumanta; Yu, Hua; Müller-Newen, Gerhard; Jove, Richard

    2014-02-15

    Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here, we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.

  12. Fourier transform infrared (FTIR) spectromicroscopic characterization of stem-like cell populations in human esophageal normal and adenocarcinoma cell lines.

    PubMed

    Zhao, R; Quaroni, L; Casson, A G

    2010-01-01

    We have tested an approach to identify putative cancer stem cells that involves measurement of the infrared absorption spectrum of individual cells in an aqueous environment, and their subsequent classification using multivariate data analysis techniques. Two primary esophageal cell lines were characterized: the immortalized normal esophageal epithelial cell line, Het-1A, and the esophageal adenocarcinoma cell line, OE33. In addition, we also evaluated spheroids, reflecting stem-like cell populations, which were derived from each parent cell line when grown in serum-free media. As differences in cell size appeared to be a strong discriminating factor, a correction needs to be performed to allow a reliable classification based on infrared absorption spectra. We demonstrated that stem-like cells derived from Het-1A could easily be discriminated on the basis of absorbance differences in the 1000-1200 cm(-1) spectral interval, whereas this was not possible for OE33. Furthermore, we found that changes due to aging of OE33 cells in culture dominated the infrared absorption spectra and somewhat limited the potential of this approach to identify stem-like cell populations using this in vitro model system.

  13. Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells

    PubMed Central

    Hong, Su-Hyung; Bai, Shoumin; He, Zhen; Malik, Fayaz; Xu, Jiahui; Zhou, Lei; Chen, Weilong; Martin-Trevino, Rachel; Wu, Xiaojian; Lan, Ping; Yi, Yongju; Ginestier, Christophe; Ibarra, Ingrid; Shang, Li; McDermott, Sean; Luther, Tahra; Clouthier, Shawn G.; Wicha, Max S.; Liu, Suling

    2015-01-01

    Increasing evidence suggests that lineage specific subpopulations and stem-like cells exist in normal and malignant breast tissues. Epigenetic mechanisms maintaining this hierarchical homeostasis remain to be investigated. In this study, we found the level of microRNA221 (miR-221) was higher in stem-like and myoepithelial cells than in luminal cells isolated from normal and malignant breast tissue. In normal breast cells, over-expression of miR-221 generated more myoepithelial cells whereas knock-down of miR-221 increased luminal cells. Over-expression of miR-221 stimulated stem-like cells in luminal type of cancer and the miR-221 level was correlated with clinical outcome in breast cancer patients. Epithelial-mesenchymal transition (EMT) was induced by overexpression of miR-221 in normal and breast cancer cells. The EMT related gene ATXN1 was found to be a miR-221 target gene regulating breast cell hierarchy. In conclusion, we propose that miR-221 contributes to lineage homeostasis of normal and malignant breast epithelium. PMID:25686829

  14. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits

    PubMed Central

    Calvani, Maura; Taddei, Maria Letizia; Giannoni, Elisa; Kopetz, Scott; Kazmi, Syed Mohammad Ali; Pia, Morelli Maria; Pettazzoni, Piergiorgio; Sacco, Elena; Caselli, Anna; Vanoni, Marco; Landriscina, Matteo; Cirri, Paolo; Chiarugi, Paola

    2015-01-01

    Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer. PMID:26527315

  15. Effect of Corilagin on the Proliferation and NF-κB in U251 Glioblastoma Cells and U251 Glioblastoma Stem-Like Cells

    PubMed Central

    Yang, Wen-Tao; Li, Gen-Hua; Li, Zheng-You; Feng, Song; Liu, Xue-Qin; Han, Guang-Kui; Zhang, Hao; Qin, Xian-Yun; Zhang, Ran; Nie, Quan-Min; Jin, Feng

    2016-01-01

    Background. This study is to explore the effect of corilagin on the proliferation and NF-κB signaling pathway in U251 glioblastoma cells and U251 glioblastoma stem-like cells. Methods. CD133 positive U251 glioblastoma cells were separated by immunomagnetic beads to isolate glioblastoma stem-like cells. U251 cells and stem-like cells were intervened by different corilagin concentrations (0, 25, 50, and 100 μg/mL) for 48 h, respectively. Cell morphology, cell counting kit-8 assay, flow cytometry, dual luciferase reporter assay, and a western blot were used to detect and analyze the cell proliferation and cell cycle and investigate the expression of IKBα protein in cytoplasm and NF-κB/p65 in nucleus. Results. Corilagin inhibited the cell proliferation of U251 cells and their stem-like cells and the inhibition role was stronger in U251 stem-like cells (P < 0.05). The cell cycle was arrested at G2/M phase in the U251 cells following corilagin intervention; the proportion of cells in G2/M phase increased as the concentration of corilagin increased (P < 0.05). The U251 stem-like cells were arrested at the S phase following treatment with corilagin; the proportion of cells in the S phase increased as the concentration of corilagin increased (P < 0.05). The ratio of dual luciferase activities of U251 stem-like cells was lower than that of U251 cells in the same corilagin concentration. With increasing concentrations of corilagin, the IKBα expression in cytoplasm of U251 cells and U251 stem-like cells was increased, but the p65 expression in nucleus of U251 cells and U251 stem-like cells was decreased (P < 0.05). Conclusion. Corilagin can inhibit the proliferation of glioblastoma cells and glioblastoma stem-like cells; the inhibition on glioblastoma stem-like cell proliferation is stronger than glioblastoma cells. This different result indicates that the effect of corilagin on U251 cells and U251 stem-like cells may have close relationships with mechanism of cell

  16. Helping Kids Help

    ERIC Educational Resources Information Center

    Heiss, E. Renee

    2008-01-01

    Educators need to help kids help others so that they can help themselves. Volunteering does not involve competition or grades. This is one area where students don't have to worry about measuring up to the expectations of parents, teachers, and coaches. Students participate in charitable work to add another line to a college transcript or job…

  17. Helping Users Help Themselves.

    ERIC Educational Resources Information Center

    O'Malley, Claire E.

    This discussion of the design of user-initiated help systems in computers focuses on the information that users actively seek to help them with their tasks, with emphasis on how to help users ask the questions that will bridge the gap between the initial internal (mental) form of the query and their information need as expressed by the system.…

  18. Synergistic inhibition of characteristics of liver cancer stem-like cells with a combination of sorafenib and 8-bromo-7-methoxychrysin in SMMC-7721 cell line.

    PubMed

    Zou, Hui; Cao, Xiaozheng; Xiao, Qiao; Sheng, Xifeng; Ren, Kaiqun; Quan, Meifang; Song, Zhengwei; Li, Duo; Zheng, Yu; Zeng, Wenbin; Cao, Jianguo; Peng, Yaojin

    2016-09-01

    Sorafenib, a multi-kinase inhibitor, has shown its promising antitumor effect in a series of clinical trials, and has been approved as the current standard treatment for advanced hepatocellular carcinoma (HCC). 8-Bromo‑7-methoxychrysin (BrMC) is a novel chrysin synthetic analogue that has been reported to inhibit the growth of various tumor cells and possess properties for targeting liver cancer stem cells (LCSCs) . The present study investigated the synergistic targeting effects on the properties of liver cancer stem-like cells (LCSLCs) by a combination of sorafenib and BrMC in SMMC-7721 cell line. We also investigated whether this effect involves regulation of HIF-1α, Twist and NF-κB protein. We found that the sphere-forming cells (SFCs) from the SMMC‑7721 cells possessed the properties of LCSLCs. Sorafenib diminished the self-renewal capacity and downregulated the expression of stem cell biomarkers (CD133, CD44 and ALDH1) in a dose-dependent manner, while BrMC cooperated with sorafenib to strengthen this inhibition. Moreover, the combination of sorafenib and BrMC led to a remarkable decrease in the cellular migration and invasion, the downregulation of N-cadherin protein and upregulation of E-cadherin protein, and increase of cell apoptosis in LCSLCs. BrMC has a remarkable antagonistic effect on the upregulation of protein expression and DNA binding activity of NF-κB (p65) induced by sorafenib. In addition, our results indicated that the synergistic inhibition of sorafenib and BrMC on the characteristics of LCSLCs involves the downregulated expression of HIF-1α and EMT regulator Twist1. Collectively, the combination therapy of sorafenib and BrMC could be a new and promising therapeutic approach in the treatment of HCC.

  19. 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype.

    PubMed

    Chang, Tung-Cheng; Yeh, Chi-Tai; Adebayo, Bamodu Oluwaseun; Lin, Ying-Chin; Deng, Li; Rao, Yerra Koteswara; Huang, Chun-Chih; Lee, Wei-Hwa; Wu, Alexander T H; Hsiao, Michael; Wu, Chih-Hsiung; Wang, Liang-Shun; Tzeng, Yew-Min

    2015-10-15

    4-Acetylantroquinonol B (4-AAQB), closely related to the better known antroquinonol, is a bioactive isolate of the mycelia of Antrodia camphorata, a Taiwanese mushroom with documented anti-inflammatory, hypoglycemic, vasorelaxative, and recently demonstrated, antiproliferative activity. Based on its traditional use, we hypothesized that 4-AAQB may play an active role in the suppression of cellular transformation, tumor aggression and progression, as well as chemoresistance in colorectal carcinoma (CRC). In this study, we investigated the antiproliferative role of 4-AAQB and its underlying molecular mechanism. We also compared its anticancer therapeutic potential with that of antroquinonol and the CRC combination chemotherapy of choice - folinic acid, fluorouracil and oxaliplatin (FOLFOX). Our results showed that 4-AAQB was most effective in inhibiting tumor proliferation, suppressing tumor growth and attenuating stemness-related chemoresistance. 4-AAQB negatively regulates vital oncogenic and stem cell maintenance signal transduction pathways, including the Lgr5/Wnt/β-catenin, JAK-STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, as well as inducing a dose-dependent downregulation of ALDH and other stemness related factors. These results were validated in vivo, with animal studies showing 4-AAQB possessed comparable tumor-shrinking ability as FOLFOX and potentiates ability of the later to reduce tumor size. Thus, 4-AAQB, a novel small molecule, projects as a potent therapeutic agent for monotherapy or as a component of standard combination chemotherapy.

  20. Isolation and phenotypic characterization of cancer stem-like side population cells in colon cancer.

    PubMed

    Feng, Long; Wu, Jian-Bing; Yi, Feng-Ming

    2015-09-01

    Previous studies in cancer biology suggest that chemotherapeutic drug resistance and tumor relapse are driven by cells within a tumor termed 'cancer stem cells'. In the present study, a Hoechst 33342 dye exclusion technique was used to identify cancer stem‑like side population (SP) cells in colon carcinoma, which accounted for 3.4% of the total cell population. Following treatment with verapamil, the population of SP cells was reduced to 0.6%. In addition, the sorted SP cells exhibited marked multidrug resistance and enhanced cell survival rates compared with non‑SP cells. The SP cells were able to generate more tumor spheres and were CD133 positive. Subsequent biochemical analysis revealed that the levels of the adenosine triphosphate‑binding cassette sub‑family G member 2 transporter protein, B‑cell lymphoma anti‑apoptotic factor and autocrine production of interleukin‑4 were significantly enhanced in the colon cancer SP cells, which contributed to drug resistance, protection of the cells from apoptosis and tumor recurrence. Therefore, the findings suggested that treatment failure and colon tumorigenesis is dictated by a small population of SP cells, which indicate a potential target in future therapies.

  1. Substrate-mediated reprogramming of human fibroblasts into neural crest stem-like cells and their applications in neural repair.

    PubMed

    Tseng, Ting-Chen; Hsieh, Fu-Yu; Dai, Niann-Tzyy; Hsu, Shan-Hui

    2016-09-01

    Cell- and gene-based therapies have emerged as promising strategies for treating neurological diseases. The sources of neural stem cells are limited while the induced pluripotent stem (iPS) cells have risk of tumor formation. Here, we proposed the generation of self-renewable, multipotent, and neural lineage-related neural crest stem-like cells by chitosan substrate-mediated gene transfer of a single factor forkhead box D3 (FOXD3) for the use in neural repair. A simple, non-toxic, substrate-mediated method was applied to deliver the naked FOXD3 plasmid into human fibroblasts. The transfection of FOXD3 increased cell proliferation and up-regulated the neural crest marker genes (FOXD3, SOX2, and CD271), stemness marker genes (OCT4, NANOG, and SOX2), and neural lineage-related genes (Nestin, β-tubulin and GFAP). The expression levels of stemness marker genes and neural crest maker genes in the FOXD3-transfected fibroblasts were maintained until the fifth passage. The FOXD3 reprogrammed fibroblasts based on the new method significantly rescued the neural function of the impaired zebrafish. The chitosan substrate-mediated delivery of naked plasmid showed feasibility in reprogramming somatic cells. Particularly, the FOXD3 reprogrammed fibroblasts hold promise as an easily accessible cellular source with neural crest stem-like behavior for treating neural diseases in the future. PMID:27341268

  2. Derivation of Porcine Embryonic Stem-Like Cells from In Vitro-Produced Blastocyst-Stage Embryos

    PubMed Central

    Hou, Dao-Rong; Jin, Yong; Nie, Xiao-Wei; Zhang, Man-Ling; Ta, Na; Zhao, Li-Hua; Yang, Ning; Chen, Yuan; Wu, Zhao-Qiang; Jiang, Hai-Bin; Li, Yan-Ru; Sun, Qing-Yuan; Dai, Yi-Fan; Li, Rong-Feng

    2016-01-01

    Efficient isolation of embryonic stem (ES) cells from pre-implantation porcine embryos has remained a challenge. Here, we describe the derivation of porcine embryonic stem-like cells (pESLCs) by seeding the isolated inner cell mass (ICM) from in vitro-produced porcine blastocyst into α-MEM with basic fibroblast growth factor (bFGF). The pESL cells kept the normal karyotype and displayed flatten clones, similar in phenotype to human embryonic stem cells (hES cells) and rodent epiblast stem cells. These cells exhibited alkaline phosphatase (AP) activity and expressed pluripotency markers such as OCT4, NANOG, SOX2, SSEA-4, TRA-1-60, and TRA-1-81 as determined by both immunofluorescence and RT-PCR. Additionally, these cells formed embryoid body (EB), teratomas and also differentiated into 3 germ layers in vitro and in vivo. Microarray analysis showed the expression of the pluripotency markers, PODXL, REX1, SOX2, KLF5 and NR6A1, was significantly higher compared with porcine embryonic fibroblasts (PEF), but expression of OCT4, TBX3, REX1, LIN28A and DPPA5, was lower compared to the whole blastocysts or ICM of blastocyst. Our results showed that porcine embryonic stem-like cells can be established from in vitro-produced blastocyst-stage embryos, which promote porcine naive ES cells to be established. PMID:27173828

  3. Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells.

    PubMed

    Kathagen, Annegret; Schulte, Alexander; Balcke, Gerd; Phillips, Heidi S; Martens, Tobias; Matschke, Jakob; Günther, Hauke S; Soriano, Robert; Modrusan, Zora; Sandmann, Thomas; Kuhl, Carsten; Tissier, Alain; Holz, Mareike; Krawinkel, Lutz A; Glatzel, Markus; Westphal, Manfred; Lamszus, Katrin

    2013-11-01

    Fluctuations in oxygen tension during tissue remodeling impose a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastoma, the most common malignant brain tumor, possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. We identified a reciprocal metabolic switch between the pentose phosphate pathway (PPP) and glycolysis in glioblastoma stem-like (GS) cells. Expression of PPP enzymes is upregulated by acute oxygenation but downregulated by hypoxia, whereas glycolysis enzymes, particularly those of the preparatory phase, are regulated inversely. Glucose flux through the PPP is reduced under hypoxia in favor of flux through glycolysis. PPP enzyme expression is elevated in human glioblastomas compared to normal brain, especially in highly proliferative tumor regions, whereas expression of parallel preparatory phase glycolysis enzymes is reduced in glioblastomas, except for strong upregulation in severely hypoxic regions. Hypoxia stimulates GS cell migration but reduces proliferation, whereas oxygenation has opposite effects, linking the metabolic switch to the "go or grow" potential of the cells. Our findings extend Warburg's observation that tumor cells predominantly utilize glycolysis for energy production, by suggesting that PPP activity is elevated in rapidly proliferating tumor cells but suppressed by acute severe hypoxic stress, favoring glycolysis and migration to protect cells against hypoxic cell damage.

  4. Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance.

    PubMed

    Dahan, P; Martinez Gala, J; Delmas, C; Monferran, S; Malric, L; Zentkowski, D; Lubrano, V; Toulas, C; Cohen-Jonathan Moyal, E; Lemarie, A

    2014-11-27

    Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.

  5. Derivation of Porcine Embryonic Stem-Like Cells from In Vitro-Produced Blastocyst-Stage Embryos.

    PubMed

    Hou, Dao-Rong; Jin, Yong; Nie, Xiao-Wei; Zhang, Man-Ling; Ta, Na; Zhao, Li-Hua; Yang, Ning; Chen, Yuan; Wu, Zhao-Qiang; Jiang, Hai-Bin; Li, Yan-Ru; Sun, Qing-Yuan; Dai, Yi-Fan; Li, Rong-Feng

    2016-01-01

    Efficient isolation of embryonic stem (ES) cells from pre-implantation porcine embryos has remained a challenge. Here, we describe the derivation of porcine embryonic stem-like cells (pESLCs) by seeding the isolated inner cell mass (ICM) from in vitro-produced porcine blastocyst into α-MEM with basic fibroblast growth factor (bFGF). The pESL cells kept the normal karyotype and displayed flatten clones, similar in phenotype to human embryonic stem cells (hES cells) and rodent epiblast stem cells. These cells exhibited alkaline phosphatase (AP) activity and expressed pluripotency markers such as OCT4, NANOG, SOX2, SSEA-4, TRA-1-60, and TRA-1-81 as determined by both immunofluorescence and RT-PCR. Additionally, these cells formed embryoid body (EB), teratomas and also differentiated into 3 germ layers in vitro and in vivo. Microarray analysis showed the expression of the pluripotency markers, PODXL, REX1, SOX2, KLF5 and NR6A1, was significantly higher compared with porcine embryonic fibroblasts (PEF), but expression of OCT4, TBX3, REX1, LIN28A and DPPA5, was lower compared to the whole blastocysts or ICM of blastocyst. Our results showed that porcine embryonic stem-like cells can be established from in vitro-produced blastocyst-stage embryos, which promote porcine naive ES cells to be established. PMID:27173828

  6. Gefitinib Radiosensitizes Stem-Like Glioma Cells: Inhibition of Epidermal Growth Factor Receptor-Akt-DNA-PK Signaling, Accompanied by Inhibition of DNA Double-Strand Break Repair

    SciTech Connect

    Kang, Khong Bee; Zhu Congju; Wong Yinling; Gao Qiuhan; Ty, Albert; Wong, Meng Cheong

    2012-05-01

    Purpose: We compared radiosensitivity of brain tumor stem cells (BTSCs) with matched nonstem glioma cells, and determined whether gefitinib enhanced BTSC radiosensitivity by inhibiting epidermal growth factor receptor (EGFR)-Akt-DNA-dependent protein kinase (DNA-PK) signaling, followed by enhanced DNA double-stand breaks (DSBs) and inhibition of DSB repair. Methods and Materials: Radiosensitivity of stem-like gliomaspheres and nonstem glioma cells (obtained at patient neurosurgical resection) were evaluated by clonogenic assays, {gamma}-H{sub 2}AX immunostaining and cell cycle distribution. Survival of irradiated and nonirradiated NOD-SCID mice intracranially implanted with stem-like gliomaspheres were monitored. Glioma cells treated with gefitinib, irradiation, or both were assayed for clonogenic survival, {gamma}-H{sub 2}AX immunostaining, DNA-PKcs expression, and phosphorylation of EGFR and Akt. Results: Stem-like gliomaspheres displayed BTSC characteristics of self-renewal; differentiation into lineages of neurons, oligodendrocytes, and astrocytes; and initiation of glioma growth in NOD-SCID mice. Irradiation dose-dependently reduced clonogenic survival, induced G{sub 2}/M arrest and increased {gamma}-H{sub 2}AX immunostaining of nonstem glioma cells, but not stem-like gliomaspheres. There was no difference in survival of irradiated and nonirradiated mice implanted with stem-like gliomaspheres. The addition of gefitinib significantly inhibited clonogenic survival, increased {gamma}-H{sub 2}AX immunostaining, and reduced DNA-PKcs expression of irradiated stem-like gliomaspheres, without affecting irradiated-nonstem glioma cells. Gefitinib alone, and when combined with irradiation, inhibited phosphorylation of EGFR (Y1068 and Y1045) and Akt (S473) in stem-like gliomaspheres. In nonstem glioma cells, gefitinib alone inhibited EGFR Y1068 phosphorylation, with further inhibition by combined gefitinib and irradiation. Conclusions: Stem-like gliomaspheres are

  7. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.

    PubMed

    Zeniou, Maria; Fève, Marie; Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

    2015-01-01

    Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.

  8. FoxM1 Drives a Feed-forward STAT3-activation Signaling Loop that Promotes the Self-renewal and Tumorigenicity of Glioblastoma Stem-like Cells

    PubMed Central

    Gong, Ai-hua; Wei, Ping; Zhang, Sicong; Yao, Jun; Yuan, Ying; Zhou, Ai-dong; Lang, Frederick F.; Heimberger, Amy B.; Rao, Ganesh; Huang, Suyun

    2015-01-01

    The growth factor PDGF controls the development of glioblastoma (GBM) but its contribution to the function of GBM stem-like cells (GSC) has been little studied. Here we report that the transcription factor FoxM1 promotes PDGFA-STAT3 signaling to drive GSC self-renewal and tumorigenicity. In GBM we found a positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A expression, acting to maintain the stem-like qualities of GSC in part through this mechanism. Analysis of the human cancer genomic database TCGA revealed that GBM express higher levels of STAT3, a PDGF-A effector signaling molecule, as compared with normal brain. FoxM1 regulated STAT3 transcription through interactions with the β-catenin/TCF4 complex. FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties. Further mechanistic investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was sufficient to confer stem-like properties to glioma cells. Collectively, our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. PMID:25832656

  9. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.

    PubMed

    Zeniou, Maria; Fève, Marie; Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

    2015-01-01

    Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication. PMID:26270679

  10. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells

    PubMed Central

    Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A.; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

    2015-01-01

    Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication. PMID:26270679

  11. Talin1 targeting potentiates anti-angiogenic therapy by attenuating invasion and stem-like features of glioblastoma multiforme

    PubMed Central

    Kang, Wonyoung; Kim, Sung Heon; Cho, Hee Jin; Jin, Juyoun; Lee, Jeongwu; Joo, Kyeung Min; Nam, Do-Hyun

    2015-01-01

    Glioblastoma multiforme (GBM) possesses florid angiogenesis. However, the anti-angiogenic agent, Bevacizumab, did not improve overall survival of GBM patients. For more durable anti-angiogenic treatment, we interrogated resistant mechanisms of GBM against Bevacizumab. Serial orthotopic transplantation of in vivo Bevacizumab-treated GBM cells provoked complete refractoriness to the anti-angiogenic treatment. These tumors were also highly enriched with malignant phenotypes such as invasiveness, epithelial to mesenchymal transition, and stem-like features. Through transcriptome analysis, we identified that Talin1 (TLN1) significantly increased in the refractory GBMs. Inhibition of TLN1 not only attenuated malignant characteristics of GBM cells but also reversed the resistance to the Bevacizumab treatment. These data implicate TLN1 as a novel therapeutic target for GBM to overcome resistance to anti-angiogenic therapies. PMID:26336988

  12. Direct differentiation of hepatic stem-like WB cells into insulin-producing cells using small molecules.

    PubMed

    Liu, Jianping; Liu, Yanmei; Wang, Honggang; Hao, Haojie; Han, Qingwang; Shen, Jing; Shi, Jun; Li, Chunlin; Mu, Yiming; Han, Weidong

    2013-01-01

    Recent evidence suggests that experimental induction of hepatocytes into pancreatic cells provides new cell transplantation therapy prospects for type 1 diabetes mellitus. Stepwise differentiation from rat liver epithelial stem-like WB-F344 cells (WB cells) into functional insulin-secreting cells will identify key steps in β-cell development and may yet prove useful for transplantation therapy for diabetic patients. An essential step in this protocol was the generation of pancreatic precursor cell that express Pdx1 based on induction by a combination of 5-aza-2'-deoxycytidine, trichostatin A, retinoic acid, and a mix of insulin, transferrin and selenite. The Pdx1-expressing cells express other pancreatic markers and contribute to endocrine cells in vitro and in vivo. This study indicates an efficient chemical protocol for differentiating WB cells into functional insulin-producing cells using small molecules, and represents a promising hepatocyte-based treatment for diabetes mellitus.

  13. Lineage-restricted OLIG2-RTK signaling governs the molecular subtype of glioma stem-like cells

    PubMed Central

    Kupp, Robert; Shtayer, Lior; Tien, An-Chi; Szeto, Emily; Sanai, Nader; Rowitch, David H.; Mehta, Shwetal

    2016-01-01

    SUMMARY The bHLH transcription factor OLIG2 is a master regulator of oligodendroglial fate decisions and tumorigenic competence of glioma stem-like cells (GSCs). However, the molecular mechanisms underlying dysregulation of OLIG2 function during gliomagenesis remains poorly understood. Here, we show that OLIG2 modulates growth factor signaling in two distinct populations of GSCs, characterized by expression of either the EGFR or PDGFRα. Biochemical analyses of OLIG2 function in normal and malignant neural progenitors reveal a positive feedforward loop between OLIG2 and EGFR to sustain co-expression. Furthermore, loss of OLIG2 function results in mesenchymal transformation in PDGFRαHIGH GSCs, a phenomenon that appears to be circumscribed in EGFRHIGH GSCs. Exploitation of OLIG2’s dual and antithetical, pro-mitotic (EGFR-driven) and lineage-specifying (PDGFRα-driven) functions by glioma cells, appears to be critical for sustaining growth factor signaling and GSC molecular subtype. PMID:27626655

  14. Genome-wide microarray expression and genomic alterations by array-CGH analysis in neuroblastoma stem-like cells.

    PubMed

    Ordóñez, Raquel; Gallo-Oller, Gabriel; Martínez-Soto, Soledad; Legarra, Sheila; Pata-Merci, Noémie; Guegan, Justine; Danglot, Giselle; Bernheim, Alain; Meléndez, Bárbara; Rey, Juan A; Castresana, Javier S

    2014-01-01

    Neuroblastoma has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to the existence of Cancer Stem Cells (CSC), a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the CSC-like cell population content of two commercial neuroblastoma cell lines by the use of conditioned cell culture media for neurospheres, and compared genomic gains and losses and genome expression by array-CGH and microarray analysis, respectively (in CSC-like versus standard tumor cells culture). Despite the array-CGH did not show significant differences between standard and CSC-like in both analyzed cell lines, the microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the CSC-like phenotype. Some signalling pathways detected seem to be involved in self-renewal of normal tissues (Wnt, Notch, Hh and TGF-β) and contribute to CSC phenotype. We focused on the aberrant activation of TGF-β and Hh signalling pathways, confirming the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by RT-qPCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk among different pathways in neuroblastoma and its importance in CSC-like cells. PMID:25392930

  15. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition.

    PubMed

    Zhang, Jie; Wang, Wenjing; Qian, Lin; Zhang, Qiuwan; Lai, Dongmei; Qi, Cong

    2015-11-01

    Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent. PMID:26323892

  16. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition.

    PubMed

    Zhang, Jie; Wang, Wenjing; Qian, Lin; Zhang, Qiuwan; Lai, Dongmei; Qi, Cong

    2015-11-01

    Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent.

  17. High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant

    PubMed Central

    Farnie, Gillian; Sotgia, Federica; Lisanti, Michael P.

    2015-01-01

    Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12-μm), relative to the smaller cell population (4–8-μm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of breast cancer cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population. PMID:26421710

  18. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells

    PubMed Central

    Peiris-Pagès, Maria; Ozsvari, Bela; Smith, Duncan L.; Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Cappello, Anna Rita; Pezzi, Vincenzo; Lisanti, Michael P.; Sotgia, Federica

    2015-01-01

    Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERRα significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/β-catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (XCT790, oligomycin A, or doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90 protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally, doxycycline is an FDA-approved antibiotic, which is very well-tolerated in patients. As such, doxycycline could be re-purposed clinically as a ‘safe’ mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent tumor recurrence and distant metastasis, thereby avoiding patient relapse

  19. Targeting Colorectal Cancer Stem-Like Cells with Anti-CD133 Antibody-Conjugated SN-38 Nanoparticles.

    PubMed

    Ning, Sin-Tzu; Lee, Shin-Yu; Wei, Ming-Feng; Peng, Cheng-Liang; Lin, Susan Yun-Fan; Tsai, Ming-Hsien; Lee, Pei-Chi; Shih, Ying-Hsia; Lin, Chun-Yen; Luo, Tsai-Yueh; Shieh, Ming-Jium

    2016-07-20

    Cancer stem-like cells play a key role in tumor development, and these cells are relevant to the failure of conventional chemotherapy. To achieve favorable therapy for colorectal cancer, PEG-PCL-based nanoparticles, which possess good biological compatibility, were fabricated as nanocarriers for the topoisomerase inhibitor, SN-38. For cancer stem cell therapy, CD133 (prominin-1) is a theoretical cancer stem-like cell (CSLC) marker for colorectal cancer and is a proposed therapeutic target. Cells with CD133 overexpression have demonstrated enhanced tumor-initiating ability and tumor relapse probability. To resolve the problem of chemotherapy failure, SN-38-loaded nanoparticles were conjugated with anti-CD133 antibody to target CD133-positive (CD133(+)) cells. In this study, anti-CD133 antibody-conjugated SN-38-loaded nanoparticles (CD133Ab-NPs-SN-38) efficiently bound to HCT116 cells, which overexpress CD133 glycoprotein. The cytotoxic effect of CD133Ab-NPs-SN-38 was greater than that of nontargeted nanoparticles (NPs-SN-38) in HCT116 cells. Furthermore, CD133Ab-NPs-SN-38 could target CD133(+) cells and inhibit colony formation compared with NPs-SN-38. In vivo studies in an HCT116 xenograft model revealed that CD133Ab-NPs-SN-38 suppressed tumor growth and retarded recurrence. A reduction in CD133 expression in HCT116 cells treated with CD133Ab-NPs-SN-38 was also observed in immunohistochemistry results. Therefore, this CD133-targeting nanoparticle delivery system could eliminate CD133-positive cells and is a potential cancer stem cell targeted therapy. PMID:27348241

  20. Akt-mediated phosphorylation of Oct4 is associated with the proliferation of stem-like cancer cells

    PubMed Central

    ZHAO, QING-WEI; ZHOU, YAN-WEN; LI, WEN-XIN; KANG, BO; ZHANG, XIAO-QIAN; YANG, YING; CHENG, JIE; YIN, SHENG-YONG; TONG, YING; HE, JIAN-QIN; YAO, HANG-PING; ZHENG, MIN; WANG, YING-JIE

    2015-01-01

    Oct4 protein encoded by POU5F1 plays a pivotal role in maintaining the self-renewal of pluripotent stem cells; however, its presence in cancer cells remains controversial. In the present study, we provided evidence that the transcripts of authentic OCT4 gene (OCT4A) and its multiple pseudogenes were detected in a variety of cancer cell lines. A few major bands were also detected by western blotting using an anti-Oct4A monoclonal antibody. Moreover, an anti-Oct4-pT235 antibody was used to identify a band in the majority of the tested cancer cell lines that coincided with one of the anti-Oct4A bands which was decreasable by a specific shRNA. The Oct4-pT235 signals were also detected in human glioblastoma and liver cancer specimens by immunofluorescence microscopy and immunohistochemistry. U87 glioblastoma cells were cultured in a neural stem cell medium to induce the formation of neurospheres rich in stem-like cancer cells. The levels of Oct4-pT235 in the sphere cells were markedly increased compared to their monolayer parental cells, a result that was accompanied by upregulation of the PI3K-Akt pathway. Akti-1/2, a specific inhibitor of Akt, effectively reduced the level of Oct4-pT235 and attenuated the proliferation of U87 sphere cells. ITE, an agonist of the aryl hydrocarbon receptor, also significantly attenuated the Akt-mediated phosphorylation of Oct4 in glioblastoma and liver cancer cells, and reduced their tumorigenic potential in a xenograft tumor model. Taken together, we concluded that the Akt-mediated phosphorylation of Oct4A or its homolog protein was associated with the proliferation of stem-like cancer cells that may serve as a novel biomarker and drug target for certain types of cancer. PMID:25625591

  1. Chromatin remodeling system, cancer stem-like attractors, and cellular reprogramming.

    PubMed

    Zhang, Yue; Moriguchi, Hisashi

    2011-11-01

    The cancer cell attractors theory provides a next-generation understanding of carcinogenesis and natural explanation of punctuated clonal expansions of tumor progression. The impressive notion of atavism of cancer is now updated but more evidence is awaited. Besides, the mechanisms that the ectopic expression of some germline genes result in somatic tumors such as melanoma and brain tumors are emerging but are not well understood. Cancer could be triggered by cells undergoing abnormal cell attractor transitions, and may be reversible with "cyto-education". From mammals to model organisms like Caenorhabditis elegans and Drosophila melanogaster, the versatile Mi-2β/nucleosome remodeling and histone deacetylation complexes along with their functionally related chromatin remodeling complexes (CRCs), i.e., the dREAM/Myb-MuvB complex and Polycomb group complex are likely master regulators of cell attractors. The trajectory that benign cells switch to cancerous could be the reverse of navigation of embryonic cells converging from a series of intermediate transcriptional states to a final adult state, which is supported by gene expression dynamics inspector assays and some cross-species genetic evidence. The involvement of CRCs in locking cancer attractors may help find the recipes of perturbing genes to achieve successful reprogramming such that the reprogrammed cancer cell function in the same way as the normal cells.

  2. Enhancement of cancer stem-like and epithelial−mesenchymal transdifferentiation property in oral epithelial cells with long-term nicotine exposure: Reversal by targeting SNAIL

    SciTech Connect

    Yu, Cheng-Chia; Chang, Yu-Chao

    2013-02-01

    Cigarette smoking is one of the major risk factors in the development and further progression of tumorigenesis, including oral squamous cell carcinoma (OSCC). Recent studies suggest that interplay cancer stem-like cells (CSCs) and epithelial−mesenchymal transdifferentiation (EMT) properties are responsible for the tumor maintenance and metastasis in OSCC. The aim of the present study was to investigate the effects of long-term exposure with nicotine, a major component in cigarette, on CSCs and EMT characteristics. The possible reversal regulators were further explored in nicotine-induced CSCs and EMT properties in human oral epithelial (OE) cells. Long-term exposure with nicotine was demonstrated to up-regulate ALDH1 population in normal gingival and primary OSCC OE cells dose-dependently. Moreover, long-term nicotine treatment was found to enhance the self-renewal sphere-forming ability and stemness gene signatures expression and EMT regulators in OE cells. The migration/cell invasiveness/anchorage independent growth and in vivo tumor growth by nude mice xenotransplantation assay was enhanced in long-term nicotine-stimulated OE cells. Knockdown of Snail in long-term nicotine-treated OE cells was found to reduce their CSCs properties. Therapeutic delivery of Si-Snail significantly blocked the xenograft tumorigenesis of long-term nicotine-treated OSCC cells and largely significantly improved the recipient survival. The present study demonstrated that the enrichment of CSCs coupled EMT property in oral epithelial cells induced by nicotine is critical for the development of OSCC tumorigenesis. Targeting Snail might offer a new strategy for the treatment of OSCC patients with smoking habit. -- Highlights: ► Sustained nicotine treatment induced CSCs properties of oral epithelial cells. ► Long-term nicotine treatment enhance EMT properties of oral epithelial cells. ► Long-term nicotine exposure increased tumorigenicity of oral epithelial cells. ► Si

  3. Pro-Oxidant Activity of Amine-Pyridine-Based Iron Complexes Efficiently Kills Cancer and Cancer Stem-Like Cells

    PubMed Central

    González-Bártulos, Marta; Aceves-Luquero, Clara; Qualai, Jamal; Cussó, Olaf; Martínez, Mª Angeles; Fernández de Mattos, Silvia; Menéndez, Javier A.; Villalonga, Priam; Costas, Miquel; Ribas, Xavi; Massaguer, Anna

    2015-01-01

    Differential redox homeostasis in normal and malignant cells suggests that pro-oxidant-induced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a pro-oxidant deviation well-tolerated by nonmalignant cells might rapidly reach a cell-death threshold in malignant cells already at a high setpoint of constitutive oxidative stress. To test this hypothesis, we took advantage of a selected number of amine-pyridine-based Fe(II) complexes that operate as efficient and robust oxidation catalysts of organic substrates upon reaction with peroxides. Five of these Fe(II)-complexes and the corresponding aminopyridine ligands were selected to evaluate their anticancer properties. We found that the iron complexes failed to display any relevant activity, while the corresponding ligands exhibited significant antiproliferative activity. Among the ligands, none of which were hemolytic, compounds 1, 2 and 5 were cytotoxic in the low micromolar range against a panel of molecularly diverse human cancer cell lines. Importantly, the cytotoxic activity profile of some compounds remained unaltered in epithelial-to-mesenchymal (EMT)-induced stable populations of cancer stem-like cells, which acquired resistance to the well-known ROS inducer doxorubicin. Compounds 1, 2 and 5 inhibited the clonogenicity of cancer cells and induced apoptotic cell death accompanied by caspase 3/7 activation. Flow cytometry analyses indicated that ligands were strong inducers of oxidative stress, leading to a 7-fold increase in intracellular ROS levels. ROS induction was associated with their ability to bind intracellular iron and generate active coordination complexes inside of cells. In contrast, extracellular complexation of iron inhibited the activity of the ligands. Iron complexes showed a high proficiency to cleave DNA through oxidative-dependent mechanisms, suggesting a likely mechanism of

  4. Tumorigenic lung tumorospheres exhibit stem-like features with significantly increased expression of CD133 and ABCG2

    PubMed Central

    Zhao, Wensi; Luo, Yi; Li, Boyi; Zhang, Tao

    2016-01-01

    Accumulating evidence supports the existence of cancer stem cells (CSCs) in human tumors, and the successful certification of CSCs may lead to the identification of therapeutic targets, which are more effective for the treatment of cancer. The use of spherical cancer models has increased in popularity in cancer stem cell investigations. Tumorospheres, which are used as a model of CSCs and are established in serum-free medium supplemented with growth factors under non-adherent conditions, are one of the most commonly used cancer spherical models and are a valuable method for enriching the CSC fraction. To investigate whether this model is applicable in lung cancer (LC), the identification of lung CSCs and their capacities is essential. In the present study, lung CSCs were enriched by sphere-forming culturing and their stem-like properties were assessed. The results indicated that the lung tumorospheres had enhanced proliferation, clonality, invasion and cisplatin-resistance, and showed significantly increased expression levels of CD133 and breast cancer resistance protein (ABCG2). These results, together with findings previously reported in literature, indicated that the sphere-forming culturing of LC cells induced the enrichment of CSCs and that the tumorospheres exhibited stem cell characteristics. In addition, the higher expression levels of CD133 and ABCG2 in the tumorospheres may provide a rationale for therapeutic targets for LC. PMID:27432082

  5. Active targeting docetaxel-PLA nanoparticles eradicate circulating lung cancer stem-like cells and inhibit liver metastasis.

    PubMed

    Yang, Nan; Jiang, Yao; Zhang, Huifeng; Sun, Bo; Hou, Chunying; Zheng, Ji; Liu, Yanyong; Zuo, Pingping

    2015-01-01

    Lung cancer is the major cause of cancer related lethality worldwide, and metastasis to distant organs is the pivotal cause of death for the vast majority of lung cancer patients. Accumulated evidence indicates that lung cancer stem-like cells (CSLCs) play important roles in metastagenesis, and these circulating CSLCs may be important targets to inhibit the subsequent metastasis. The present study was aimed at establishing CSLC-targeting polylactic acid (PLA) encapsulated docetaxel nanoparticles for antimetastatic therapy. Cyclic binding peptides were screened on CSLCs in vitro and the peptide CVKTPAQSC exhibiting high specific binding ability to pulmonary adenocarcinoma tissue was subsequently conjugated to the nanoparticles loaded with docetaxel (NDTX). Antimetastatic effect of CSLC-targeting nanoparticles loaded with docetaxel (TNDTX) was evaluated in a nude mouse model of liver metastasis. Results showed that, in the absence of targeting peptide, NDTX hardly exhibited any antimetastatic effect. However, TNDTX treatment significantly decreased the metastatic tumor area in the nude mouse liver. Histopathological and serological results also confirmed the antimetastatic efficacy of TNDTX. To our knowledge, this is the first report on establishing a CSLC-based strategy for lung cancer metastatic treatment, and we hope this will offer a potential therapeutic approach for management of metastatic lung cancer.

  6. Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization

    PubMed Central

    Rath, Barbara H; Wahba, Amy; Camphausen, Kevin; Tofilon, Philip J

    2015-01-01

    Toward developing a model system for investigating the role of the microenvironment in the radioresistance of glioblastoma (GBM), human glioblastoma stem-like cells (GSCs) were grown in coculture with human astrocytes. Using a trans-well assay, survival analyses showed that astrocytes significantly decreased the radiosensitivity of GSCs compared to standard culture conditions. In addition, when irradiated in coculture, the initial level of radiation-induced γH2AX foci in GSCs was reduced and foci dispersal was enhanced suggesting that the presence of astrocytes influenced the induction and repair of DNA double-strand breaks. These data indicate that astrocytes can decrease the radiosensitivity of GSCs in vitro via a paracrine-based mechanism and further support a role for the microenvironment as a determinant of GBM radioresponse. Chemokine profiling of coculture media identified a number of bioactive molecules not present under standard culture conditions. The gene expression profiles of GSCs grown in coculture were significantly different as compared to GSCs grown alone. These analyses were consistent with an astrocyte-mediated modification in GSC phenotype and, moreover, suggested a number of potential targets for GSC radiosensitization that were unique to coculture conditions. Along these lines, STAT3 was activated in GSCs grown with astrocytes; the JAK/STAT3 inhibitor WP1066 enhanced the radiosensitivity of GSCs under coculture conditions and when grown as orthotopic xenografts. Further, this coculture system may also provide an approach for identifying additional targets for GBM radiosensitization. PMID:26518290

  7. Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells.

    PubMed

    Kupp, Robert; Shtayer, Lior; Tien, An-Chi; Szeto, Emily; Sanai, Nader; Rowitch, David H; Mehta, Shwetal

    2016-09-13

    The basic helix-loop-helix (bHLH) transcription factor OLIG2 is a master regulator of oligodendroglial fate decisions and tumorigenic competence of glioma stem-like cells (GSCs). However, the molecular mechanisms underlying dysregulation of OLIG2 function during gliomagenesis remains poorly understood. Here, we show that OLIG2 modulates growth factor signaling in two distinct populations of GSCs, characterized by expression of either the epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRα). Biochemical analyses of OLIG2 function in normal and malignant neural progenitors reveal a positive feedforward loop between OLIG2 and EGFR to sustain co-expression. Furthermore, loss of OLIG2 function results in mesenchymal transformation in PDGFRα(HIGH) GSCs, a phenomenon that appears to be circumscribed in EGFR(HIGH) GSCs. Exploitation of OLIG2's dual and antithetical, pro-mitotic (EGFR-driven), and lineage-specifying (PDGFRα-driven) functions by glioma cells appears to be critical for sustaining growth factor signaling and GSC molecular subtype. PMID:27626655

  8. Neural stem-like cells derived from human amnion tissue are effective in treating traumatic brain injury in rat.

    PubMed

    Yan, Zhong-Jie; Zhang, Peng; Hu, Yu-Qin; Zhang, Hong-Tian; Hong, Sun-Quan; Zhou, Hong-Long; Zhang, Mao-Ying; Xu, Ru-Xiang

    2013-05-01

    Although human amnion derived mesenchymal stem cells (AMSC) are a promising source of stem cells, their therapeutic potential for traumatic brain injury (TBI) has not been widely investigated. In this study, we evaluated the therapeutic potential of AMSC using a rat TBI model. AMSC were isolated from human amniotic membrane and characterized by flow cytometry. After induction, AMSC differentiated in vitro into neural stem-like cells (AM-NSC) that expressed higher levels of the neural stem cell markers, nestin, sox2 and musashi, in comparison to undifferentiated AMSC. Interestingly, the neurotrophic factors, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), glial cell derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) were markedly upregulated after neural stem cell induction. Following transplantation in a rat TBI model, significant improvements in neurological function, brain tissue morphology, and higher levels of BDNF, NGF, NT-3, GDNF and CNTF, were observed in the AM-NSC group compared with the AMSC and Matrigel groups. However, few grafted cells survived with minimal differentiation into neural-like cells. Together, our results suggest that transplantation of AM-NSC promotes functional rehabilitation of rats with TBI, with enhanced expression of neurotrophic factors a likely mechanistic pathway.

  9. Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells.

    PubMed

    Wei, Ming-Feng; Chen, Min-Wei; Chen, Ke-Cheng; Lou, Pei-Jen; Lin, Susan Yun-Fan; Hung, Shih-Chieh; Hsiao, Michael; Yao, Cheng-Jung; Shieh, Ming-Jium

    2014-07-01

    Recent studies have indicated that cancer stem-like cells (CSCs) exhibit a high resistance to current therapeutic strategies, including photodynamic therapy (PDT), leading to the recurrence and progression of colorectal cancer (CRC). In cancer, autophagy acts as both a tumor suppressor and a tumor promoter. However, the role of autophagy in the resistance of CSCs to PDT has not been reported. In this study, CSCs were isolated from colorectal cancer cells using PROM1/CD133 (prominin 1) expression, which is a surface marker commonly found on stem cells of various tissues. We demonstrated that PpIX-mediated PDT induced the formation of autophagosomes in PROM1/CD133(+) cells, accompanied by the upregulation of autophagy-related proteins ATG3, ATG5, ATG7, and ATG12. The inhibition of PDT-induced autophagy by pharmacological inhibitors and silencing of the ATG5 gene substantially triggered apoptosis of PROM1/CD133(+) cells and decreased the ability of colonosphere formation in vitro and tumorigenicity in vivo. In conclusion, our results revealed a protective role played by autophagy against PDT in CSCs and indicated that targeting autophagy could be used to elevate the PDT sensitivity of CSCs. These findings would aid in the development of novel therapeutic approaches for CSC treatment.

  10. High-Throughput Single-Cell Derived Sphere Formation for Cancer Stem-Like Cell Identification and Analysis

    NASA Astrophysics Data System (ADS)

    Chen, Yu-Chih; Ingram, Patrick N.; Fouladdel, Shamileh; McDermott, Sean P.; Azizi, Ebrahim; Wicha, Max S.; Yoon, Euisik

    2016-06-01

    Considerable evidence suggests that many malignancies are driven by a cellular compartment that displays stem cell properties. Cancer stem-like cells (CSCs) can be identified by expression of cell surface markers or enzymatic activity, but these methods are limited by phenotypic heterogeneity and plasticity of CSCs. An alternative phenotypic methodology based on in-vitro sphere formation has been developed, but it is typically labor-intensive and low-throughput. In this work, we present a 1,024-microchamber microfluidic platform for single-cell derived sphere formation. Utilizing a hydrodynamic capturing scheme, more than 70% of the microchambers capture only one cell, allowing for monitoring of sphere formation from heterogeneous cancer cell populations for identification of CSCs. Single-cell derived spheres can be retrieved and dissociated for single-cell analysis using a custom 96-gene panel to probe heterogeneity within the clonal CSC spheres. This microfluidic platform provides reliable and high-throughput sphere formation for CSC identification and downstream clonal analysis.

  11. (1) H NMR spectroscopy of glioblastoma stem-like cells identifies alpha-aminoadipate as a marker of tumor aggressiveness.

    PubMed

    Rosi, Antonella; Ricci-Vitiani, Lucia; Biffoni, Mauro; Grande, Sveva; Luciani, Anna Maria; Palma, Alessandra; Runci, Daniele; Cappellari, Marianna; De Maria, Ruggero; Guidoni, Laura; Pallini, Roberto; Viti, Vincenza

    2015-03-01

    Patients suffering from glioblastoma multiforme (GBM) face a poor prognosis with median survival of about 14 months. High recurrence rate and failure of conventional treatments are attributed to the presence of GBM cells with stem-like properties (GSCs). Metabolite profiles of 42 GSC lines established from the tumor tissue of adult GBM patients were screened with (1) H NMR spectroscopy and compared with human neural progenitor cells from human adult olfactory bulb (OB-NPCs) and from the developing human brain (HNPCs). A first subset (n=12) of GSCs exhibited a dramatic accumulation of the metabolite α-aminoadipate (αAAD), product of the oxidation of α-aminoadipic semialdehyde catalyzed by the ALDH7A1 aldehyde dehydrogenase (ALDH) family in lysine catabolism. αAAD was low/not detectable in a second GSC subset (n=13) with the same neural metabolic profile as well as in a third GSC subset (n=17) characterized by intense lipid signals. Likewise, αAAD was not detected in the spectra of OB-NPCs or HNPCs. Inhibition of mitochondrial ATP synthase by oligomycin treatment revealed that the lysine degradative pathway leading to αAAD formation proceeds through saccharopine, as usually observed in developing brain. Survival curves indicated that high αAAD levels in GSCs significantly correlated with poor patient survival, similarly to prostate and non-small-cell-lung cancers, where activity of ALDH7A1 correlates with tumor aggressiveness. PMID:25581615

  12. High-Throughput Single-Cell Derived Sphere Formation for Cancer Stem-Like Cell Identification and Analysis

    PubMed Central

    Chen, Yu-Chih; Ingram, Patrick N.; Fouladdel, Shamileh; McDermott, Sean P.; Azizi, Ebrahim; Wicha, Max S.; Yoon, Euisik

    2016-01-01

    Considerable evidence suggests that many malignancies are driven by a cellular compartment that displays stem cell properties. Cancer stem-like cells (CSCs) can be identified by expression of cell surface markers or enzymatic activity, but these methods are limited by phenotypic heterogeneity and plasticity of CSCs. An alternative phenotypic methodology based on in-vitro sphere formation has been developed, but it is typically labor-intensive and low-throughput. In this work, we present a 1,024-microchamber microfluidic platform for single-cell derived sphere formation. Utilizing a hydrodynamic capturing scheme, more than 70% of the microchambers capture only one cell, allowing for monitoring of sphere formation from heterogeneous cancer cell populations for identification of CSCs. Single-cell derived spheres can be retrieved and dissociated for single-cell analysis using a custom 96-gene panel to probe heterogeneity within the clonal CSC spheres. This microfluidic platform provides reliable and high-throughput sphere formation for CSC identification and downstream clonal analysis. PMID:27292795

  13. HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib

    PubMed Central

    Ramírez, Alberto; Boulaiz, Houria; Morata-Tarifa, Cynthia; Perán, Macarena; Jiménez, Gema; Picon-Ruiz, Manuel; Agil, Ahmad; Cruz-López, Olga; Conejo-García, Ana; Campos, Joaquín M.; Sánchez, Ana; García, María A.; Marchal, Juan A.

    2014-01-01

    Identification of novel anticancer drugs presenting more than one molecular target and efficacy against cancer stem-like cells (CSCs) subpopulations represents a therapeutic need to combat the resistance and the high risk of relapse in patients. In the present work we show how Bozepinib [(RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine], a small anti-tumor compound, demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. The cytotoxic effects of Bozepinib were observed in both breast and colon cancer cells expressing different receptor patterns. Bozepinib inhibited HER-2 signaling pathway and JNK and ERKs kinases. In addition, Bozepinib has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Moreover, the modulation of pathways involved in tumorigenesis by Bozepinib was also evident in microarrays analysis. Interestingly, Bozepinib inhibited both mamo- and colono-spheres formation and eliminated ALDH+ CSCs subpopulations at a low micromolar range similar to Salinomycin. Bozepinib induced the down-regulation of c-MYC, β-CATENIN and SOX2 proteins and the up-regulation of the GLI-3 hedgehog-signaling repressor. Finally, Bozepinib shows in vivo anti-tumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting sub-acute toxicity. These findings support further studies on the therapeutic potential of Bozepinib in cancer patients. PMID:24946763

  14. In vitro screening of clinical drugs identifies sensitizers of oncolytic viral therapy in glioblastoma stem-like cells.

    PubMed

    Berghauser Pont, L M E; Balvers, R K; Kloezeman, J J; Nowicki, M O; van den Bossche, W; Kremer, A; Wakimoto, H; van den Hoogen, B G; Leenstra, S; Dirven, C M F; Chiocca, E A; Lawler, S E; Lamfers, M L M

    2015-12-01

    Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV. PMID:26196249

  15. Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells.

    PubMed

    Kupp, Robert; Shtayer, Lior; Tien, An-Chi; Szeto, Emily; Sanai, Nader; Rowitch, David H; Mehta, Shwetal

    2016-09-13

    The basic helix-loop-helix (bHLH) transcription factor OLIG2 is a master regulator of oligodendroglial fate decisions and tumorigenic competence of glioma stem-like cells (GSCs). However, the molecular mechanisms underlying dysregulation of OLIG2 function during gliomagenesis remains poorly understood. Here, we show that OLIG2 modulates growth factor signaling in two distinct populations of GSCs, characterized by expression of either the epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRα). Biochemical analyses of OLIG2 function in normal and malignant neural progenitors reveal a positive feedforward loop between OLIG2 and EGFR to sustain co-expression. Furthermore, loss of OLIG2 function results in mesenchymal transformation in PDGFRα(HIGH) GSCs, a phenomenon that appears to be circumscribed in EGFR(HIGH) GSCs. Exploitation of OLIG2's dual and antithetical, pro-mitotic (EGFR-driven), and lineage-specifying (PDGFRα-driven) functions by glioma cells appears to be critical for sustaining growth factor signaling and GSC molecular subtype.

  16. miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal

    PubMed Central

    Martini, Maurizio; Signore, Michele; Biffoni, Mauro; Giannetti, Stefano; Morgante, Liliana; Marziali, Giovanna; Ilari, Ramona; Pagliuca, Alfredo; Larocca, Luigi Maria; De Maria, Ruggero; Pallini, Roberto; Ricci-Vitiani, Lucia

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene. Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities. Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients. PMID:26437223

  17. Anti-Cancer Stem-like Cell Compounds in Clinical Development – An Overview and Critical Appraisal

    PubMed Central

    Marcucci, Fabrizio; Rumio, Cristiano; Lefoulon, François

    2016-01-01

    Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with elevated tumor-initiating potential. Upon differentiation, they replenish the bulk of the tumor cell population. Enhanced tumor-forming capacity, resistance to antitumor drugs, and metastasis-forming potential are the hallmark traits of CSCs. Given these properties, it is not surprising that CSCs have become a therapeutic target of prime interest in drug discovery. In fact, over the last few years, an enormous number of articles describing compounds endowed with anti-CSC activities have been published. In the meanwhile, several of these compounds and also approaches that are not based on the use of pharmacologically active compounds (e.g., vaccination, radiotherapy) have progressed into clinical studies. This article gives an overview of these compounds, proposes a tentative classification, and describes their biological properties and their developmental stage. Eventually, we discuss the optimal clinical setting for these compounds, the need for biomarkers allowing patient selection, the redundancy of CSC signaling pathways and the utility of employing combinations of anti-CSC compounds and the therapeutic limitations posed by the plasticity of CSCs. PMID:27242955

  18. B7H1 Expression and Epithelial-To-Mesenchymal Transition Phenotypes on Colorectal Cancer Stem-Like Cells

    PubMed Central

    Zhi, Yidan; Mou, Zhirong; Chen, Jun; He, Yujun; Dong, Hui; Fu, Xiaolan; Wu, Yuzhang

    2015-01-01

    Cancer stem cells (CSCs) can invade and metastasize by epithelial-to-mesenchymal transition (EMT). However, how they escape immune surveillance is unclear. B7H1 is crucial negative co-stimulatory molecule but little information about whether it works in CSCs. Therefore, we determined the expression of B7H1 and EMT-associated markers in colorectal cancer stem-like cells to investigate a possible immunoevasion way of CSCs. We enriched CD133+ colorectal cancer cells which manifested the CSCs-like properties such as higher levels of other stem cell markers Oct-4 and Sox-2, tumor sphere forming ability and more tumorigenic in NOD/SCID mice. These CD133+ cells possess EMT gene expression profile including higher level of Snail, Twist, vimentin, fibronectin and lower level of E-cadherin. Moreover, CD133+ cells in both cell line and colorectal cancer tissues expressed high level of negative co-stimulate molecule B7H1. Furthermore, some B7H1+ cancer cells also showed the characteristic of EMT, indicating EMT cells could escape immune attack during metastasis. B7H1 expression and EMT phenotypes on CSCs indicates a possible immunoevasion way. PMID:26284927

  19. Chitosan scaffolds for in vitro buffalo embryonic stem-like cell culture: an approach to tissue engineering.

    PubMed

    Thein-Han, Wah W; Kitiyanant, Yindee

    2007-01-01

    Three-dimensional (3D) porous chitosan scaffolds are attractive candidates for tissue engineering applications. Chitosan scaffolds of 70, 88, and 95% degree of deacetylation (% DD) with the same molecular weight were developed and their properties with buffalo embryonic stem-like (ES-like) cells were investigated in vitro. Scaffolds were fabricated by freezing and lyophilization. They showed open pore structure with interconnecting pores under scanning electron microscopy (SEM). Higher % DD chitosan scaffolds had greater mechanical strength, slower degradation rate, lower water uptake ability, but similar water retention ability, when compared to lower % DD chitosan. As a strategy to tissue engineering, buffalo ES-like cells were cultured on scaffolds for 28 days. It appeared that chitosan was cytocompatible and cells proliferated well on 88 and 95% DD scaffolds. In addition, the buffalo ES-like cells maintained their pluripotency during the culture period. Furthermore, the SEM and histological study showed that the polygonal buffalo ES-like cells proliferated well and attached to the pores. This study proved that 3D biodegradable highly deacetylated chitosan scaffolds are promising candidates for ES-like cell based tissue engineering and this chitosan scaffold and ES cell based system can be used as in vitro model for subsequent clinical applications.

  20. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth.

    PubMed

    Atapattu, Lakmali; Saha, Nayanendu; Chheang, Chanly; Eissman, Moritz F; Xu, Kai; Vail, Mary E; Hii, Linda; Llerena, Carmen; Liu, Zhanqi; Horvay, Katja; Abud, Helen E; Kusebauch, Ulrike; Moritz, Robert L; Ding, Bi-Sen; Cao, Zhongwei; Rafii, Shahin; Ernst, Matthias; Scott, Andrew M; Nikolov, Dimitar B; Lackmann, Martin; Janes, Peter W

    2016-08-22

    The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. PMID:27503072

  1. In vivo monitoring of CD44+ cancer stem-like cells by γ-irradiation in breast cancer

    PubMed Central

    KIM, MI HYUN; KIM, MIN HWAN; KIM, KWANG SEOK; PARK, MYUNG-JIN; JEONG, JAE-HOON; PARK, SEUNG WOO; JI, YOUNG HOON; KIM, KWANG IL; LEE, TAE SUP; RYU, PHIL YOUL; KANG, JOO HYUN; LEE, YONG JIN

    2016-01-01

    There is increasing evidence that cancer contains cancer stem cells (CSCs) that are capable of regenerating a tumor following chemotherapy or radiotherapy. CD44 and CD133 are used to identify CSCs. This study investigated non-invasive in vivo monitoring of CD44-positive cancer stem-like cells in breast cancer by γ-irradiation using molecular image by fusing the firefly luciferase (fLuc) gene with the CD44 promoter. We generated a breast cancer cell line stably expressing fLuc gene by use of recombinant lentiviral vector controlled by CD44 promoter (MCF7-CL). Irradiated MCF7-CL spheres showed upregulated expression of CD44 and CD133, by immunofluorescence and flow cytometry. Also, gene expression levels of CSCs markers in irradiated spheres were clearly increased. CD44+ CSCs increased fLuc expression and tumor growth in vivo and in vitro. When MCF7-CL was treated with siCD44 and irradiated, CD44 expression was inhibited and cell survival ratio was decreased. MCF7-CL subsets were injected into the mice and irradiated by using a cobalt-60 source. Then, in vivo monitoring was performed to observe the bioluminescence imaging (BLI). When breast cancer was irradiated, relative BLI signal was increased, but tumor volume was decreased compared to non-irradiated tumor. These results indicate that increased CD44 expression, caused by general feature of CSCs by irradiation and sphere formation, can be monitored by using bioluminescence imaging. This system could be useful to evaluate CD44-expressed CSCs in breast cancer by BLI in vivo as well as in vitro for radiotherapy. PMID:27098303

  2. Omega-3 Eicosapentaenoic Acid Decreases CD133 Colon Cancer Stem-Like Cell Marker Expression While Increasing Sensitivity to Chemotherapy

    PubMed Central

    De Carlo, Flavia; Witte, Theodore R.; Hardman, W. Elaine; Claudio, Pier Paolo

    2013-01-01

    Colorectal cancer is the third leading cause of cancer-related death in the western world. In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs. However, these studies address the effects of n-3 PUFAs on the bulk of the tumor cells and not on the undifferentiated colon cancer stem-like cells (CSLCs) that are responsible for tumor formation and maintenance. CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse. Colon CSLCs have been immunophenotyped using several antibodies against cellular markers including CD133, CD44, EpCAM, and ALDH. Anti-CD133 has been used to isolate a population of colon cancer cells that retains stem cells properties (CSLCs) from both established cell lines and primary cell cultures. We demonstrated that the n-3 PUFA, eicosapentaenoic acid (EPA), was actively incorporated into the membrane lipids of COLO 320 DM cells. 25 uM EPA decreased the cell number of the overall population of cancer cells, but not of the CD133 (+) CSLCs. Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers, Cytokeratin 20 (CK20) and Mucin 2 (MUC2). Finally, we demonstrated that EPA increased the sensitivity of COLO 320 DM cells (total population) to both standard-of-care chemotherapies (5-Fluorouracil and oxaliplatin), whereas EPA increased the sensitivity of the CD133 (+) CSLCs to only 5-Fluorouracil. PMID:23874993

  3. Radiation Response of Cancer Stem-Like Cells From Established Human Cell Lines After Sorting for Surface Markers

    SciTech Connect

    Al-Assar, Osama; Muschel, Ruth J.; Mantoni, Tine S.; McKenna, W. Gillies; Brunner, Thomas B.

    2009-11-15

    Purpose: A subpopulation of cancer stem-like cells (CSLC) is hypothesized to exist in different cancer cell lines and to mediate radioresistance in solid tumors. Methods and Materials: Cells were stained for CSLC markers and sorted (fluorescence-activated cell sorter/magnetic beads) to compare foci and radiosensitivity of phosphorylated histone H2AX at Ser 139 (gamma-H2AX) in sorted vs. unsorted populations in eight cell lines from different organs. CSLC properties were examined using anchorage-independent growth and levels of activated Notch1. Validation consisted of testing tumorigenicity and postirradiation enrichment of CSLC in xenograft tumors. Results: The quantity of CSLC was generally in good agreement with primary tumors. CSLC from MDA-MB-231 (breast) and Panc-1 and PSN-1 (both pancreatic) cells had fewer residual gamma-H2AX foci than unsorted cells, pointing to radioresistance of CSLC. However, only MDA-MB-231 CSLC were more radioresistant than unsorted cells. Furthermore, MDA-MB-231 CSLC showed enhanced anchorage-independent growth and overexpression of activated Notch1 protein. The expression of cancer stem cell surface markers in the MDA-MB-231 xenograft model was increased after exposure to fractionated radiation. In contrast to PSN-1 cells, a growth advantage for MDA-MB-231 CSLC xenograft tumors was found compared to tumors arising from unsorted cells. Conclusions: CSLC subpopulations showed no general radioresistant phenotype, despite the quantities of CSLC subpopulations shown to correspond relatively well in other reports. Likewise, CSLC characteristics were found in some but not all of the tested cell lines. The reported problems in testing for CSLC in cell lines may be overcome by additional techniques, beyond sorting for markers.

  4. Arsenic trioxide inhibits cancer stem-like cells via down-regulation of Gli1 in lung cancer.

    PubMed

    Chang, Ke-Jie; Yang, Meng-Hang; Zheng, Jin-Cheng; Li, Bing; Nie, Wei

    2016-01-01

    Cancer stem cells (CSCs) are responsible for the tumorigenesis and recurrence, so targeting CSCs is a potential effective method to cure cancers. Activated Hedgehog signaling pathway has been proved to be implicated in the maintenance of self-renewal of CSCs, and arsenic trioxide (As2O3) has been reported to inhibit Gli1, a key transcription factor of Hedgehog pathway. In this study, we evaluated whether As2O3 has inhibitory effects on cancer stem-like cells (CSLCs) in lung cancer and further explored the possible mechanism. CCK8 assay and colony formation assay were performed to demonstrate the ability of As2O3 to inhibit the growth of NCI-H460 and NCI-H446 cells, which represented non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), respectively. Tumor sphere formation assay was carried out to evaluate the effects of As2O3 on stem cell-like subpopulations. The expression of stem cell biomarkers CD133 and stem cell transcription factors such as Sox2 and Oct4 were detected. Moreover, the effects of As2O3 on expression of Gli1 and its target genes were observed. We found that As2O3 inhibited the cell proliferation and reduced the colony formation ability. Importantly, As2O3 decreased the formation of tumor spheres. The expression of stem cell biomarker CD133 and stem cell transcription factors such as Sox2 and Oct4 were markedly reduced by As2O3 treatment. Furthermore, As2O3 decreased the expression of Gli1, N-myc and GAS1. Our results suggested that As2O3 is a promising agent to inhibit CSLCs in lung cancer. In addition, the mechanism of CSLCs inhibition might involve Gli1 down-regulation. PMID:27158399

  5. In vivo monitoring of CD44+ cancer stem-like cells by γ-irradiation in breast cancer.

    PubMed

    Kim, Mi Hyun; Kim, Min Hwan; Kim, Kwang Seok; Park, Myung-Jin; Jeong, Jae-Hoon; Park, Seung Woo; Ji, Young Hoon; Kim, Kwang Il; Lee, Tae Sup; Ryu, Phil Youl; Kang, Joo Hyun; Lee, Yong Jin

    2016-06-01

    There is increasing evidence that cancer contains cancer stem cells (CSCs) that are capable of regenerating a tumor following chemotherapy or radiotherapy. CD44 and CD133 are used to identify CSCs. This study investigated non-invasive in vivo monitoring of CD44-positive cancer stem-like cells in breast cancer by γ-irradiation using molecular image by fusing the firefly luciferase (fLuc) gene with the CD44 promoter. We generated a breast cancer cell line stably expressing fLuc gene by use of recombinant lentiviral vector controlled by CD44 promoter (MCF7-CL). Irradiated MCF7-CL spheres showed upregulated expression of CD44 and CD133, by immunofluorescence and flow cytometry. Also, gene expression levels of CSCs markers in irradiated spheres were clearly increased. CD44+ CSCs increased fLuc expression and tumor growth in vivo and in vitro. When MCF7-CL was treated with siCD44 and irradiated, CD44 expression was inhibited and cell survival ratio was decreased. MCF7-CL subsets were injected into the mice and irradiated by using a cobalt-60 source. Then, in vivo monitoring was performed to observe the bioluminescence imaging (BLI). When breast cancer was irradiated, relative BLI signal was increased, but tumor volume was decreased compared to non-irradiated tumor. These results indicate that increased CD44 expression, caused by general feature of CSCs by irradiation and sphere formation, can be monitored by using bioluminescence imaging. This system could be useful to evaluate CD44- expressed CSCs in breast cancer by BLI in vivo as well as in vitro for radiotherapy. PMID:27098303

  6. Metformin inhibits the proliferation, metastasis, and cancer stem-like sphere formation in osteosarcoma MG63 cells in vitro.

    PubMed

    Chen, Xu; Hu, Chuanzhen; Zhang, Weibin; Shen, Yuhui; Wang, Jun; Hu, Fangqiong; Yu, Pei

    2015-12-01

    Metformin is an oral drug that has been widely used to treat type 2 diabetes mellitus. Interestingly, accumulated evidence indicate that metformin may reduce the risk of cancer in patients with type 2 diabetes and inhibit tumor cell growth and survival in numerous malignancies, including osteosarcoma (OS) cells. In the present study, we aimed to investigate the effects of metformin on the proliferation, migration, invasion, and sphere formation in OS MG63 cells in vitro. Metformin suppressed OS MG63 cell proliferation in a dose- and time-dependent manner and markedly blocked anti-metastatic potentials, migration, and invasion, by downregulating matrix metalloproteinase 2 (MMP2) and MMP9. Besides, we established OS cancer stem-like cell (CSC) model with sarcosphere formation assay and demonstrated that metformin posed damage on CSCs in OS by inhibiting sphere formation and by inducing their stemness loss. The stemness of CSCs in OS such as self-renewal and differentiation potentials was both impaired with a significant decrease of Oct-4 and Nanog activation. Consistent with this, the positive rates of CD90, CD133, and stage-specific embryonic antigen-4 (SSEA-4) were all observed with reductions in response to metformin exposure. In addition, Western blot showed that metformin activated AMPKα at Tyr172, followed by a downregulated phosphorylation of mammalian target of rapamycin (mTOR)/S6 and feedback activation of p-AKT Ser(473) in both OS MG63 cells and CSCs. This indicates that AMPK/mTOR/S6 signaling pathway might be involved in the growth inhibition of both OS MG63 cells and CSCs. These results suggest that metformin, a potential anti-neoplastic agent, might make it a novel therapeutic choice for the treatment of OS in the future.

  7. Bufalin suppresses cancer stem-like cells in gemcitabine-resistant pancreatic cancer cells via Hedgehog signaling

    PubMed Central

    Wang, Haiyong; Ning, Zhouyu; Li, Yingyi; Zhu, Xiaoyan; Meng, Zhiqiang

    2016-01-01

    Cancer stem cells (CSCs) are important in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Agents with the ability to suppress CSCs are likely to provide novel opportunities for combating tumor proliferation and metastasis. The present study aimed to evaluate the effects of bufalin on pancreatic CSCs in vivo and in vitro. Using a serum-free suspension culture, tumor spheres were enriched in a gemcitabine-resistant human pancreatic cancer cell line, which had a higher percentage of CSCs, and western blotting, flow cytometry, and colony and tumor formation assays were used to demonstrate that these sphere cells exhibited CSC characteristics. Using these cancer stem-like cells as a model, the present study examined the effect of bufalin on pancreatic CSCs. It was demonstrated that bufalin inhibited the number of tumor spheres, and western blotting and immunohistochemical assays showed that the expression levels of CD24 and epithelial specific antigen (ESA) were downregulated by bufalin. Furthermore, in a subcutaneous xenograft model of implanted gemcitabine-resistant MiaPaCa2 cells, bufalin inhibited tumor growth and prolonged the duration of tumor formation. Additionally, the expression levels of CD24 and ESA were inhibited in the bufalin-treated mice. Notably, in another cancer model injected with tumor cells via the tail vein, fewer metastatic lesions were detected in the group in which tumor cells were pretreated with bufalin in vitro, compared with those without pretreatment. Of note, the Hedgehog (Hh) signaling pathway was found to be inhibited in the bufalin-treated cells. Taken together, these results suggested that bufalin suppressed pancreatic CSCs in gemcitabine-resistant MiaPaCa2 cells, and the Hh signaling pathway may be involved in this process. PMID:27432228

  8. Chronic Exposure to Combined Carcinogens Enhances Breast Cell Carcinogenesis with Mesenchymal and Stem-Like Cell Properties

    PubMed Central

    Pluchino, Lenora Ann; Wang, Hwa-Chain Robert

    2014-01-01

    Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens. PMID:25372613

  9. Salinomycin Promotes Anoikis and Decreases the CD44+/CD24- Stem-Like Population via Inhibition of STAT3 Activation in MDA-MB-231 Cells

    PubMed Central

    Oh, Eunhye; Lee, Nahyun; Cho, Youngkwan; Seo, Jae Hong

    2015-01-01

    Triple-negative breast cancer (TNBC) is an aggressive tumor subtype with an enriched CD44+/CD24- stem-like population. Salinomycin is an antibiotic that has been shown to target cancer stem cells (CSC); however, the mechanisms of action involved have not been well characterized. The objective of the present study was to investigate the effect of salinomycin on cell death, migration, and invasion, as well as CSC-like properties in MDA-MB-231 breast cancer cells. Salinomycin significantly induced anoikis-sensitivity, accompanied by caspase-3 and caspase-8 activation and PARP cleavage, during anchorage-independent growth. Salinomycin treatment also caused a marked suppression of cell migration and invasion with concomitant downregulation of MMP-9 and MMP-2 mRNA levels. Notably, salinomycin inhibited the formation of mammospheres and effectively reduced the CD44+/CD24- stem-like population during anchorage-independent growth. These observations were associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, interleukin-6 (IL-6)-induced STAT3 activation was strongly suppressed by salinomycin challenge. These findings support the notion that salinomycin may be potentially efficacious for targeting breast cancer stem-like cells through the inhibition of STAT3 activation. PMID:26528725

  10. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

    PubMed

    Farace, Cristiano; Oliver, Jaime Antonio; Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  11. Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: Understanding WNT/FGF-driven anabolic signaling.

    PubMed

    Lamb, Rebecca; Bonuccelli, Gloria; Ozsvári, Béla; Peiris-Pagès, Maria; Fiorillo, Marco; Smith, Duncan L; Bevilacqua, Generoso; Mazzanti, Chiara Maria; McDonnell, Liam A; Naccarato, Antonio Giuseppe; Chiu, Maybo; Wynne, Luke; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2015-10-13

    that high mitochondrial mass is a new metabolic biomarker for the enrichment of anabolic CSCs, as functionally assessed by mammosphere-forming activity. This observation has broad implications for understanding the role of mitochondrial biogenesis in the propagation of stem-like cancer cells. Technically, this general metabolic approach could be applied to any cancer type, to identify and target the mitochondrial-rich CSC population.The implications of our work for understanding the role of mitochondrial metabolism in viral oncogenesis driven by random promoter insertions are also discussed, in the context of MMTV and ALV infections. PMID:26421711

  12. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells

    PubMed Central

    Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell–microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  13. CD133 Expression Is Not Synonymous to Immunoreactivity for AC133 and Fluctuates throughout the Cell Cycle in Glioma Stem-Like Cells

    PubMed Central

    Eich, Marcus; Braukmann, Alina; Sprang, Bettina; Spirin, Pavel; Pardo, Luis A.; Giese, Alf; Kim, Ella L.

    2015-01-01

    A transmembrane protein CD133 has been implicated as a marker of stem-like glioma cells and predictor for therapeutic response in malignant brain tumours. CD133 expression is commonly evaluated by using antibodies specific for the AC133 epitope located in one of the extracellular domains of membrane-bound CD133. There is conflicting evidence regarding the significance of the AC133 epitope as a marker for identifying stem-like glioma cells and predicting the degree of malignancy in glioma cells. The reasons for discrepant results between different studies addressing the role of CD133/AC133 in gliomas are unclear. A possible source for controversies about CD133/AC133 is the widespread assumption that expression patterns of the AC133 epitope reflect linearly those of the CD133 protein. Consequently, the readouts from AC133 assessments are often interpreted in terms of the CD133 protein. The purpose of this study is to determine whether and to what extent do the readouts obtained with anti-AC133 antibody correspond to the level of CD133 protein expressed in stem-like glioma cells. Our study reveals for the first time that CD133 expressed on the surface of glioma cells is poorly immunoreactive for AC133. Furthermore, we provide evidence that the level of CD133 occupancy on the surface of glioma cells fluctuates during the cell cycle. Our results offer a new explanation for numerous inconsistencies regarding the biological and clinical significance of CD133/AC133 in human gliomas and call for caution in interpreting the lack or presence of AC133 epitope in glioma cells. PMID:26086074

  14. Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells

    PubMed Central

    Morata-Tarifa, Cynthia; Jiménez, Gema; García, María A.; Entrena, José M.; Griñán-Lisón, Carmen; Aguilera, Margarita; Picon-Ruiz, Manuel; Marchal, Juan A.

    2016-01-01

    Cancer stem cells are responsible for tumor progression, metastasis, therapy resistance and cancer recurrence, doing their identification and isolation of special relevance. Here we show that low adherent breast and colon cancer cells subpopulations have stem-like properties. Our results demonstrate that trypsin-sensitive (TS) breast and colon cancer cells subpopulations show increased ALDH activity, higher ability to exclude Hoechst 33342, enlarged proportion of cells with a cancer stem-like cell phenotype and are enriched in sphere- and colony-forming cells in vitro. Further studies in MDA-MB-231 breast cancer cells reveal that TS subpopulation expresses higher levels of SLUG, SNAIL, VIMENTIN and N-CADHERIN while show a lack of expression of E-CADHERIN and CLAUDIN, being this profile characteristic of the epithelial-to-mesenchymal transition (EMT). The TS subpopulation shows CXCL10, BMI-1 and OCT4 upregulation, differing also in the expression of several miRNAs involved in EMT and/or cell self-renewal such as miR-34a-5p, miR-34c-5p, miR-21-5p, miR-93-5p and miR-100-5p. Furthermore, in vivo studies in immunocompromised mice demonstrate that MDA-MB-231 TS cells form more and bigger xenograft tumors with shorter latency and have higher metastatic potential. In conclusion, this work presents a new, non-aggressive, easy, inexpensive and reproducible methodology to isolate prospectively cancer stem-like cells for subsequent biological and preclinical studies. PMID:26752044

  15. Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma.

    PubMed

    Ashizawa, Tadashi; Miyata, Haruo; Iizuka, Akira; Komiyama, Masaru; Oshita, Chie; Kume, Akiko; Nogami, Masahiro; Yagoto, Mika; Ito, Ichiro; Oishi, Takuma; Watanabe, Reiko; Mitsuya, Koichi; Matsuno, Kenji; Furuya, Toshio; Okawara, Tadashi; Otsuka, Masami; Ogo, Naohisa; Asai, Akira; Nakasu, Yoko; Yamaguchi, Ken; Akiyama, Yasuto

    2013-07-01

    Signal transducer and activator of transcription (STAT) 3, a member of a family of DNA-binding molecules, is a potential target in the treatment of cancer. The highly phosphorylated STAT3 in cancer cells contributes to numerous physiological and oncogenic signaling pathways. Furthermore, a significant association between STAT3 signaling and glioblastoma multiforme stem-like cell (GBM-SC) development and maintenance has been demonstrated in recent studies. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the present study, we focused on cancer stem-like cells derived from recurrent GBM patients and investigated the efficacy of STX-0119. Three GBM stem cell lines showed many stem cell markers such as CD133, EGFR, Nanog, Olig2, nestin and Yamanaka factors (c-myc, KLF4, Oct3/4 and SOX2) compared with parental cell lines. These cell lines also formed tumors in vivo and had similar histological to surgically resected tumors. STAT3 phosphorylation was activated more in the GBM-SC lines than serum-derived GB cell lines. The growth inhibitory effect of STX-0119 on GBM-SCs was moderate (IC50 15-44 µM) and stronger compared to that of WP1066 in two cell lines. On the other hand, the effect of temozolomide was weak in all the cell lines (IC50 53-226 µM). Notably, STX-0119 demonstrated strong inhibition of the expression of STAT3 target genes (c-myc, survivin, cyclin D1, HIF-1α and VEGF) and stem cell-associated genes (CD44, Nanog, nestin and CD133) as well as the induction of apoptosis in one stem-like cell line. Interestingly, VEGFR2 mRNA was also remarkably inhibited by STX-0119. In a model using transplantable stem-like cell lines in vivo GB-SCC010 and 026, STX-0119 inhibited the growth of GBM-SCs at 80 mg/kg. STX-0119, an inhibitor of STAT3, may serve as a novel therapeutic compound against GBM-SCs even in temozolomide-resistant GBM patients and has the potential for GBM-SC-specific therapeutics in

  16. EMMPRIN Down-regulating miR-106a/b Modifies Breast Cancer Stem-like Cell Properties via Interaction with Fibroblasts Through STAT3 and HIF-1α

    PubMed Central

    Liu, Yonglei; Zhang, Jingling; Sun, Xiangjun; Li, Meilin

    2016-01-01

    Extracellular matrix metalloproteinase inducer (EMMPRIN) is a heavily glycosylated protein and expresses in cancer cells widely, which plays important roles in tumor progression. However, the role of EMMPRIN in breast cancer stem-like cell properties by interaction with fibroblasts is not known. In the present study, we investigated the effects of fibroblasts on breast cancer stem-like cells. We found that fibroblasts activated by co-cultured breast cancer cells produced higher levels of EMMPRIN, which stimulated the stem-like cell specific, self-renewal and sphere-forming phenotype in breast cancer cells. Increased EMMPRIN expression in activated fibroblasts increased the expression of STAT3 and HIF-1α and showed cancer stem-like cell features in breast cancer cells. We also found that EMMPRIN could down-regulate miR-106a and miR-106b expression in breast cancer cells, which led to activating STAT3 and enhancing HIF-1α expression. Our results illustrated that EMMPRIN has an important role in breast cancer stem-like cells by activation STAT3/HIF-1α through interaction with cancer cells and fibroblasts. The study for the first time indicated that cancer cells and fibroblasts interaction promotes breast cancer cells showing stem-like cells through up-regulation EMMPRIN, and led to inhibiting miR-106a/b expression which targets both STAT3 and HIF-1α expression. PMID:27325313

  17. Pygo2 associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion.

    PubMed

    Chen, Jiakun; Luo, Qicong; Yuan, Yuanyang; Huang, Xiaoli; Cai, Wangyu; Li, Chao; Wei, Tongzhen; Zhang, Ludi; Yang, Meng; Liu, Qingfeng; Ye, Guodong; Dai, Xing; Li, Boan

    2010-12-01

    Resent studies have identified Pygopus as a core component of the β-catenin/T-cell factor (TCF)/lymphoid-enhancing factor 1 (LEF) transcriptional activation complex required for the expression of canonical Wg/Wnt target genes in Drosophila. However, the biochemical involvement of mammalian Pygopus proteins in β-catenin/TCF/LEF gene activation remains controversial. In this study, we perform a series of molecular/biochemical experiments to demonstrate that Pygo2 associates with histone-modifying enzymatic complexes, specifically the MLL2 histone methyltransferase (HMT) and STAGA histone acetyltransferase (HAT) complexes, to facilitate their interaction with β-catenin and to augment Wnt1-induced, TCF/LEF-dependent transcriptional activation in breast cancer cells. We identify a critical domain in Pygo2 encompassing the first 47 amino acids that mediates its HMT/HAT interaction. We further demonstrate the importance of this domain in Pygo2's ability to transcriptionally activate both artificial and endogenous Wnt target genes and to expand breast cancer stem-like cells in culture. This work now links mechanistically Pygo2's role in histone modification to its enhancement of the Wnt-dependent transcriptional program and cancer stem-like cell expansion.

  18. Loss of Brain-enriched miR-124 MicroRNA Enhances Stem-like Traits and Invasiveness of Glioma Cells*

    PubMed Central

    Xia, Hongping; Cheung, William K. C.; Ng, Samuel S.; Jiang, Xiaochun; Jiang, Songshan; Sze, Johnny; Leung, Gilberto K. K.; Lu, Gang; Chan, Danny T. M.; Bian, Xiu-Wu; Kung, Hsiang-fu; Poon, Wai Sang; Lin, Marie C.

    2012-01-01

    miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133+ cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re-expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR-124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2. PMID:22253443

  19. The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis.

    PubMed

    Ferreyra Solari, Nazarena E; Belforte, Fiorella S; Canedo, Lucía; Videla-Richardson, Guillermo A; Espinosa, Joaquín M; Rossi, Mario; Serna, Eva; Riudavets, Miguel A; Martinetto, Horacio; Sevlever, Gustavo; Perez-Castro, Carolina

    2016-09-15

    KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383-94. ©2016 AACR.

  20. Identification and analysis of CD133(+) melanoma stem-like cells conferring resistance to taxol: An insight into the mechanisms of their resistance and response.

    PubMed

    El-Khattouti, Abdelouahid; Selimovic, Denis; Haïkel, Youssef; Megahed, Mosaad; Gomez, Christian R; Hassan, Mohamed

    2014-02-01

    The presence and the involvement of cancer stem-like cells (CSCs) in tumor initiation and progression, and chemo-resistance are documented. Herein, we functionally analyzed melanoma stem-like cells (MSC)/CD133(+) cells on their resistance and response to taxol-induced apoptosis. Besides being taxol resistant, the CD133(+) cells demonstrated a growth advantage over the CD133(-) subpopulation. Taxol induced apoptosis on CD133(-) cells, but not on CD133(+) cells. In the CD133(-) subpopulation, the exposure to taxol induced the activation of apoptosis signal-regulating kinase1 (ASK1)/c-jun-N-terminal kinase (JNK), p38, extracellular signal regulated kinase (ERK) pathways and Bax expression, while in CD133(+) cells taxol was able only to enhance the activity of the ERK pathway. In CD133(+) cells, the direct gene transfer of Bax overcame the acquired resistance to taxol. Taken together, our data provide an insight into the mechanistic cascade of melanoma resistance to taxol and suggest Bax gene transfer as a complementary approach to chemotherapy.

  1. Functional and molecular characterization of cancer stem-like cells in bladder cancer: a potential signature for muscle-invasive tumors

    PubMed Central

    Ferreira-Teixeira, Margarida; Parada, Belmiro; Rodrigues-Santos, Paulo; Alves, Vera; Ramalho, José S.; Caramelo, Francisco; Sousa, Vitor; Reis, Flávio; Gomes, Célia M.

    2015-01-01

    Striking evidence associates cancer stem cells (CSCs) to the high recurrence rates and poor survival of patients with muscle-invasive bladder cancer (BC). However, the prognostic implication of those cells in risk stratification is not firmly established, mainly due to the functional and phenotypic heterogeneity of CSCs populations, as well as, to the conflicting data regarding their identification based on a single specific marker. This emphasizes the need to exploit putative CSC-related molecular markers with potential prognostic significance in BC patients. This study aimed to isolate and characterize bladder CSCs making use of different functional and molecular approaches. The data obtained provide strong evidence that muscle-invasive BC is enriched with a heterogeneous stem-like population characterized by enhanced chemoresistance and tumor initiating properties, able to recapitulate the heterogeneity of the original tumor. Additionally, a logistic regression analysis identified a 2-gene stem-like signature (SOX2 and ALDH2) that allows a 93% accurate discrimination between non-muscle-invasive and invasive tumors. Our findings suggest that a stemness-related gene signature, combined with a cluster of markers to more narrowly refine the CSC phenotype, could better identify BC patients that would benefit from a more aggressive therapeutic intervention targeting CSCs population. PMID:26452033

  2. Application of mitochondrial pyruvate carrier blocker UK5099 creates metabolic reprogram and greater stem-like properties in LnCap prostate cancer cells in vitro

    PubMed Central

    Zhong, Yali; Li, Xiaoran; Yu, Dandan; Li, Xiaoli; Li, Yaqing; Long, Yuan; Yuan, Yuan; Ji, Zhenyu; Zhang, Mingzhi; Wen, Jian-Guo; Nesland, Jahn M.; Suo, Zhenhe

    2015-01-01

    Aerobic glycolysis is one of the important hallmarks of cancer cells and eukaryotic cells. In this study, we have investigated the relationship between blocking mitochondrial pyruvate carrier (MPC) with UK5099 and the metabolic alteration as well as stemness phenotype of prostatic cancer cells. It was found that blocking pyruvate transportation into mitochondrial attenuated mitochondrial oxidative phosphorylation (OXPHOS) and increased glycolysis. The UK5099 treated cells showed significantly higher proportion of side population (SP) fraction and expressed higher levels of stemness markers Oct3/4 and Nanog. Chemosensitivity examinations revealed that the UK5099 treated cells became more resistant to chemotherapy compared to the non-treated cells. These results demonstrate probably an intimate connection between metabolic reprogram and stem-like phenotype of LnCap cells in vitro. We propose that MPC blocker (UK5099) application may be an ideal model for Warburg effect studies, since it attenuates mitochondrial OXPHOS and increases aerobic glycolysis, a phenomenon typically reflected in the Warburg effect. We conclude that impaired mitochondrial OXPHOS and upregulated glycolysis are related with stem-like phenotype shift in prostatic cancer cells. PMID:26413751

  3. Prostaglandin E receptor EP4 is a therapeutic target in breast cancer cells with stem-like properties.

    PubMed

    Kundu, Namita; Ma, Xinrong; Kochel, Tyler; Goloubeva, Olga; Staats, Paul; Thompson, Keyata; Martin, Stuart; Reader, Jocelyn; Take, Yukinori; Collin, Peter; Fulton, Amy

    2014-01-01

    The cyclooxygenase pathway is strongly implicated in breast cancer progression but the role of this pathway in the biology of breast cancer stem/progenitor cells has not been defined. Recent attention has focused on targeting the cyclooxygenase 2 (COX-2) pathway downstream of the COX-2 enzyme by blocking the activities of individual prostaglandin E (EP) receptors. Prostaglandin E receptor 4 (EP4) is widely expressed in primary invasive ductal carcinomas of the breast and antagonizing this receptor with small molecule inhibitors or shRNA directed to EP4 inhibits metastatic potential in both syngeneic and xenograft models. Breast cancer stem/progenitor cells are defined as a subpopulation of cells that drive tumor growth, metastasis, treatment resistance, and relapse. Mammosphere-forming breast cancer cells of human (MDA-MB-231, SKBR3) or murine (66.1, 410.4) origin of basal-type, Her-2 phenotype and/or with heightened metastatic capacity upregulate expression of both EP4 and COX-2 and are more tumorigenic compared to the bulk population. In contrast, luminal-type or non-metastatic counterparts (MCF7, 410, 67) do not increase COX-2 and EP4 expression in mammosphere culture. Treatment of mammosphere-forming cells with EP4 inhibitors (RQ-15986, AH23848, Frondoside A) or EP4 gene silencing, but not with a COX inhibitor (Indomethacin) reduces both mammosphere-forming capacity and the expression of phenotypic markers (CD44(hi)/CD24(low), aldehyde dehydrogenase) of breast cancer stem cells. Finally, an orally delivered EP4 antagonist (RQ-08) reduces the tumor-initiating capacity and markedly inhibits both the size of tumors arising from transplantation of mammosphere-forming cells and phenotypic markers of stem cells in vivo. These studies support the continued investigation of EP4 as a potential therapeutic target and provide new insight regarding the role of EP4 in supporting a breast cancer stem cell/tumor-initiating phenotype.

  4. Helping Children Help Themselves. Revised.

    ERIC Educational Resources Information Center

    Alberta Dept. of Agriculture, Edmonton.

    Youth leaders and parents can use this activity oriented publication to help children six to twelve years of age become more independent by acquiring daily living skills. The publication consists of five units, each of which contains an introduction, learning activities, and lists of resource materials. Age-ability levels are suggested for…

  5. Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells.

    PubMed

    Toledo, Chad M; Ding, Yu; Hoellerbauer, Pia; Davis, Ryan J; Basom, Ryan; Girard, Emily J; Lee, Eunjee; Corrin, Philip; Hart, Traver; Bolouri, Hamid; Davison, Jerry; Zhang, Qing; Hardcastle, Justin; Aronow, Bruce J; Plaisier, Christopher L; Baliga, Nitin S; Moffat, Jason; Lin, Qi; Li, Xiao-Nan; Nam, Do-Hyun; Lee, Jeongwu; Pollard, Steven M; Zhu, Jun; Delrow, Jeffery J; Clurman, Bruce E; Olson, James M; Paddison, Patrick J

    2015-12-22

    To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, most likely as a result of oncogenic signaling, causing GBM-specific lethality. PMID:26673326

  6. Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells.

    PubMed

    Toledo, Chad M; Ding, Yu; Hoellerbauer, Pia; Davis, Ryan J; Basom, Ryan; Girard, Emily J; Lee, Eunjee; Corrin, Philip; Hart, Traver; Bolouri, Hamid; Davison, Jerry; Zhang, Qing; Hardcastle, Justin; Aronow, Bruce J; Plaisier, Christopher L; Baliga, Nitin S; Moffat, Jason; Lin, Qi; Li, Xiao-Nan; Nam, Do-Hyun; Lee, Jeongwu; Pollard, Steven M; Zhu, Jun; Delrow, Jeffery J; Clurman, Bruce E; Olson, James M; Paddison, Patrick J

    2015-12-22

    To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, most likely as a result of oncogenic signaling, causing GBM-specific lethality.

  7. Human glioblastoma stem-like cells accumulate protoporphyrin IX when subjected to exogenous 5-aminolaevulinic acid, rendering them sensitive to photodynamic treatment.

    PubMed

    Schimanski, Adrian; Ebbert, Lara; Sabel, Michael C; Finocchiaro, Gaetano; Lamszus, Katrin; Ewelt, Christian; Etminan, Nima; Fischer, Johannes C; Sorg, Rüdiger V

    2016-10-01

    Glioblastoma (GBM) is the most frequent and lethal primary brain tumor in adults. Despite multimodal therapy combining resection, radio- and alkylating chemotherapy, disease recurrence is universal and prognosis of patients is poor. Glioblastoma stem-like cells (GSC), which can be grown as neurospheres from primary tumors in vitro, appear to be resistant to the established therapies and are suspected to be the driving force for disease recurrence. Thus, efficacy of emerging therapies may depend on targeting GSC. 5-aminolaevulinic acid-mediated photodynamic therapy (5-ALA/PDT) is a promising therapeutic approach in GBM. It utilizes the selective accumulation of the photosensitizer protoporphyrin IX (PPIX) in GBM cells after application of 5-ALA. When exposed to laser light of 635nm wavelength, PPIX initiates a photochemical reaction resulting in the generation of reactive oxygen species, which kill the tumor cells. Whether GSC accumulate PPIX and are sensitive to 5-ALA/PDT is currently unknown. Therefore, human GSC were derived from primary tumors and grown as neurospheres under serum free conditions. When subjected to exogenous 5-ALA, a dose- and time-dependent accumulation of PPIX in GSC was observed by flow cytometry, which varied between individual GSC preparations. Subsequent exposure to laser light of 635nm wavelength substantially killed GSC, whereas treatment with 5-ALA or exposure to laser light only had no effect. LD50 values differed between GSC preparations, but were negatively correlated with PPIX accumulation in GSC. In summary, we report for the first time that glioblastoma stem-like cells accumulate PPIX when subjected to 5-aminolaevulinic acid and are sensitive to 5-aminolaevulinc acid based photodynamic therapy. PMID:27588717

  8. The PRKCI and SOX2 Oncogenes are Co-amplified and Cooperate to Activate Hedgehog Signaling in Lung Squamous Cell Carcinoma

    PubMed Central

    Justilien, Verline; Walsh, Michael P.; Ali, Syed A.; Thompson, E. Aubrey; Murray, Nicole R.; Fields, Alan P.

    2014-01-01

    SUMMARY We report that two oncogenes co-amplified on chromosome 3q26, PRKCI and SOX2, cooperate to drive a stem-like phenotype in lung squamous cell carcinoma (LSCC). PKCι phosphorylates SOX2, a master transcriptional regulator of stemness, and recruits it to the promoter of Hedgehog Acyl Transferase (HHAT), which catalyzes the rate-limiting step in Hh ligand production. PKCι-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary LSCC tumors coordinately overexpress PKCι, SOX2, and HHAT, and require PKCι-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKCι and SOX2 are genetically, biochemically and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell autonomous Hh signaling axis. PMID:24525231

  9. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: A name change to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features would help prevent overtreatment.

    PubMed

    Thompson, Lester Dr

    2016-07-01

    Encapsulated follicular variant of papillary thyroid carcinoma is a common thyroid gland cancer, with a highly indolent behavior. Recently, reclassification as a non-malignant neoplasm has been proposed. There is no comprehensive, community hospital based longitudinal evaluation of encapsulated follicular variant of papillary thyroid carcinoma. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma were identified in a review of all thyroid gland surgeries performed in 2002 within the Southern California Permanente Medical Group. All histology slides were reviewed and follow-up obtained. Seventy-five women and nineteen men, aged 20-80 years (mean 45.6 years), had a single (n=61), multiple (same lobe; n=20), or bilateral (n=13) tumor(s), ranging in size from 0.7 to 9.5 cm in diameter (mean 3.3 cm). Histologically, all cases demonstrated a well-formed tumor capsule, with capsular and/or lymphovascular invasion in 17 and no invasion in 77 cases. Lymph node metastases were not identified. The tumors had a follicular architecture, without necrosis or >3 mitoses/10 high-power fields (HPFs). Classical papillary thyroid carcinoma nuclear features were seen in at least three HPFs per 3 mm of tumor diameter, including enlarged, elongated, crowded, and overlapping nuclei, irregular nuclear contours, nuclear grooves, and nuclear chromatin clearing. Lobectomy alone (n=41), thyroidectomy alone (n=34), or completion thyroidectomy (n=19) was the initial treatment combined with post-op radioablative iodine in 25 patients. All patients were without evidence of disease after a median follow-up of 11.8 years. Encapsulated follicular variant of papillary thyroid carcinoma showed benign behavior, supporting conservative surgery alone and reclassification of these tumors to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).

  10. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions.

    PubMed

    Majumder, Mousumi; Xin, Xiping; Liu, Ling; Girish, Gannareddy V; Lala, Peeyush K

    2014-09-01

    We previously established that COX-2 overexpression promotes breast cancer progression and metastasis. As long-term use of COX-2 inhibitors (COX-2i) can promote thrombo-embolic events, we tested an alternative target, prostaglandin E2 receptor EP4 subtype (EP4), downstream of COX-2. Here we used the highly metastatic syngeneic murine C3L5 breast cancer model to test the role of EP4-expressing macrophages in vascular endothelial growth factor (VEGF)-C/D production, angiogenesis, and lymphangiogenesis in situ, the role of EP4 in stem-like cell (SLC) functions of tumor cells, and therapeutic effects of an EP4 antagonist RQ-15986 (EP4A). C3L5 cells expressed all EP receptors, produced VEGF-C/D, and showed high clonogenic tumorsphere forming ability in vitro, functions inhibited with COX-2i or EP4A. Treating murine macrophage RAW 264.7 cell line with COX-2i celecoxib and EP4A significantly reduced VEGF-A/C/D production in vitro, measured with quantitative PCR and Western blots. Orthotopic implants of C3L5 cells in C3H/HeJ mice showed rapid tumor growth, angiogenesis, lymphangiogenesis (CD31/LYVE-1 and CD31/PROX1 immunostaining), and metastasis to lymph nodes and lungs. Tumors revealed high incidence of EP4-expressing, VEGF-C/D producing macrophages identified with dual immunostaining of F4/80 and EP4 or VEGF-C/D. Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in treated mice revealed markedly reduced VEGF-A/C/D and phosphorylated Akt/ERK proteins, VEGF-C/D positive macrophage infiltration, and proliferative/apoptotic cell ratios. Knocking down COX-2 or EP4 in C3L5 cells or treating cells in vitro with celecoxib or EP4A and treating tumor-bearing mice in vivo with the same drug reduced SLC properties of tumor cells including preferential co-expression of COX-2 and SLC markers ALDH1A, CD44, OCT-3/4, β-catenin, and SOX-2. Thus, EP4 is an excellent therapeutic target to block

  11. Effective Targeting Survivin, Caspase-3 and MicroRNA-16-1 Expression by Methyl-3-pentyl-6-methoxyprodigiosene Triggers Apoptosis in Colorectal Cancer Stem-Like Cells.

    PubMed

    Sam, Sohrab; Sam, Mohammad Reza; Esmaeillou, Mohammad; Safaralizadeh, Reza

    2016-10-01

    Over-expression of the proto-oncogene survivin in colorectal cancer stem cells (CCSCs) is thought to be one the primary causes for therapy failure. It has also been reported that tumor suppressor miR-16-1 is down-regulated in colorectal cancer (CRC) cells. Therefore, the search for new anti-proliferative agents which target survivin or miR-16-1 in CCSCs is warranted. Several studies have shown that prodigiosin isolated from cell wall of Serratia marcescens induces apoptosis in different kinds of cancer cells. Here, we investigated the effects of prodigiosin on HCT-116 cells that serve as a model for CRC initiating cells with stem-like cells properties. HCT-116 cells were treated with 100, 200 and 400 nM prodigiosin after which cell number, viability, growth-rate, survivin and miRNA-16-1 expression, caspase-3 activation and apoptotic rate were evaluated. Prodigiosin decreased significantly growth-rate in a dose-and time-dependent manner. After a 48 h treatment with 100, 200 and 400 nM prodigiosin, growth-rates were measured to be 84.4 ± 9.2 %, 58 ± 6.5 % and 46.3 ± 5.2 %, respectively, compared to untreated cells. We also found that treatment for 48 h with indicated concentrations of prodigiosin resulted in 41 %, 54.5 % and 63 % decrease in survivin mRNA levels and induced 32 %, 48 % and 61 % decrease in survivin protein levels as well as resulted in 128.3 ± 10 %, 178.7 ± 6.1 % and 205 ± 7.6 % increase in caspase-3 activation respectively compared to untreated cells. Prodigiosin caused a significant increase in miRNA-16-1 expression at a concentration of 100 nM and treatment with different concentrations of prodigiosin resulted in 2.2- to 3-fold increase in miRNA-16-1/survivin ratios compared to untreated cells. An increase in number of apoptotic cells ranging from 28.2 % to 86.8 % was also observed with increasing prodigiosin concentrations. Our results provide the first evidence that survivin and miRNA-16-1 as potential

  12. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions

    PubMed Central

    Majumder, Mousumi; Xin, Xiping; Liu, Ling; Girish, Gannareddy V; Lala, Peeyush K

    2014-01-01

    We previously established that COX-2 overexpression promotes breast cancer progression and metastasis. As long-term use of COX-2 inhibitors (COX-2i) can promote thrombo-embolic events, we tested an alternative target, prostaglandin E2 receptor EP4 subtype (EP4), downstream of COX-2. Here we used the highly metastatic syngeneic murine C3L5 breast cancer model to test the role of EP4-expressing macrophages in vascular endothelial growth factor (VEGF)-C/D production, angiogenesis, and lymphangiogenesis in situ, the role of EP4 in stem-like cell (SLC) functions of tumor cells, and therapeutic effects of an EP4 antagonist RQ-15986 (EP4A). C3L5 cells expressed all EP receptors, produced VEGF-C/D, and showed high clonogenic tumorsphere forming ability in vitro, functions inhibited with COX-2i or EP4A. Treating murine macrophage RAW 264.7 cell line with COX-2i celecoxib and EP4A significantly reduced VEGF-A/C/D production in vitro, measured with quantitative PCR and Western blots. Orthotopic implants of C3L5 cells in C3H/HeJ mice showed rapid tumor growth, angiogenesis, lymphangiogenesis (CD31/LYVE-1 and CD31/PROX1 immunostaining), and metastasis to lymph nodes and lungs. Tumors revealed high incidence of EP4-expressing, VEGF-C/D producing macrophages identified with dual immunostaining of F4/80 and EP4 or VEGF-C/D. Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in treated mice revealed markedly reduced VEGF-A/C/D and phosphorylated Akt/ERK proteins, VEGF-C/D positive macrophage infiltration, and proliferative/apoptotic cell ratios. Knocking down COX-2 or EP4 in C3L5 cells or treating cells in vitro with celecoxib or EP4A and treating tumor-bearing mice in vivo with the same drug reduced SLC properties of tumor cells including preferential co-expression of COX-2 and SLC markers ALDH1A, CD44, OCT-3/4, β-catenin, and SOX-2. Thus, EP4 is an excellent therapeutic target to block

  13. Oxidative stress induces the acquisition of cancer stem-like phenotype in breast cancer detectable by using a Sox2 regulatory region-2 (SRR2) reporter

    PubMed Central

    Gopal, Keshav; Gupta, Nidhi; Zhang, Haifeng; Alshareef, Abdulraheem; Alqahtani, Hind; Bigras, Gilbert; Lewis, Jamie; Douglas, Donna; Kneteman, Norman; Lavasanifar, Afsaneh; Lai, Raymond

    2016-01-01

    We have previously identified a novel intra-tumoral dichotomy in breast cancer based on the differential responsiveness to a Sox2 reporter (SRR2), with cells responsive to SRR2 (RR) being more stem-like than unresponsive cells (RU). Here, we report that RR cells derived from MCF7 and ZR751 displayed a higher tolerance to oxidative stress than their RU counterparts, supporting the concept that the RR phenotype correlates with cancer stemness. Sox2 is directly implicated in this differential H2O2 tolerance, since siRNA knockdown of Sox2 in RR cells leveled this difference. Interestingly, H2O2 converted a proportion of RU cells into RR cells, as evidenced by their expression of luciferase and GFP, markers of SRR2 activity. Compared to RU cells, converted RR cells showed a significant increase in mammosphere formation and tolerance to H2O2. Converted RR cells also adopted the biochemical features of RR cells, as evidenced by their substantial increase in Sox2-SRR2 binding and the expression of 3 signature genes of RR cells (CD133, GPR49 and MUC15). Lastly, the H2O2-induced RU/RR conversion was detectable in a SCID mouse xenograft model and primary tumor cells. To conclude, the H2O2-induced RU/RR conversion has provided a novel model to study the acquisition of cancer stemness and plasticity. PMID:26683522

  14. Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells

    PubMed Central

    Park, So-Yeon; Kim, Min-Jin; Park, Sang-A; Kim, Jung-Shin; Min, Kyung-Nan; Kim, Dae-Kee; Lim, Woosung; Nam, Jeong-Seok; Sheen, Yhun Yhong

    2015-01-01

    Distant relapse after chemotherapy is an important clinical issue for treating breast cancer patients and results from the development of cancer stem-like cells (CSCs) during chemotherapy. Here we report that blocking epithelial-to-mesenchymal transition (EMT) suppresses paclitaxel-induced CSCs properties by using a MDA-MB-231-xenografted mice model (in vivo), and breast cancer cell lines (in vitro). Paclitaxel, one of the cytotoxic taxane-drugs such as docetaxel, increases mesenchymal markers (Vimentin and Fibronectin) and decreases an epithelial marker (Zo-1). Blocking TGF-β signaling with the TGF-β type I receptor kinase (ALK5) inhibitor, EW-7197, suppresses paclitaxel-induced EMT and CSC properties such as mammosphere-forming efficiency (MSFE), aldehyde dehydrogenase (ALDH) activity, CD44+/CD24− ratio, and pluripotency regulators (Oct4, Nanog, Klf4, Myc, and Sox2). The combinatorial treatment of EW-7197 improves the therapeutic effect of paclitaxel by decreasing the lung metastasis and increasing the survival time in vivo. We confirmed that Snail is increased by paclitaxel-induced intracellular reactive oxygen species (ROS) and EW-7197 suppresses the paclitaxel-induced Snail and EMT by attenuating paclitaxel-induced intracellular ROS. Knock-down of SNAI1 suppresses paclitaxel-induced EMT and CSC properties. These data together suggest that blocking the Snail-induced EMT with the ALK5 inhibitor attenuates metastasis after paclitaxel-therapy and that this combinatorial approach could prove useful in treating breast cancer. PMID:26462028

  15. All-trans retinoic acid impairs the vasculogenic mimicry formation ability of U87 stem-like cells through promoting differentiation

    PubMed Central

    LING, GENG-QIANG; LIU, YI-JING; KE, YI-QUAN; CHEN, LEI; JIANG, XIAO-DAN; JIANG, CHUAN-LU; YE, WEI

    2015-01-01

    The poor therapeutic effect of traditional antiangiogenic therapy on glioblastoma multiforme (GBM) may be attributed to vasculogenic mimicry (VM), which was previously reported to be promoted by cancer stem-like cells (SLCs). All-trans retinoic acid (ATRA), a potent reagent which drives differentiation, was reported to be able to eradicate cancer SLCs in certain malignancies. The aim of the present study was to investigate the effects of ATRA on the VM formation ability of U87 glioblastoma SLCs. The expression of cancer SLC markers CD133 and nestin was detected using immunocytochemistry in order to identify U87 SLCs. In addition, the differentiation of these SLCs was observed through detecting the expression of glial fibrillary acidic protein (GFAP), β-tubulin III and galactosylceramidase (Galc) using immunofluorescent staining. The results showed that the expression levels of GFAP, β-tubulin III and Galc were upregulated following treatment with ATRA in a dose-dependent manner. Furthermore, ATRA significantly reduced the proliferation, invasiveness, tube formation and vascular endothelial growth factor (VEGF) secretion of U87 SLCs. In conclusion, the VM formation ability of SLCs was found to be negatively correlated with differentiation. These results therefore suggested that ATRA may serve as a promising novel agent for the treatment of GBM due to its role in reducing VM formation. PMID:25760394

  16. Targeted therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximab-conjugated iron-oxide nanoparticles

    PubMed Central

    Kaluzova, Milota; Bouras, Alexandros; Machaidze, Revaz; Hadjipanayis, Costas G.

    2015-01-01

    Malignant gliomas remain aggressive and lethal primary brain tumors in adults. The epidermal growth factor receptor (EGFR) is frequently overexpressed in the most common malignant glioma, glioblastoma (GBM), and represents an important therapeutic target. GBM stem-like cells (GSCs) present in tumors are felt to be highly tumorigenic and responsible for tumor recurrence. Multifunctional magnetic iron-oxide nanoparticles (IONPs) can be directly imaged by magnetic resonance imaging (MRI) and designed to therapeutically target cancer cells. The targeting effects of IONPs conjugated to the EGFR inhibitor, cetuximab (cetuximab-IONPs), were determined with EGFR- and EGFRvIII-expressing human GBM neurospheres and GSCs. Transmission electron microscopy revealed cetuximab-IONP GBM cell binding and internalization. Fluorescence microscopy and Prussian blue staining showed increased uptake of cetuximab-IONPs by EGFR- as well as EGFRvIII-expressing GSCs and neurospheres in comparison to cetuximab or free IONPs. Treatment with cetuximab-IONPs resulted in a significant antitumor effect that was greater than with cetuximab alone due to more efficient, CD133-independent cellular targeting and uptake, EGFR signaling alterations, EGFR internalization, and apoptosis induction in EGFR-expressing GSCs and neurospheres. A significant increase in survival was found after cetuximab-IONP convection-enhanced delivery treatment of 3 intracranial rodent GBM models employing human EGFR-expressing GBM xenografts. PMID:25871395

  17. Chloroquine or Chloroquine-PI3K/Akt Pathway Inhibitor Combinations Strongly Promote γ-Irradiation-Induced Cell Death in Primary Stem-Like Glioma Cells

    PubMed Central

    Firat, Elke; Weyerbrock, Astrid; Gaedicke, Simone; Grosu, Anca-Ligia; Niedermann, Gabriele

    2012-01-01

    We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote γ-irradiationγIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote γIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 µM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted γIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in γ-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes γIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, γIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death. PMID:23091617

  18. Combination of carbon ion beam and gemcitabine causes irreparable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo

    PubMed Central

    Sai, Sei; Wakai, Toshifumi; Vares, Guillaume; Yamada, Shigeru; Kamijo, Takehiko; Kamada, Tadashi; Shirai, Toshiyuki

    2015-01-01

    We try to elucidate whether a carbon ion beam alone or in combination with gemcitabine has advantages over X-ray in targeting putative pancreatic cancer stem-like cells (CSCs) in vitro and in vivo. Colony, spheroid formation and tumorigenicity assays confirmed that CD44+/ESA+ cells sorted from PANC1 and PK45 cells have more CSC properties than CD44−/ESA− cells. The number of colonies and spheroids formed from CSCs after carbon ion beam irradiation was significantly reduced compared to after X-ray irradiation, and they were extremely highly suppressed when carbon ion beam combined with gemcitabine. The relative biological effectiveness (RBE) values for the carbon ion beam relative to X-ray at the D10 levels for CSCs were 2.23-2.66. Expressions of multiple cell death-related genes were remarkably highly induced, and large numbers of γH2AX foci in CSCs were formed after carbon ion beam combined with gemcitabine. The highly expressed CSC markers were significantly inhibited after 30 Gy of carbon ion beam and almost lost after 25 Gy carbon ion beam combined with 50 mg/kg gemcitabine. In conclusion, a carbon ion beam combined with gemcitabine has superior potential to kill pancreatic CSCs via irreparable clustered DSB compared to a carbon ion alone or X-rays combined with gemcitabine. PMID:25849939

  19. The long non-coding RNA – HIF1A-AS2 facilitates the maintenance of mesenchymal glioblastoma stem-like cells in hypoxic niches

    PubMed Central

    Mineo, Marco; Ricklefs, Franz; Rooj, Arun K.; Lyons, Shawn M.; Ivanov, Pavel; Ansari, Khairul I.; Nakano, Ichiro; Chiocca, E. Antonio; Godlewski, Jakub; Bronisz, Agnieszka

    2016-01-01

    Long-non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia inducible lncRNA, up-regulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal and hypoxia-dependent molecular reprogramming. Amongst the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Down-regulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome/targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context. PMID:27264189

  20. Inhibition of CK2α Down-Regulates Hedgehog/Gli Signaling Leading to a Reduction of a Stem-Like Side Population in Human Lung Cancer Cells

    PubMed Central

    Zhang, Shulin; Wang, Yucheng; Mao, Jian-Hua; Hsieh, David; Kim, Il-Jin; Hu, Li-Min; Xu, Zhidong; Long, Hao; Jablons, David M.; You, Liang

    2012-01-01

    Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells. PMID:22768056

  1. Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP-9 upregulation.

    PubMed

    Long, Haixia; Xie, Rongkai; Xiang, Tong; Zhao, Zhongquan; Lin, Sheng; Liang, Zhiqing; Chen, Zhengtang; Zhu, Bo

    2012-10-01

    The concept of cancer stem cells (CSCs) proposes that solely CSCs are capable of generating tumor metastases. However, how CSCs maintain their invasion and migration abilities, the most important properties of metastatic cells, still remains elusive. Here we used CD133 to mark a specific population from human ovarian cancer cell line and ovarian cancer tissue and determined its hyperactivity in migration and invasion. Therefore, we labeled this population as cancer stem-like cells (CSLCs). In comparison to CD133- non-CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. Mechanistically, we identified that this enhanced invasiveness is mediated through nuclear factor κB (NF-κB) activation and the consequently elevated MMP9 secretion. Our results suggested that the autocrine activation of CCR1 and CCR3 by CCL5 represents one of major mechanisms underlying the metastatic property of ovarian CSLCs. PMID:22887854

  2. The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches.

    PubMed

    Mineo, Marco; Ricklefs, Franz; Rooj, Arun K; Lyons, Shawn M; Ivanov, Pavel; Ansari, Khairul I; Nakano, Ichiro; Chiocca, E Antonio; Godlewski, Jakub; Bronisz, Agnieszka

    2016-06-14

    Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming. Among the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Downregulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs' speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context. PMID:27264189

  3. Kinome-wide shRNA Screen Identifies the Receptor Tyrosine Kinase AXL as a Key Regulator for Mesenchymal Glioblastoma Stem-like Cells

    PubMed Central

    Cheng, Peng; Phillips, Emma; Kim, Sung-Hak; Taylor, David; Hielscher, Thomas; Puccio, Laura; Hjelmeland, Anita B.; Lichter, Peter; Nakano, Ichiro; Goidts, Violaine

    2015-01-01

    Summary Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers. PMID:25921812

  4. IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden.

    PubMed

    van der Zee, Marten; Sacchetti, Andrea; Cansoy, Medine; Joosten, Rosalie; Teeuwssen, Miriam; Heijmans-Antonissen, Claudia; Ewing-Graham, Patricia C; Burger, Curt W; Blok, Leen J; Fodde, Riccardo

    2015-09-01

    Cancer stem-like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDH(hi)) in a tumor might positively correlate with the presence of stem- and progenitor-like tumor cells in this disease setting. In support of this hypothesis, ALDH could be used to enrich for CSC in endometrial cancer cell lines and primary tumors, as illustrated by the increased tumor-initiating capacity of ALDH(hi) cells in immunodeficient mice. ALDH(hi) cells also exhibited greater clonogenic and organoid-forming capacity compared with ALDH(lo) cells. Notably, the number of ALDH(hi) cells in tumor cell lines and primary tumors inversely correlated with differentiation grade. Expression analysis revealed upregulation of IL6 receptor subunits and signal transducers CD126 and GP130 in ALDH(hi) endometrial cancer cells. Accordingly, targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth. Overall, our results provide a preclinical rationale to target IL6 or its effector functions as a novel therapeutic option in endometrial cancer.

  5. p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.

    PubMed

    Qi, Xiaomei; Yin, Ning; Ma, Shao; Lepp, Adrienne; Tang, Jun; Jing, Weiqing; Johnson, Bryon; Dwinell, Michael B; Chitambar, Christopher R; Chen, Guan

    2015-09-01

    Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38γ mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38γ contributes to TNBC remains unknown. Here, we show that p38γ activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38γ silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38γ MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38γ depends on its activity to stimulate CSC expansion and breast cancer progression, indicating a therapeutic opportunity by application of its pharmacological inhibitor. Indeed, the non-toxic p38γ specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38γ stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38γ can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38γ activity with pirfenidone may be a novel strategy for the treatment of TNBC.

  6. Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma.

    PubMed

    Lin, K-Y; Ye, H; Han, B-W; Wang, W-T; Wei, P-P; He, B; Li, X-J; Chen, Y-Q

    2016-06-30

    Cholangiocarcinoma (CCA), which is a poor prognosis malignancy that arises from the malignant transformation of cholangiocytes, is associated with chronic inflammation of the biliary epithelium. Thus far, the molecular mechanisms of the origin and neoplastic processes of CCA that are promoted by inflammation are still unclear and need to be fully elucidated. Here using small RNA sequencing to determine the microRNA (miRNA) expression profiles in CCA, we found that let-7c, miR-99a and miR-125b, which are three miRNAs of the same cluster, were downregulated in CCA and targeted interleukin 6 (IL-6), IL-6R and type 1 insulin-like growth factor, which are important cytokines and receptors of the IL-6/signal transducer and activator 3 (STAT3) pathway and have key roles in inflammation and CCA initiation. We also found that enforced expression of let-7c, miR-99a or miR-125b could reduce the activity of STAT3 and further suppress CCA tumorigenicity in vivo and inhibit the migration and invasion of CCA cells in vitro. Surprisingly, let-7c/miR-99a/miR-125b cluster also significantly decreased the ability of CCA cells for cancer stem cell-like mammosphere generation by downregulating CD133 and CD44, which suggests the pivotal roles of let-7c, miR-99a and miR-125b in CCA by regulating both inflammation and stem-like properties. Our findings showed potential links between miRNAs and inflammation, and provide a potential treatment strategy for developing an miRNA-based therapy via IL-6/STAT3 targeting for CCA. PMID:26455324

  7. Histone Deacetylase 1/Sp1/MicroRNA-200b Signaling Accounts for Maintenance of Cancer Stem-Like Cells in Human Lung Adenocarcinoma

    PubMed Central

    Pan, Ban-Zhou; De, Wei; Wang, Rui; Chen, Long-Bang

    2014-01-01

    The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR-200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells. PMID:25279705

  8. [Elevated expression of B7-H6 in U87 cells-derived glioma stem like cells is associated with biological characteristics].

    PubMed

    Chen, Hanqing; Shi, Zhengpeng; Gao, Bing; Fu, Fengqing; Zhang, Xueguang

    2016-09-01

    Objective To investigate the expression and biological significance of costimulatory molecule B7-H6, a member of B7 family, in glioma stem like cells (GSLCs). Methods In virtue of the ability of forming neurospheres in vitro , GSLCs were isolated from U87 cells by cell sub-cloning. Real-time quantitative PCR and flow cytometry were performed to detect the expressions of stem cell related markers (c-myc, Sox2, CD133, nestin, and CXCR4), as well as the expressions of B7 family molecules. The different doses of adriamycin, carboplatin, cisplatin, were used to treat GSLCs for testing their chemotherapy-resistance. After the expression of B7-H6 in GSLCs was knockdown by siRNA, CCK-8 method was used to detect cell proliferation. Results GSLCs were successfully isolated from U87 cells, which formed neurospheres in vitro . The expressions of multiple stem cell markers were up-regulated and the GSLCs showed enhanced chemo therapy-resistance. B7 family members, B7-H1, B7-H3, B7-H4 and B7-H6 were expressed in GSLCs. Compared with primary U87 cells, GSLCs presented with a remarkably increased expression of B7-H6 on cell membrane. When B7-H6 was silenced by siRNA, cell proliferation was inhibited along with the decrease of c-myc expression. Conclusion The expression of B7-H6 is up-regulated in U87-derived GSLCs, which is associated with the biological characteristics of GSLCs.

  9. The ABCG2 transporter is a key molecular determinant of the efficacy of sonodynamic therapy with Photofrin in glioma stem-like cells.

    PubMed

    Xu, Zhong-Ye; Wang, Kai; Li, Xiao-Qing; Chen, Song; Deng, Jin-Mu; Cheng, Yuan; Wang, Zhi-Gang

    2013-01-01

    We aimed to investigate the role of the ABCG2 transporter in the efficacy of sonodynamic therapy (SDT) with Photofrin in the glioma stem-like cells (GSCs) isolated and cultured from U251 glioma cells. Immunocytochemistry and flow cytometry analyses showed that ABCG2 was overexpressed in GSCs, and the percentage of ABCG2-positive GSCs was approximately 100%. The effect of ABCG2 on Photofrin extrusion in the absence or presence of a specific inhibitor of ABCG2 (fumitremorgin C; FTC) was investigated by determining the intracellular concentration of Photofrin in GSCs incubated with 20μg/ml Photofrin. Extrusion of Photofrin by ABCG2 was inhibited by 10μM FTC, which significantly increased the intracellular Photofrin concentration (p<0.05) from 0.32±0.11μg/10(6) cells to 0.89±0.13μg/10(6) cells. MTT and TUNEL assays showed that the antitumor effect of SDT (incubation of GSCs with 20μg/ml Photofrin for 6h in the dark and ultrasonic activation at 1.0MHz and 0.5W/cm(2) for 2min) was significantly improved by FTC pretreatment (p<0.05). Moreover, incubation of GSCs with FTC significantly increased the relative production of ROS in response to SDT. The overexpression of ABCG2 in GSCs results in efflux of Photofrin, indicating that the antitumor effect of SDT with Photofrin may be reduced in GSCs overexpressing ABCG2. However, since FTC improves the efficacy of SDT in GSCs by inhibiting ABCG2-mediated efflux of Photofrin, FTC may be useful in SDT treatment of ABCG2-expressing cancer cells. PMID:22771084

  10. [Elevated expression of B7-H6 in U87 cells-derived glioma stem like cells is associated with biological characteristics].

    PubMed

    Chen, Hanqing; Shi, Zhengpeng; Gao, Bing; Fu, Fengqing; Zhang, Xueguang

    2016-09-01

    Objective To investigate the expression and biological significance of costimulatory molecule B7-H6, a member of B7 family, in glioma stem like cells (GSLCs). Methods In virtue of the ability of forming neurospheres in vitro , GSLCs were isolated from U87 cells by cell sub-cloning. Real-time quantitative PCR and flow cytometry were performed to detect the expressions of stem cell related markers (c-myc, Sox2, CD133, nestin, and CXCR4), as well as the expressions of B7 family molecules. The different doses of adriamycin, carboplatin, cisplatin, were used to treat GSLCs for testing their chemotherapy-resistance. After the expression of B7-H6 in GSLCs was knockdown by siRNA, CCK-8 method was used to detect cell proliferation. Results GSLCs were successfully isolated from U87 cells, which formed neurospheres in vitro . The expressions of multiple stem cell markers were up-regulated and the GSLCs showed enhanced chemo therapy-resistance. B7 family members, B7-H1, B7-H3, B7-H4 and B7-H6 were expressed in GSLCs. Compared with primary U87 cells, GSLCs presented with a remarkably increased expression of B7-H6 on cell membrane. When B7-H6 was silenced by siRNA, cell proliferation was inhibited along with the decrease of c-myc expression. Conclusion The expression of B7-H6 is up-regulated in U87-derived GSLCs, which is associated with the biological characteristics of GSLCs. PMID:27609569

  11. Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs)

    PubMed Central

    Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B.; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

    2016-01-01

    Bedaquiline (a.k.a., Sirturo) is an anti-microbial agent, which is approved by the FDA for the treatment of multi-drug resistant pulmonary tuberculosis (TB). Bedaquiline is a first-in-class diaryl-quinoline compound, that mechanistically inhibits the bacterial ATP-synthase, and shows potent activity against both drug-sensitive and drug-resistant TB. Interestingly, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. Thus, we hypothesized that, in mammalian cells, bedaquiline might also target the mitochondrial ATP-synthase, leading to mitochondrial dysfunction and ATP depletion. Here, we show that bedaquiline has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that bedaquiline treatment of MCF7 breast cancer cells inhibits mitochondrial oxygen-consumption, as well as glycolysis, but induces oxidative stress. Importantly, bedaquiline significantly blocks the propagation and expansion of MCF7-derived CSCs, with an IC-50 of approx. 1-μM, as determined using the mammosphere assay. Similarly, bedaquiline also reduces both the CD44+/CD24low/− CSC and ALDH+ CSC populations, under anchorage-independent growth conditions. In striking contrast, bedaquiline significantly increases oxygen consumption in normal human fibroblasts, consistent with the fact that it is well-tolerated in patients treated for TB infections. As such, future pre-clinical studies and human clinical trials in cancer patients may be warranted. Interestingly, we also highlight that bedaquiline shares certain structural similarities with trans-piceatannol and trans-resveratrol, which are known natural flavonoid inhibitors of the mitochondrial ATP-synthase (complex V) and show anti-aging properties. PMID:27344270

  12. The ABCG2 transporter is a key molecular determinant of the efficacy of sonodynamic therapy with Photofrin in glioma stem-like cells.

    PubMed

    Xu, Zhong-Ye; Wang, Kai; Li, Xiao-Qing; Chen, Song; Deng, Jin-Mu; Cheng, Yuan; Wang, Zhi-Gang

    2013-01-01

    We aimed to investigate the role of the ABCG2 transporter in the efficacy of sonodynamic therapy (SDT) with Photofrin in the glioma stem-like cells (GSCs) isolated and cultured from U251 glioma cells. Immunocytochemistry and flow cytometry analyses showed that ABCG2 was overexpressed in GSCs, and the percentage of ABCG2-positive GSCs was approximately 100%. The effect of ABCG2 on Photofrin extrusion in the absence or presence of a specific inhibitor of ABCG2 (fumitremorgin C; FTC) was investigated by determining the intracellular concentration of Photofrin in GSCs incubated with 20μg/ml Photofrin. Extrusion of Photofrin by ABCG2 was inhibited by 10μM FTC, which significantly increased the intracellular Photofrin concentration (p<0.05) from 0.32±0.11μg/10(6) cells to 0.89±0.13μg/10(6) cells. MTT and TUNEL assays showed that the antitumor effect of SDT (incubation of GSCs with 20μg/ml Photofrin for 6h in the dark and ultrasonic activation at 1.0MHz and 0.5W/cm(2) for 2min) was significantly improved by FTC pretreatment (p<0.05). Moreover, incubation of GSCs with FTC significantly increased the relative production of ROS in response to SDT. The overexpression of ABCG2 in GSCs results in efflux of Photofrin, indicating that the antitumor effect of SDT with Photofrin may be reduced in GSCs overexpressing ABCG2. However, since FTC improves the efficacy of SDT in GSCs by inhibiting ABCG2-mediated efflux of Photofrin, FTC may be useful in SDT treatment of ABCG2-expressing cancer cells.

  13. Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.

    PubMed

    Nabissi, Massimo; Morelli, Maria Beatrice; Amantini, Consuelo; Liberati, Sonia; Santoni, Matteo; Ricci-Vitiani, Lucia; Pallini, Roberto; Santoni, Giorgio

    2015-10-15

    Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.

  14. MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

    PubMed Central

    Yan, Li; Cao, Rui; Liu, YuanBo; Wang, LianZhao; Pan, Bo; Lv, XiaoYan; Jiao, Hu; Zhuang, Qiang; Sun, XueJian; Xiao, Ran

    2016-01-01

    Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids. PMID:27596120

  15. Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer.

    PubMed

    Wahdan-Alaswad, Reema; Harrell, J Chuck; Fan, Zeying; Edgerton, Susan M; Liu, Bolin; Thor, Ann D

    2016-01-01

    Mesenchymal stem-like/claudin-low (MSL/CL) breast cancers are highly aggressive, express low cell-cell adhesion cluster containing claudins (CLDN3/CLDN4/CLDN7) with enrichment of epithelial-to-mesenchymal transition (EMT), immunomodulatory, and transforming growth factor-β (TGF-β) genes. We examined the biological, molecular and prognostic impact of TGF-β upregulation and/or inhibition using in vivo and in vitro methods. Using publically available breast cancer gene expression databases, we show that upregulation and enrichment of a TGF-β gene signature is most frequent in MSL/CL breast cancers and is associated with a worse outcome. Using several MSL/CL breast cancer cell lines, we show that TGF-β elicits significant increases in cellular proliferation, migration, invasion, and motility, whereas these effects can be abrogated by a specific inhibitor against TGF-β receptor I and the anti-diabetic agent metformin, alone or in combination. Prior reports from our lab show that TNBC is exquisitely sensitive to metformin treatment. Mechanistically, metformin blocks endogenous activation of Smad2 and Smad3 and dampens TGF-β-mediated activation of Smad2, Smad3, and ID1 both at the transcriptional and translational level. We report the use of ID1 and ID3 as clinical surrogate markers, where high expression of these TGF-β target genes was correlated to poor prognosis in claudin-low patients. Given TGF-β's role in tumorigenesis and immunomodulation, blockade of this pathway using direct kinase inhibitors or more broadly acting inhibitors may dampen or abolish pro-carcinogenic and metastatic signaling in patients with MCL/CL TNBC. Metformin therapy (with or without other agents) may be a heretofore unrecognized approach to reduce the oncogenic activities associated with TGF-β mediated oncogenesis. PMID:26919310

  16. Curcumin reduces the expression of survivin, leading to enhancement of arsenic trioxide-induced apoptosis in myelodysplastic syndrome and leukemia stem-like cells

    PubMed Central

    Zeng, Yingjian; Weng, Guangyang; Fan, Jiaxin; Li, Zhangqiu; Wu, Jianwei; Li, Yuanming; Zheng, Rong; Xia, Pingfang; Guo, Kunyuan

    2016-01-01

    Low response, treatment-related complications and relapse due to the low sensitivity of myelodysplastic syndrome (MDS) and leukemia stem cells (LSCs) or pre-LSCs to arsenic trioxide (ATO), represent the main problems following treatment with ATO alone in patients with MDS. To solve these problems, a chemosensitization agent can be applied to increase the susceptibility of these cells to ATO. Curcumin (CUR), which possesses a wide range of anticancer activities, is a commonly used chemosensitization agent for various types of tumors, including hematopoietic malignancies. In the present study, we investigated the cytotoxic effects and potential mechanisms in MDS-SKM-1 and leukemia stem-like KG1a cells treated with CUR and ATO alone or in combination. CUR and ATO exhibited growth inhibition detected by MTT assays and apoptosis analyzed by Annexin V/PI analyses in both SKM-1 and KG1a cells. Apoptosis of SKM-1 and KG1a cells determined by Annexin V/PI was significantly enhanced in the combination groups compared with the groups treated with either agent alone. Further evaluation was performed by western blotting for two hallmark markers of apoptosis, caspase-3 and cleaved-PARP. Co-treatment of the cells with CUR and ATO resulted in significant synergistic effects. In SKM-1 and KG1a cells, 31 and 13 proteins analyzed by protein array assays were modulated, respectively. Notably, survivin protein expression levels were downregulated in both cell lines treated with CUR alone and in combination with ATO, particularly in the latter case. Susceptibility to apoptosis was significantly increased in SKM-1 and KG1a cells treated with siRNA-survivin and ATO. These results suggested that CUR increased the sensitivity of SKM-1 and KG1a cells to ATO by downregulating the expression of survivin. PMID:27430728

  17. Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like Cells

    PubMed Central

    Chen, Shu-Mei; Li, Ying-Ying; Tu, Chiao-Hui; Salazar, Nicole; Tseng, Yuan-Yun; Huang, Shiang-Fu

    2016-01-01

    Background Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity. Methods We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit. Results MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors. Conclusions These results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells. PMID:27537345

  18. Single cell dual adherent-suspension co-culture micro-environment for studying tumor-stromal interactions with functionally selected cancer stem-like cells.

    PubMed

    Chen, Yu-Chih; Zhang, Zhixiong; Fouladdel, Shamileh; Deol, Yadwinder; Ingram, Patrick N; McDermott, Sean P; Azizi, Ebrahim; Wicha, Max S; Yoon, Euisik

    2016-08-01

    Considerable evidence suggests that cancer stem-like cells (CSCs) are critical in tumor pathogenesis, but their rarity and transience has led to much controversy about their exact nature. Although CSCs can be functionally identified using dish-based tumorsphere assays, it is difficult to handle and monitor single cells in dish-based approaches; single cell-based microfluidic approaches offer better control and reliable single cell derived sphere formation. However, like normal stem cells, CSCs are heavily regulated by their microenvironment, requiring tumor-stromal interactions for tumorigenic and proliferative behaviors. To enable single cell derived tumorsphere formation within a stromal microenvironment, we present a dual adherent/suspension co-culture device, which combines a suspension environment for single-cell tumorsphere assays and an adherent environment for co-culturing stromal cells in close proximity by selectively patterning polyHEMA in indented microwells. By minimizing dead volume and improving cell capture efficiency, the presented platform allows for the use of small numbers of cells (<100 cells). As a proof of concept, we co-cultured single T47D (breast cancer) cells and primary cancer associated fibroblasts (CAF) on-chip for 14 days to monitor sphere formation and growth. Compared to mono-culture, co-cultured T47D have higher tumorigenic potential (sphere formation rate) and proliferation rates (larger sphere size). Furthermore, 96-multiplexed single-cell transcriptome analyses were performed to compare the gene expression of co-cultured and mono-cultured T47D cells. Phenotypic changes observed in co-culture correlated with expression changes in genes associated with proliferation, apoptotic suppression, tumorigenicity and even epithelial-to-mesechymal transition. Combining the presented platform with single cell transcriptome analysis, we successfully identified functional CSCs and investigated the phenotypic and transcriptome effects induced

  19. Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).

    PubMed

    Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2016-08-01

    Bedaquiline (a.k.a., Sirturo) is an anti-microbial agent, which is approved by the FDA for the treatment of multi-drug resistant pulmonary tuberculosis (TB). Bedaquiline is a first-in-class diaryl-quinoline compound, that mechanistically inhibits the bacterial ATP-synthase, and shows potent activity against both drug-sensitive and drug-resistant TB. Interestingly, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. Thus, we hypothesized that, in mammalian cells, bedaquiline might also target the mitochondrial ATP-synthase, leading to mitochondrial dysfunction and ATP depletion. Here, we show that bedaquiline has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that bedaquiline treatment of MCF7 breast cancer cells inhibits mitochondrial oxygen-consumption, as well as glycolysis, but induces oxidative stress. Importantly, bedaquiline significantly blocks the propagation and expansion of MCF7-derived CSCs, with an IC-50 of approx. 1-μM, as determined using the mammosphere assay. Similarly, bedaquiline also reduces both the CD44+/CD24low/- CSC and ALDH+ CSC populations, under anchorage-independent growth conditions. In striking contrast, bedaquiline significantly increases oxygen consumption in normal human fibroblasts, consistent with the fact that it is well-tolerated in patients treated for TB infections. As such, future pre-clinical studies and human clinical trials in cancer patients may be warranted. Interestingly, we also highlight that bedaquiline shares certain structural similarities with trans-piceatannol and trans-resveratrol, which are known natural flavonoid inhibitors of the mitochondrial ATP-synthase (complex V) and show anti-aging properties. PMID:27344270

  20. MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes.

    PubMed

    Yan, Li; Cao, Rui; Liu, YuanBo; Wang, LianZhao; Pan, Bo; Lv, XiaoYan; Jiao, Hu; Zhuang, Qiang; Sun, XueJian; Xiao, Ran

    2016-01-01

    Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids. PMID:27596120

  1. Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination.

    PubMed

    Fonseca, Nuno A; Rodrigues, Ana S; Rodrigues-Santos, Paulo; Alves, Vera; Gregório, Ana C; Valério-Fernandes, Ângela; Gomes-da-Silva, Lígia C; Rosa, Manuel Santos; Moura, Vera; Ramalho-Santos, João; Simões, Sérgio; Moreira, João Nuno

    2015-11-01

    Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes. Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC. Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care.

  2. Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer.

    PubMed

    Wahdan-Alaswad, Reema; Harrell, J Chuck; Fan, Zeying; Edgerton, Susan M; Liu, Bolin; Thor, Ann D

    2016-01-01

    Mesenchymal stem-like/claudin-low (MSL/CL) breast cancers are highly aggressive, express low cell-cell adhesion cluster containing claudins (CLDN3/CLDN4/CLDN7) with enrichment of epithelial-to-mesenchymal transition (EMT), immunomodulatory, and transforming growth factor-β (TGF-β) genes. We examined the biological, molecular and prognostic impact of TGF-β upregulation and/or inhibition using in vivo and in vitro methods. Using publically available breast cancer gene expression databases, we show that upregulation and enrichment of a TGF-β gene signature is most frequent in MSL/CL breast cancers and is associated with a worse outcome. Using several MSL/CL breast cancer cell lines, we show that TGF-β elicits significant increases in cellular proliferation, migration, invasion, and motility, whereas these effects can be abrogated by a specific inhibitor against TGF-β receptor I and the anti-diabetic agent metformin, alone or in combination. Prior reports from our lab show that TNBC is exquisitely sensitive to metformin treatment. Mechanistically, metformin blocks endogenous activation of Smad2 and Smad3 and dampens TGF-β-mediated activation of Smad2, Smad3, and ID1 both at the transcriptional and translational level. We report the use of ID1 and ID3 as clinical surrogate markers, where high expression of these TGF-β target genes was correlated to poor prognosis in claudin-low patients. Given TGF-β's role in tumorigenesis and immunomodulation, blockade of this pathway using direct kinase inhibitors or more broadly acting inhibitors may dampen or abolish pro-carcinogenic and metastatic signaling in patients with MCL/CL TNBC. Metformin therapy (with or without other agents) may be a heretofore unrecognized approach to reduce the oncogenic activities associated with TGF-β mediated oncogenesis.

  3. MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

    NASA Astrophysics Data System (ADS)

    Yan, Li; Cao, Rui; Liu, Yuanbo; Wang, Lianzhao; Pan, Bo; Lv, Xiaoyan; Jiao, Hu; Zhuang, Qiang; Sun, Xuejian; Xiao, Ran

    2016-09-01

    Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids.

  4. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment.

    PubMed

    Würth, Roberto; Bajetto, Adriana; Harrison, Jeffrey K; Barbieri, Federica; Florio, Tullio

    2014-01-01

    Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem-like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine

  5. Compound Kushen Injection suppresses human breast cancer stem-like cells by down-regulating the canonical Wnt/β-catenin pathway

    PubMed Central

    2011-01-01

    Background Cancer stem cells (CSCs) play an important role in cancer initiation, relapse and metastasis. To date, no specific medicine has been found to target CSCs as they are resistant to most conventional therapies and proliferate indefinitely. Compound Kushen Injection (CKI) has been widely used for cancer patients with remarkable therapeutic effects in Chinese clinical settings for many years. This study focused on whether CKI could inhibit MCF-7 SP cells in vitro and in vivo. Methods The analysis of CKI on SP population and the main genes of Wnt signaling pathway were studied first. Then we studied the tumorigenicity of SP cells and the effects of CKI on SP cells in vivo. The mice inoculated with 10,000 SP cells were randomly divided into three groups (6 in each group) and treated with CKI, cisplatin and saline (as a control) respectively for 7 weeks. The tumor formation rates of each group were compared. The main genes and proteins of the Wnt signaling pathway were analyzed by RT-PCR and western blot. Results CKI suppressed the size of SP population (approximately 90%), and down-regulated the main genes of Wnt signaling pathway. We also determined that MCF-7 SP cells were more tumorigenic than non-SP and unsorted cells. The Wnt signaling pathway was up-regulated in tumors derived from SP cells compared with that in tumors from non-SP cells. The tumor formation rate of the CKI Group was 33% (2/6, P < 0.05), and that of Cisplatin Group was 50%(3/6, P < 0.05), whereas that of the Control Group was 100% (6/6).The RT-PCR and western blot results indicated that CKI suppressed tumor growth by down-regulating the Wnt/β-catenin pathway, while cisplatin activated the Wnt/β-catenin pathway and might spare SP cells. Conclusions It suggested that CKI may serve as a novel drug targeting cancer stem-like cells, though further studies are recommended. PMID:22032476

  6. The novel inhibitor BRM270 downregulates tumorigenesis by suppression of NF-κB signaling cascade in MDR-induced stem like cancer-initiating cells.

    PubMed

    Mongre, Raj Kumar; Sodhi, Simrinder Singh; Ghosh, Mrinmoy; Kim, Jeong Hyun; Kim, Nameun; Park, Yang Ho; Kim, Sung Jin; Heo, Yoo Jeong; Sharma, Neelesh; Jeong, Dong Kee

    2015-01-01

    The nuclear factor κB (NF-κB) and interleukin-6 (IL-6) contribute to multidrug resistance (MDR) in tumor chemotherapy. The essential phenomenon of oncogenic activation of NF-κB in cancer-initiating cells showing MDR resulting from increased IL-6 expression is still unclear. Cancer stem cells (CSCs) have been the objective of intensive study. The aim of this study was to investigate the selective and potential efficacy of BRM270 against stem-like cancer-initiating cells (SLCICs) via the molecular mechanisms of its anticancer effects. Co-regulation of NF-κB and Cdk6 might be new arena to mitigate tumorigenesis. In the present study phyto-drug based approach provides a new avenue in understanding the amelioration and regulatory mechanisms in CSCs. In the present study, an in vivo tumor metastasis model of osteosarcoma was established by injecting Cal72 and SaOS-2 SLCICs into the right lower flank of nude mice. Later the development of tumor was analyzed by LICOR Biosciences (Pearl image analyzer). Significant suppression of activation of NF-κB and LPS-induced gene expression and apoptosis by BRM270 was confirmed by FACS, western blotting and qPCR. Further, both p65 and Cdk6 were significantly (P<0.05) overexpressed in BRM270 non-treated Cal72 SLCICs compared to treated group. BRM270 directly dephosphorylated RelA and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of interleukin-6, a cytokine implicated in cancer metastasis. BRM270-mediated cell shrinkage, pyknosis, karyorrhexis and programmed cell death (PCD) were observed by Hoechst 33342 staining while flow cytometry analysis showed significant (P<0.05) decrease in cell population from G0-G1 phases. These findings suggest that activation of the oncogenic Cdk6-NF-κB pathway, resulting from increased IL-6 expression, plays a central role in CD133 expressing SLCICs augmented MDR and neoplasia. This study proposes targeting of NF-κB, and Cdk6 with IL-6 as potential

  7. The novel myxofibrosarcoma cell line MUG-Myx1 expresses a tumourigenic stem-like cell population with high aldehyde dehydrogenase 1 activity

    PubMed Central

    2013-01-01

    Background Myxofibrosarcoma comprises a spectrum of malignant neoplasms withprominent myxoid stromata, cellular pleomorphism, and distinct curvilinear vascular patterns. These neoplasms mainly affect patients in the sixth to eighth decades of life and the overall 5-year survival rate is 60–70%. Methods After the establishment of the novel myxofibrosarcoma cell lines MUG-Myx1, cells were characterized using short tandem repeat (STR), copy number variation (CNV), and genotype/loss-of-heterozygosity (LOH) analyses. The growth behaviour of the cells was analyzed with the xCELLigence system and an MTS assay. The tumourigenicity of MUG-Myx1 was proved in NOD/SCID mice. Additionally, a stem-like cell population with high enzymatic activity of aldehyde dehydrogenase 1 (ALDH1high) was isolated for the first time from myxofibrosarcoma cells using the Aldefluor® assay followed by FACS analysis. Results The frozen primary parental tumour tissue and the MUG-Myx1 cell line showed the same STR profile at the markers D3S1358, TH01, D21S11, D18S51, Penta E, D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta D, Amelogenin, D8S1179, TPOX, and FGY. Typically, myxofibrosarcoma gain and/or amplification was mapped to 7p21.3-q31.1, q31.1-q31.33, q33-q36.2, p21.3, p21.2, p14.1-q11.23, q31.33-q33, p21.2-p14.1, q11.23-q21.3, q36.2-q36.3, which, respectively are known to harbour tumour-associated genes, including TIF, BRAF, MLL3, SMO, and MET. Typically an LOH for myxofibrosarcoma on chr5 q21 was found. In addition, MUG-Myx1 ALDH1high cells showed an upregulation of the ABC transporter ABCB1 and ABCG2; higher c-Myc, E-cadherin and SOX-2 expression; and a higher potential for tumourigenicity and proliferation levels. Conclusion The new myxofibrosarcoma cell line MUG-Myx1 was established to enrich the bank of publicly available cell lines, with respect to providing comprehensive genetic and epigenetic characterization. Furthermore, because of their tumourigenicity, the cell line is also

  8. Adrenocortical carcinoma

    MedlinePlus

    ... this tumor. Adrenocortical carcinoma can produce the hormones cortisol, aldosterone, estrogen, or testosterone, as well as other ... Symptoms of increased cortisol or other adrenal gland hormones: ... high on the back just below the neck ( buffalo hump ) Flushed, ...

  9. p53 Expression Helps Identify High Risk Oral Tongue Pre- malignant Lesions and Correlates with Patterns of Invasive Tumour Front and Tumour Depth in Oral Tongue Squamous Cell Carcinoma Cases.

    PubMed

    Viveka, Thangaraj Soundara; Shyamsundar, Vidyarani; Krishnamurthy, Arvind; Ramani, Pratibha; Ramshankar, Vijayalakshmi

    2016-01-01

    Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cancer subtype with a maximum propensity for regional spread. Our objective was to study if p53 expression might have any correlation with aggressive patterns of invasion within oral tongue cancers as well as with the histologically identified degree of oral tongue dysplasia. p53 immunoexpression was studied using immunohistochemistry in early staged OTSCCs (n=155), oral tongue dysplasias, (n=29) and oral tongue normal specimens (n=10) and evaluated for correlations with histological and clinicopathological parameters. Our study (n=194) showed a pattern of p53 expression increasing with different grades of tongue dysplasia to different grades of invasive OTSCC (p=0.000). Among the OTSCC tumours, positive p53 expression was seen in 43.2% (67/155) and a higher p53 labelling index was significantly associated with increased Bryne's grade of the tumour invasive front (p=0.039) and increased tumour depth (p=0.018). Among the OTSCC patients with tobacco habits, (n=91), a higher p53 labelling index was significantly associated with increased risk of local recurrence (p=0.025) and with lymphovascular space involvement (p=0.014). Evaluation of p53 through varying degrees of dysplasia to oral tongue cancer indicates that p53 expression is linked to aggressive features of oral tongue cancers and tongue precancers entailing a closer monitoring in positive cases. Among the OTSCCs, p53 expression is associated with tumour aggressiveness correlating with increased grading of invasive tumour front and tumour depth.

  10. Parent Tookit: Homework Help. Helpful Tips.

    ERIC Educational Resources Information Center

    All Kinds of Minds, 2006

    2006-01-01

    This check list contains tips for parents to help students reinforce and build upon what children learn at school: (1) Set a consistent time each day for doing homework; (2) Encourage children to make a homework checklist; (3) Provide assistance to help get started on a task; (4) Help children make a list of all needed materials before starting…

  11. Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

    PubMed Central

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cuyàs, Elisabet; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Fernández-Arroyo, Salvador; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

    2014-01-01

    Therapeutic interventions based on metabolic inhibitor-based therapies are expected to be less prone to acquired resistance. However, there has not been any study assessing the possibility that the targeting of the tumor cell metabolism may result in unforeseeable resistance. We recently established a pre-clinical model of estrogen-dependent MCF-7 breast cancer cells that were chronically adapted to grow (> 10 months) in the presence of graded, millimolar concentrations of the anti-diabetic biguanide metformin, an AMPK agonist/mTOR inhibitor that has been evaluated in multiple in vitro and in vivo cancer studies and is now being tested in clinical trials. To assess what impact the phenomenon of resistance might have on the metformin-like “dirty” drugs that are able to simultaneously hit several metabolic pathways, we employed the ingenuity pathway analysis (IPA) software to functionally interpret the data from Agilent whole-human genome arrays in the context of biological processes, networks, and pathways. Our findings establish, for the first time, that a “global” targeting of metabolic reprogramming using metformin certainly imposes a great selective pressure for the emergence of new breast cancer cellular states. Intriguingly, acquired resistance to metformin appears to trigger a transcriptome reprogramming toward a metastatic stem-like profile, as many genes encoding the components of the degradome (KLK11, CTSF, FREM1, BACE-2, CASP, TMPRSS4, MMP16, HTRA1), cancer cell migration and invasion factors (TP63, WISP2, GAS3, DKK1, BCAR3, PABPC1, MUC1, SPARCL1, SEMA3B, SEMA6A), stem cell markers (DCLK1, FAK), and key pro-metastatic lipases (MAGL and Cpla2) were included in the signature. Because this convergent activation of pathways underlying tumor microenvironment interactions occurred in low-proliferative cancer cells exhibiting a notable downregulation of the G2/M DNA damage checkpoint regulators that maintain genome stability (CCNB1, CCNB2, CDC20, CDC25C

  12. Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile.

    PubMed

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cuyàs, Elisabet; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Fernández-Arroyo, Salvador; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

    2014-01-01

    Therapeutic interventions based on metabolic inhibitor-based therapies are expected to be less prone to acquired resistance. However, there has not been any study assessing the possibility that the targeting of the tumor cell metabolism may result in unforeseeable resistance. We recently established a pre-clinical model of estrogen-dependent MCF-7 breast cancer cells that were chronically adapted to grow (> 10 months) in the presence of graded, millimolar concentrations of the anti-diabetic biguanide metformin, an AMPK agonist/mTOR inhibitor that has been evaluated in multiple in vitro and in vivo cancer studies and is now being tested in clinical trials. To assess what impact the phenomenon of resistance might have on the metformin-like "dirty" drugs that are able to simultaneously hit several metabolic pathways, we employed the ingenuity pathway analysis (IPA) software to functionally interpret the data from Agilent whole-human genome arrays in the context of biological processes, networks, and pathways. Our findings establish, for the first time, that a "global" targeting of metabolic reprogramming using metformin certainly imposes a great selective pressure for the emergence of new breast cancer cellular states. Intriguingly, acquired resistance to metformin appears to trigger a transcriptome reprogramming toward a metastatic stem-like profile, as many genes encoding the components of the degradome (KLK11, CTSF, FREM1, BACE-2, CASP, TMPRSS4, MMP16, HTRA1), cancer cell migration and invasion factors (TP63, WISP2, GAS3, DKK1, BCAR3, PABPC1, MUC1, SPARCL1, SEMA3B, SEMA6A), stem cell markers (DCLK1, FAK), and key pro-metastatic lipases (MAGL and Cpla2) were included in the signature. Because this convergent activation of pathways underlying tumor microenvironment interactions occurred in low-proliferative cancer cells exhibiting a notable downregulation of the G 2/M DNA damage checkpoint regulators that maintain genome stability (CCNB1, CCNB2, CDC20, CDC25C, AURKA

  13. The Progress and Prospects of Putative Biomarkers for Liver Cancer Stem Cells in Hepatocellular Carcinoma.

    PubMed

    Xiang, Yan; Yang, Ting; Pang, Bing-Yao; Zhu, Ying; Liu, Yong-Ning

    2016-01-01

    Accumulating evidence suggests that hepatocellular carcinoma (HCC) is organized by liver cancer stem cells (LCSCs), which are a subset of cells with "stem-like" characteristics. Identification of the LCSCs is a fundamental and important problem in HCC research. LCSCs have been investigated by various stem cell biomarkers. There is still lack of consensus regarding the existence of a "global" marker for LCSCs in HCC. In this review article, we summarize the progress and prospects of putative biomarkers for LCSCs in the past decades, which is essential to develop future therapies targeting CSCs and to predict prognosis and curative effect of these therapies. PMID:27610139

  14. [Thymic carcinomas].

    PubMed

    Ströbel, P; Weis, C-A; Marx, A

    2016-09-01

    Thymic carcinomas (TC) are approximately 10 times less prevalent than thymomas but of high clinical relevance because they are more aggressive, less frequently resectable than thymomas and usually refractory to classical and targeted long-term treatment approaches. Furthermore, in children and adolescents TC are more frequent than thymomas and particularly in this age group, germ cell tumors need to be a differential diagnostic consideration. In diagnostic terms pathologists face two challenges: a), the distinction between thymic carcinomas and thymomas with a similar appearance and b), the distinction between TC and histologically similar metastases and tumor extensions from other primary tumors. Overcoming these diagnostic challenges is the focus of the new WHO classification of thymic epithelial tumors. The objectives of this review are to highlight novel aspects of the WHO classification of thymic carcinomas and to address therapeutically relevant diagnostic pitfalls. PMID:27538748

  15. Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer.

    PubMed

    Bora-Singhal, Namrata; Perumal, Deepak; Nguyen, Jonathan; Chellappan, Srikumar

    2015-07-01

    Non-small cell lung cancer (NSCLC) patients have very low survival rates because the current therapeutic strategies are not fully effective. Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents. Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors. Sonic Hedgehog and associated Gli transcription factors play a major role in embryonic development and have recently been found to be reactivated in NSCLC, and elevated Gli1 levels correlate with poor prognosis. The Hedgehog pathway has been implicated in the functions of cancer stem cells, although the underlying molecular mechanisms are not clear. In this context, we demonstrate that Gli1 is a strong regulator of embryonic stem cell transcription factor Sox2. Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells. Gli1 was found to transcriptionally regulate Sox2 through its promoter region, and Gli1 could be detected on the Sox2 promoter. Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells. Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations.

  16. Conversion of Prostate Adenocarcinoma to Small Cell Carcinoma-Like by Reprogramming.

    PubMed

    Borges, Gisely T; Vêncio, Eneida F; Quek, Sue-Ing; Chen, Adeline; Salvanha, Diego M; Vêncio, Ricardo Z N; Nguyen, Holly M; Vessella, Robert L; Cavanaugh, Christopher; Ware, Carol B; Troisch, Pamela; Liu, Alvin Y

    2016-09-01

    The lineage relationship between prostate adenocarcinoma and small cell carcinoma was studied by using the LuCaP family of xenografts established from primary neoplasm to metastasis. Expression of four stem cell transcription factor (TF) genes, LIN28A, NANOG, POU5F1, SOX2, were analyzed in the LuCaP lines. These genes, when force expressed in differentiated cells, can reprogram the recipients into stem-like induced pluripotent stem (iPS) cells. Most LuCaP lines expressed POU5F1, while LuCaP 145.1, representative of small cell carcinoma, expressed all four. Through transcriptome database query, many small cell carcinoma genes were also found in stem cells. To test the hypothesis that prostate cancer progression from "differentiated" adenocarcinoma to "undifferentiated" small cell carcinoma could involve re-expression of stem cell genes, the four TF genes were transduced via lentiviral vectors into five adenocarcinoma LuCaP lines-70CR, 73CR, 86.2, 92, 105CR-as done in iPS cell reprogramming. The resultant cells from these five transductions displayed a morphology of small size and dark appearing unlike the parentals. Transcriptome analysis of LuCaP 70CR* ("*" to denote transfected progeny) revealed a unique gene expression close to that of LuCaP 145.1. In a prostate principal components analysis space based on cell-type transcriptomes, the different LuCaP transcriptome datapoints were aligned to suggest a possible ordered sequence of expression changes from the differentiated luminal-like adenocarcinoma cell types to the less differentiated, more stem-like small cell carcinoma types, and LuCaP 70CR*. Prostate cancer progression can thus be molecularly characterized by loss of differentiation with re-expression of stem cell genes. J. Cell. Physiol. 231: 2040-2047, 2016. © 2016 Wiley Periodicals, Inc.

  17. Basal Cell Carcinoma (BCC)

    MedlinePlus

    ... carcinomas: Infiltrating basal cell carcinomas can be more aggressive and locally destructive than other types of basal ... to treat them early and with slightly more aggressive techniques. Excision – The basal cell carcinoma is cut ...

  18. Thyroid cancer - medullary carcinoma

    MedlinePlus

    Thyroid - medullary carcinoma; Cancer - thyroid (medullary carcinoma); MTC; Thyroid nodule - medullary ... The cause of medullary carcinoma of the thyroid (MTC) is unknown. MTC is very rare. It can occur in children and adults. Unlike other types ...

  19. Characterization of cancer stem-like cells derived from mouse induced pluripotent stem cells transformed by tumor-derived extracellular vesicles.

    PubMed

    Yan, Ting; Mizutani, Akifumi; Chen, Ling; Takaki, Mai; Hiramoto, Yuki; Matsuda, Shuichi; Shigehiro, Tsukasa; Kasai, Tomonari; Kudoh, Takayuki; Murakami, Hiroshi; Masuda, Junko; Hendrix, Mary J C; Strizzi, Luigi; Salomon, David S; Fu, Li; Seno, Masaharu

    2014-01-01

    Several studies have shown that cancer niche can perform an active role in the regulation of tumor cell maintenance and progression through extracellular vesicles-based intercellular communication. However, it has not been reported whether this vesicle-mediated communication affects the malignant transformation of normal stem cells/progenitors. We have previously reported that the conditioned medium derived from the mouse Lewis Lung Carcinoma (LLC) cell line can convert mouse induced pluripotent stem cells (miPSCs) into cancer stem cells (CSCs), indicating that normal stem cells when placed in an aberrant microenvironment can give rise to functionally active CSCs. Here, we focused on the contribution of tumor-derived extracellular vesicles (tEVs) that are secreted from LLC cells to induce the transformation of miPSCs into CSCs. We isolated tEVs from the conditioned medium of LLC cells, and then the differentiating miPSCs were exposed to tEVs for 4 weeks. The resultant tEV treated cells (miPS-LLCev) expressed Nanog and Oct3/4 proteins comparable to miPSCs. The frequency of sphere formation of the miPS-LLCev cells in suspension culture indicated that the self-renewal capacity of the miPS-LLCev cells was significant. When the miPS-LLCev cells were subcutaneously transplanted into Balb/c nude mice, malignant liposarcomas with extensive angiogenesis developed. miPS-LLCevPT and miPS-LLCevDT, the cells established from primary site and disseminated liposarcomas, respectively, showed their capacities to self-renew and differentiate into adipocytes and endothelial cells. Moreover, we confirmed the secondary liposarcoma development when these cells were transplanted. Taken together, these results indicate that miPS-LLCev cells possess CSC properties. Thus, our current study provides the first evidence that tEVs have the potential to induce CSC properties in normal tissue stem cells/progenitors. PMID:25057308

  20. Characterization of Cancer Stem-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Transformed by Tumor-Derived Extracellular Vesicles

    PubMed Central

    Yan, Ting; Mizutani, Akifumi; Chen, Ling; Takaki, Mai; Hiramoto, Yuki; Matsuda, Shuichi; Shigehiro, Tsukasa; Kasai, Tomonari; Kudoh, Takayuki; Murakami, Hiroshi; Masuda, Junko; Hendrix, Mary J. C.; Strizzi, Luigi; Salomon, David S.; Fu, Li; Seno, Masaharu

    2014-01-01

    Several studies have shown that cancer niche can perform an active role in the regulation of tumor cell maintenance and progression through extracellular vesicles-based intercellular communication. However, it has not been reported whether this vesicle-mediated communication affects the malignant transformation of normal stem cells/progenitors. We have previously reported that the conditioned medium derived from the mouse Lewis Lung Carcinoma (LLC) cell line can convert mouse induced pluripotent stem cells (miPSCs) into cancer stem cells (CSCs), indicating that normal stem cells when placed in an aberrant microenvironment can give rise to functionally active CSCs. Here, we focused on the contribution of tumor-derived extracellular vesicles (tEVs) that are secreted from LLC cells to induce the transformation of miPSCs into CSCs. We isolated tEVs from the conditioned medium of LLC cells, and then the differentiating miPSCs were exposed to tEVs for 4 weeks. The resultant tEV treated cells (miPS-LLCev) expressed Nanog and Oct3/4 proteins comparable to miPSCs. The frequency of sphere formation of the miPS-LLCev cells in suspension culture indicated that the self-renewal capacity of the miPS-LLCev cells was significant. When the miPS-LLCev cells were subcutaneously transplanted into Balb/c nude mice, malignant liposarcomas with extensive angiogenesis developed. miPS-LLCevPT and miPS-LLCevDT, the cells established from primary site and disseminated liposarcomas, respectively, showed their capacities to self-renew and differentiate into adipocytes and endothelial cells. Moreover, we confirmed the secondary liposarcoma development when these cells were transplanted. Taken together, these results indicate that miPS-LLCev cells possess CSC properties. Thus, our current study provides the first evidence that tEVs have the potential to induce CSC properties in normal tissue stem cells/progenitors. PMID:25057308

  1. Diagnosis of hepatocellular carcinoma

    PubMed Central

    Di Bisceglie, Adrian M.

    2005-01-01

    Hepatocellular carcinoma (HCC) is responsible for a large proportion of cancer deaths worldwide. HCC is frequently diagnosed after the development of clinical deterioration at which time survival is measured in months. Long-term survival requires detection of small tumors, often present in asymptomatic individuals, which may be more amenable to invasive therapeutic options. Surveillance of high-risk individuals for HCC is commonly performed using the serum marker alfa-fetoprotein (AFP) often in combination with ultrasonography. Various other serologic markers are currently being tested to help improve surveillance accuracy. Diagnosis of HCC often requires more sophisticated imaging modalities such as CT scan and MRI, which have multiphasic contrast enhancement capabilities. Serum AFP used alone can be helpful if levels are markedly elevated, which occurs in fewer than half of cases at time of diagnosis. Confirmation by liver biopsy can be performed under circumstances when the diagnosis of HCC remains unclear. PMID:18333158

  2. Hepatic cancer stem cell marker granulin-epithelin precursor and β-catenin expression associate with recurrence in hepatocellular carcinoma

    PubMed Central

    Cheung, Phyllis F.Y.; Cheung, Tan To; Yip, Chi Wai; Ng, Linda W.C.; Fung, Sze Wai; Lo, Chung Mau; Fan, Sheung Tat; Cheung, Siu Tim

    2016-01-01

    Granulin-epithelin precursor (GEP) has been demonstrated to confer enhanced cancer stem-like cell properties in hepatocellular carcinoma (HCC) cell line models in our previous studies. Here, we aimed to examine the GEP-expressing cells in relation to the stem cell related molecules and stem-like cell properties in the prospective HCC clinical cohort. GEP protein levels were significantly higher in HCCs than the paralleled non-tumor liver tissues, and associated with venous infiltration. GEPhigh cells isolated from clinical HCC samples exhibited higher levels of stem cell marker CD133, pluripotency-associated signaling molecules β-catenin, Oct4, SOX2, Nanog, and chemodrug transporter ABCB5. In addition, GEPhigh cells possessed preferential ability to form colonies and spheroids, and enhanced in vivo tumor-initiating ability while their xenografts were able to be serially subpassaged into secondary mouse recipients. Expression levels of GEP and pluripotency-associated genes were further examined in the retrospective HCC cohort and demonstrated significant correlation of GEP with β-catenin. Notably, HCC patients with high GEP and β-catenin levels demonstrated poor recurrence-free survival. In summary, GEP-positive HCC cells directly isolated from clinical specimens showed β-catenin elevation and cancer stem-like cell properties. PMID:26942873

  3. Adrenocortical Carcinoma

    PubMed Central

    Kim, Alex C.; Sabolch, Aaron; Raymond, Victoria M.; Kandathil, Asha; Caoili, Elaine M.; Jolly, Shruti; Miller, Barbra S.; Giordano, Thomas J.

    2014-01-01

    Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC. PMID:24423978

  4. Help! It's Hair Loss!

    MedlinePlus

    ... Homework? Here's Help White House Lunch Recipes Help! It's Hair Loss! KidsHealth > For Kids > Help! It's Hair Loss! Print A A A Text Size ... part above the skin, is dead. (That's why it doesn't hurt to get a haircut!) This ...

  5. Oral Rigosertib for Squamous Cell Carcinoma

    ClinicalTrials.gov

    2016-05-18

    Head and Neck Squamous Cell Carcinoma; Anal Squamous Cell Carcinoma; Lung Squamous Cell Carcinoma; Cervical Squamous Cell Carcinoma; Esophageal Squamous Cell Carcinoma; Skin Squamous Cell Carcinoma; Penile Squamous Cell Carcinoma

  6. Adrenocortical carcinoma.

    PubMed

    Baudin, Eric

    2015-06-01

    Recent developments in the treatment of adrenocortical carcinoma (ACC) include diagnostic and prognostic risk stratification algorithms, increasing evidence of the impact of historical therapies on overall survival, and emerging targets from integrated epigenomic and genomic analyses. Advances include proper clinical and molecular characterization of all patients with ACC, standardization of proliferative index analyses, referral of these patients to large cancer referral centers at the time of first surgery, and development of new trials in patients with well-characterized ACC. Networking and progress in the molecular characterization of ACC constitute the basis for significant future therapeutic breakthroughs. PMID:26038209

  7. Thyroid carcinoma

    SciTech Connect

    Friedman, M.; Skolnik, E.M.; Baim, H.M.; Becker, S.P.; Katz, A.H.; Mantravadi, R.V.

    1980-12-01

    Differentiated thyroid carcinoma was studied with regard to mode of presentation, initial findings, treatment and survival. The classic signs, symptoms, physical and scan findings were found to be present in approximately 70% of the patients. Prognosis was found to be dependent on age of presentation more than any other factor. Patients with prior exposure to radiation were found to have more extensive disease and require more extensive surgery but ultimately had the same prognosis for 15-year cure. Treatment for distant metastatic disease by surgery, radioactive iodine and external radiation all resulted in long-term survival in certain cases.

  8. [New developments in molecular diagnostics of carcinomas of the salivary glands: "translocation carcinomas"].

    PubMed

    Skálová, Alena; Šteiner, Petr; Vaneček, Tomáš

    2016-01-01

    In recent years the discovery of translocations and the fusion oncogenes that they result in has changed the way diagnoses are made in salivary gland pathology. These genetic aberrations are recurrent; and at the very least serve as powerful diagnostic tools in salivary gland tumors diagnosis and classification. They also show promise as prognostic markers and hopefully as targets of therapy. In this review the 4 carcinomas currently known to harbor translocations will be discussed, namely mucoepidermoid carcinoma, adenoid cystic carcinoma, mammary analogue secretory carcinoma, and hyalinizing clear cell carcinoma. The discovery and implications of each fusion will be highlighted and how they have helped to reshape the current classification of salivary gland tumors. PMID:27526014

  9. The diagnostic utility of the triple markers Napsin A, TTF-1, and PAX8 in differentiating between primary and metastatic lung carcinomas.

    PubMed

    El-Maqsoud, Nehad M R Abd; Tawfiek, Ehab Rifat; Abdelmeged, Ayman; Rahman, Mohamed Fathy Abdel; Moustafa, Alaa A E

    2016-03-01

    Napsin A and thyroid transcription factor-1 (TTF-1) are useful biomarkers for differentiating lung adenocarcinoma from squamous cell carcinoma and also for differentiating primary lung adenocarcinoma from metastatic lung carcinoma. Pair-boxed 8 (PAX8) can help in distinguishing primary lung carcinoma from metastatic carcinomas and help to determine the primary sites of metastatic carcinomas. Immunohistochemistry for Napsin A, TTF-1, and PAX8 were performed on 193 cases of carcinoma: 50 primary lung carcinoma and 143 carcinomas from other sites. Napsin A and TTF-1 were positive in 54, 52 % of lung carcinomas cases, respectively. While in adenocarcinoma cases, their expressions were 86.7 and 83.3 %, respectively. PAX8 was negative in all lung carcinomas. TTF-1 and PAX8 were positive in 93.3 and 96.7 % of thyroid carcinoma cases and in 87.5 and 93.8 % of papillary carcinoma respectively, and both were positive in 100 % of follicular carcinoma. Napsin A was negative in all thyroid carcinomas. Napsin A and PAX8 were positive in 50 and 93.3 % of renal carcinoma cases and in 81.8 and 100 % of papillary carcinoma, 38.5 and 92.3 % of clear cell carcinoma, and 16.7 and 83.3 % of chromophobe carcinoma respectively. TTF-1 was negative in all renal carcinomas. PAX8 was positive in 80 % of ovarian carcinoma cases; 100 and 60 % of serous mucinous carcinomas, respectively. It was also positive in 100 % of endometrial carcinoma. Napsin A and TTF-1 were negative in both ovarian and endometrial carcinomas. Our data demonstrated that combined use of Napsin A, TTF-1, and PAX8 may help in differentiating between primary lung adenocarcinoma and metastatic lung carcinomas.

  10. Handi Helps, 1984.

    ERIC Educational Resources Information Center

    Handi Helps, 1984

    1984-01-01

    The eight issues of Handi Helps presented in this document focus on specific issues of concern to the disabled, parents, and those working with the disabled. The two-page handi help fact sheets focus on the following topics: child abuse, leukemia, arthritis, Tourette Syndrome, hemophilia, the puppet program "Meet the New Kids on the Block" and dog…

  11. The Help Desk.

    ERIC Educational Resources Information Center

    Klein, Regina; And Others

    1988-01-01

    The first of three articles describes the results of a survey that examined characteristics and responsibilities of help-desk personnel at major database and online services. The second provides guidelines to using such customer services, and the third lists help-desk numbers for online databases and systems. (CLB)

  12. Handi Helps, 1985

    ERIC Educational Resources Information Center

    Handi Helps, 1985

    1985-01-01

    The six issues of Handi Helps presented here focus on specific issues of concern to the disabled, parents, and those working with the disabled. The two-page handi help fact sheets focus on the following topics: child sexual abuse prevention, asthma, scoliosis, the role of the occupational therapist, kidnapping, and muscular dystrophy. Each handi…

  13. Helping Children Understand Divorce.

    ERIC Educational Resources Information Center

    Allers, Robert D.

    1980-01-01

    Children of divorced parents may bring many problems along when they come to school. Teachers can recognize these troubles and help children learn to handle them. They may be able to help children better understand their feelings about their parents' divorce. (CJ)

  14. Hepatocellular carcinoma.

    PubMed

    Buendia, Marie-Annick; Neuveut, Christine

    2015-02-01

    The hepatitis B virus (HBV) is a widespread human pathogen that causes liver inflammation, cirrhosis, and hepatocellular carcinoma (HCC). Recent sequencing technologies have refined our knowledge of the genomic landscape and pathogenesis of HCC, but the mechanisms by which HBV exerts its oncogenic role remain controversial. In a prevailing view, inflammation, liver damage, and regeneration may foster the accumulation of genetic and epigenetic defects leading to cancer onset. However, a more direct and specific contribution of the virus is supported by clinical and biological observations. Among genetically heterogeneous HCCs, HBV-related tumors display high genomic instability, which may be attributed to the ability of HBV to integrate its DNA into the host cell genome, provoking chromosomal alterations and insertional mutagenesis of cancer genes. The viral transactivator HBx may also participate in transformation by deregulating diverse cellular machineries. A better understanding of the complex mechanisms linking HBV to HCC will improve prevention and treatment strategies. PMID:25646384

  15. GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas.

    PubMed

    Cimino-Mathews, Ashley; Subhawong, Andrea P; Illei, Peter B; Sharma, Rajni; Halushka, Marc K; Vang, Russell; Fetting, John H; Park, Ben Ho; Argani, Pedram

    2013-07-01

    GATA3 plays an integral role in breast luminal cell differentiation and is implicated in breast cancer progression. GATA3 immunohistochemistry is a useful marker of breast cancer; however, its use in specific subtypes is unclear. Here, we evaluate GATA3 expression in 86 invasive ductal carcinomas including triple-negative, Her-2, and luminal subtypes, in addition to 13 metaplastic carcinomas and in 34 fibroepithelial neoplasms. In addition, we report GATA3 expression in matched primary and metastatic breast carcinomas in 30 patients with known estrogen receptor (ER), progesterone receptor (PR), and Her-2 status, including 5 with ER and/or PR loss from primary to metastasis. Tissue microarrays containing 5 to 10 cores per tumor were stained for GATA3, scored as follows: 0 (0-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). GATA3 labeling was seen in 67% (66/99) of primary ductal carcinomas including 43% of triple-negative and 54% of metaplastic carcinomas. In contrast, stromal GATA3 labeling was seen in only 1 fibroepithelial neoplasm. GATA3 labeling was seen in 90% (27/30) of primary breast carcinomas in the paired cohort, including 67% of triple-negative carcinomas. GATA3 labeling was overwhelmingly maintained in paired metastases. Notably, GATA3 was maintained in all "luminal loss" metastases, which showed ER and/or PR loss. In conclusion, GATA3 expression is maintained between matched primary and metastatic carcinomas including ER-negative cases. GATA3 can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack specific markers of mammary origin. Finally, GATA3 labeling may help distinguish metaplastic carcinoma from malignant phyllodes tumors.

  16. Metaplastic breast carcinomas display genomic and transcriptomic heterogeneity [corrected]. .

    PubMed

    Weigelt, Britta; Ng, Charlotte K Y; Shen, Ronglai; Popova, Tatiana; Schizas, Michail; Natrajan, Rachael; Mariani, Odette; Stern, Marc-Henri; Norton, Larry; Vincent-Salomon, Anne; Reis-Filho, Jorge S

    2015-03-01

    Metaplastic breast carcinoma is a rare and aggressive histologic type of breast cancer, preferentially displaying a triple-negative phenotype. We sought to define the transcriptomic heterogeneity of metaplastic breast cancers on the basis of current gene expression microarray-based classifiers, and to determine whether these tumors display gene copy number profiles consistent with those of BRCA1-associated breast cancers. Twenty-eight consecutive triple-negative metaplastic breast carcinomas were reviewed, and the metaplastic component present in each frozen specimen was defined (ie, spindle cell, squamous, chondroid metaplasia). RNA and DNA extracted from frozen sections with tumor cell content >60% were subjected to gene expression (Illumina HumanHT-12 v4) and copy number profiling (Affymetrix SNP 6.0), respectively. Using the best practice PAM50/claudin-low microarray-based classifier, all metaplastic breast carcinomas with spindle cell metaplasia were of claudin-low subtype, whereas those with squamous or chondroid metaplasia were preferentially of basal-like subtype. Triple-negative breast cancer subtyping using a dedicated website (http://cbc.mc.vanderbilt.edu/tnbc/) revealed that all metaplastic breast carcinomas with chondroid metaplasia were of mesenchymal-like subtype, spindle cell carcinomas preferentially of unstable or mesenchymal stem-like subtype, and those with squamous metaplasia were of multiple subtypes. None of the cases was classified as immunomodulatory or luminal androgen receptor subtype. Integrative clustering, combining gene expression and gene copy number data, revealed that metaplastic breast carcinomas with spindle cell and chondroid metaplasia were preferentially classified as of integrative clusters 4 and 9, respectively, whereas those with squamous metaplasia were classified into six different clusters. Eight of the 26 metaplastic breast cancers subjected to SNP6 analysis were classified as BRCA1-like. The diversity of histologic

  17. Helping Parents Say No.

    ERIC Educational Resources Information Center

    Duel, Debra K.

    1988-01-01

    Provides some activities that are designed to help students understand some of the reasons why parents sometimes refuse to let their children have pets. Includes mathematics and writing lessons, a student checklist, and a set of tips for parents. (TW)

  18. Can Reading Help?

    ERIC Educational Resources Information Center

    Crowe, Chris

    2003-01-01

    Ponders the effect of September 11th on teenagers. Proposes that reading books can help teenagers sort out complicated issues. Recommends young adult novels that offer hope for overcoming tragedy. Lists 50 short story collections worth reading. (PM)

  19. Hooked on Helping

    ERIC Educational Resources Information Center

    Longhurst, James; McCord, Joan

    2014-01-01

    In this article, teens presenting at a symposium on peer-helping programs describe how caring for others fosters personal growth and builds positive group cultures. Their individual thoughts and opinions are expressed.

  20. Helping Friends and Family

    MedlinePlus

    ... take them up on it! When the adjustment process gets stuck back to top There are times ... are some ways to help move the adjustment process along: Speak honestly and frankly about your feelings . ...

  1. Help Teens Manage Diabetes

    MedlinePlus

    ... Training (CST) as a part of routine diabetes management. Its aim is to improve diabetic teens' coping and communication skills, healthy behaviors, and conflict resolution. The CST training helps diabetic teens to ...

  2. Helping Teens Cope.

    ERIC Educational Resources Information Center

    Jones, Jami I.

    2003-01-01

    Considers the role of school library media specialists in helping teens cope with developmental and emotional challenges. Discusses resiliency research, and opportunities to develop programs and services especially for middle school and high school at-risk teens. (LRW)

  3. Allelic loss in colorectal carcinoma

    SciTech Connect

    Kern, S.E.; Fearon, E.R.; Tersmette, K.W.F.; Enterline, J.P.; Vogelstein, B.; Hamilton, S.R. ); Leppert, M.; Nakamura, Yusuke; White, R. )

    1989-06-02

    Clinical and pathological associations with molecular genetic alterations were studied in colorectal carcinomas from 83 patients. Fractional allelic loss, a measure of allelic deletions throughout the genome, and allelic deletions of specific chromosomal arms (the short arm of 17 and long arm of 18) each provided independent prognostic information by multivariate analysis when considered individually with Dukes' classification. Distant metastasis was significantly associated with high fractional allelic loss and with deletions of 17p and 18q. Mutations of ras proto-oncogenes and deletions of 5q had no prognostic importance. Statistically significant associations were also found between allelic losses and a family history of cancer, left-sided tumor location, and absence of extracellular tumor mucin. Allelic deletion analysis thus identified subsets of colorectal carcinoma with increased predilection for distant metastasis and cancer-related death. Further studies may define a subset of genetic alterations that can be used clinically to help assess prognosis.

  4. Liver cancer - hepatocellular carcinoma

    MedlinePlus

    Primary liver cell carcinoma; Tumor - liver; Cancer - liver; Hepatoma ... Hepatocellular carcinoma accounts for most liver cancers. This type of cancer occurs more often in men than women. It is usually diagnosed in people age 50 or older. Hepatocellular ...

  5. Squamous Cell Carcinoma (SCC)

    MedlinePlus

    ... A A Squamous cell carcinoma typically develops in sun-damaged skin in fair-skinned patients. Overview Squamous ... skin cancer. Squamous cell carcinoma usually occurs on sun-damaged skin, especially in light-skinned individuals with ...

  6. [Hepatocellular carcinoma].

    PubMed

    Colombo, Massimo; Sangiovanni, Angelo

    2016-07-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer death and the first in patients with compensated cirrhosis. Chronic infection with hepatitis B and C, alcohol, smoking, exposure to aflatoxin and metabolic syndrome, associated with diabetes and obesity are the main etiological factors. Regardless of etiology, patients with cirrhosis stand as the category at higher risk of developing HCC, and indeed are the target of surveillance programs aimed to the early diagnosis of HCC, the only chance to reduce HCC-related mortality. This notwithstanding, International Scientific Societies have issued recommendations for the management of HCC, a significant number of patients are treated outside guidelines, due to several reasons. Among queries still unsolved, the impact of biological characterization of HCC, along with the biological profiling of patients at risk of developing HCC represent main challenges for the future. Treatment personalization and multimodal treatment being further challenges. This chapter summarizes the recommendations for surveillance, diagnosis and treatment of HCC and focus on future directions. PMID:27571469

  7. Hyaluronic acid-decorated dual responsive nanoparticles of Pluronic F127, PLGA, and chitosan for targeted co-delivery of doxorubicin and irinotecan to eliminate cancer stem-like cells.

    PubMed

    Wang, Hai; Agarwal, Pranay; Zhao, Shuting; Xu, Ronald X; Yu, Jianhua; Lu, Xiongbin; He, Xiaoming

    2015-12-01

    Dual responsive nanoparticles are developed for co-delivery of multiple anticancer drugs to target the drug resistance mechanisms of cancer stem-like cells (CSCs). The nanoparticles consist of four polymers approved by the Food and Drug Administration (FDA) for medical use: Poly(d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and hyaluronic acid (HA). By combining PLGA and PF127 together, more stable and uniform-sized nanoparticles can be obtained than using PLGA or PF127 alone. The HA is used for not only actively targeting CSCs to reduce their drug resistance due to dormancy (i.e., slow metabolism), but also replacing the commonly used poly(vinyl alcohol) as a stabilizing agent to synthesize the nanoparticles using the double-emulsion approach and to allow for acidic pH-triggered drug release and thermal responsiveness. Besides minimizing drug efflux from CSCs, the nanoparticles encapsulated with doxorubicin hydrochloride (DOX, hydrophilic) and irinotecan (CPT, hydrophobic) to inhibit the activity of topoisomerases II and I, respectively, can fight against the CSC drug resistance associated with their enhanced DNA repair and anti-apoptosis. Ultimately, the two drugs-laden nanoparticles can be used to efficiently destroy the CSCs both in vitro and in vivo with up to ∼500 times of enhancement compared to the simple mixture of the two drugs.

  8. Matrix metalloproteinase-10 regulates stemness of ovarian cancer stem-like cells by activation of canonical Wnt signaling and can be a target of chemotherapy-resistant ovarian cancer

    PubMed Central

    Mariya, Tasuku; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Tabuchi, Yuta; Asano, Takuya; Saijo, Hiroshi; Kuroda, Takafumi; Yasuda, Kazuyo; Mizuuchi, Masahito; Saito, Tsuyoshi; Sato, Noriyuki

    2016-01-01

    Epithelial ovarian cancer (EOC) is one of the most lethal cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) have been reported to be origin of primary and recurrent cancers and to be resistant to several treatments. In this study, we identified matrix metalloproteinase-10 (MMP10) is expressed in CSCs/CICs of EOC. An immunohistochemical study revealed that a high expression level of MMP10 is a marker for poor prognosis and platinum resistance in multivariate analysis. MMP10 gene overexpression experiments and MMP10 gene knockdown experiments using siRNAs revealed that MMP10 has a role in the maintenance of CSCs/CICs in EOC and resistance to platinum reagent. Furthermore, MMP10 activate canonical Wnt signaling by inhibiting noncanonical Wnt signaling ligand Wnt5a. Therefore, MMP10 is a novel marker for CSCs/CICs in EOC and that targeting MMP10 is a novel promising approach for chemotherapy-resistant CSCs/CICs in EOC. PMID:27072580

  9. Hepatocellular carcinoma.

    PubMed

    Llovet, Josep M; Zucman-Rossi, Jessica; Pikarsky, Eli; Sangro, Bruno; Schwartz, Myron; Sherman, Morris; Gores, Gregory

    2016-01-01

    Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies - resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches. PMID:27158749

  10. Stretching: Does It Help?

    ERIC Educational Resources Information Center

    Vardiman, Phillip; Carrand, David; Gallagher, Philip M.

    2010-01-01

    Stretching prior to activity is universally accepted as an important way to improve performance and help prevent injury. Likewise, limited flexibility has been shown to decrease functional ability and predispose a person to injuries. Although this is commonly accepted, appropriate stretching for children and adolescents involved with sports and…

  11. Helping Perceptually Handicapped Children

    ERIC Educational Resources Information Center

    Rose, Helen S.

    1974-01-01

    Five children diagnosed as having a perceptual problem as revealed by the Bender Visual Motor Gestalt Test received special tutoring to help develop their visual discrimination abilities. The six-week program for teaching the concept of shapes employed kinesthetic, visual, tactile, and verbal processes. (CS)

  12. With a Little Help.

    ERIC Educational Resources Information Center

    Cunningham, Richard

    1997-01-01

    Describes a volunteer tutoring program coordinated by associates of the Exxon Corporation to help middle and high school students with math and science homework. Enumerates the successes of the tutoring program and highlights other outreach activities of the company in Baton Rouge. Stresses that the future of high-technology companies depends on…

  13. Help for Stressed Students

    ERIC Educational Resources Information Center

    Pope, Denise Clarke; Simon, Richard

    2005-01-01

    The authors argue that increased focus and pressure for high academic achievement, particularly among more highly-motivated and successful students, may have serious negative consequences. They present a number of strategies designed to help reduce both causes and consequences associated with academic stress and improve students' mental and…

  14. Helping Teachers Communicate

    ERIC Educational Resources Information Center

    Kise, Jane; Russell, Beth; Shumate, Carol

    2008-01-01

    Personality type theory describes normal differences in how people are energized, take in information, make decisions, and approach work and life--all key elements in how people teach and learn. Understanding one another's personality type preferences helps teachers share their instructional strategies and classroom information. Type theory…

  15. A Helping Hand.

    ERIC Educational Resources Information Center

    Renner, Jason M.

    2000-01-01

    Discusses how designing a hand washing-friendly environment can help to reduce the spread of germs in school restrooms. Use of electronic faucets, surface risk management, traffic flow, and user- friendly hand washing systems that are convenient and maximally hygienic are examined. (GR)

  16. What Helps Us Learn?

    ERIC Educational Resources Information Center

    Educational Leadership, 2010

    2010-01-01

    This article presents comments of high school students at the Howard Gardner School in Alexandria, Virginia, who were asked, What should teachers know about students to help them learn? Twelve high school students from the Howard Gardner School in Alexandria, Virginia, describe how their best teachers get to know them and thus were more able to…

  17. Ayudele! [Help Him!].

    ERIC Educational Resources Information Center

    Spencer, Maria Gutierrez, Comp.; Almance, Sofia, Comp.

    Written in Spanish and English, the booklet briefly discusses what parents can do to help their child learn at school. The booklet briefly notes the importance of getting enough sleep; eating breakfast; praising the child; developing the five senses; visiting the doctor; having a home and garden; talking, listening, and reading to the child;…

  18. Hepatocellular carcinoma.

    PubMed

    Okuda, K

    2000-01-01

    Hepatocellular carcinoma (HCC) is increasing in many countries as a result of an increase in hepatitis C virus (HCV) infection since World War II. The epidemiology of HCC varies with the global region. There have been conflicting observations from different parts of the world concerning the frequency of HCC in patients who in the distant past had post-transfusion non-A, non-B hepatitis. The genetic basis of hepatocarcinogenesis is still poorly understood. In hepatitis B virus (HVB) associated HCC, codon 249 mutation in the p 53 gene seems more related to exposure to aflatoxin B1 than to hepatocarcinogenesis itself. HCC that occurs in children in high HBV endemic regions could be associated with germ-line mutations, but little information is available; not much is known about chemical hepatocarcinogens in the environment other than aflatoxins. The X gene of HBV seems to play an important role in HBV-associated hepatocarcinogenesis. There are preliminary observations on the molecular mechanism of HCV-associated HCC, such as HCV core protein inducing HCC in transgenic mice and the NS3 genome transforming NIH 3T3 cells. Pathological distinction between preneoplastic and very early transformed lesions still depends on classical morphology, and a more genetically oriented differential diagnosis is required. Clinical diagnosis based on modern imaging has improved greatly, but is still unsatisfactory in the differential diagnosis of preneoplastic and early transformed nodules, because the vasculature changes that occur within the nodule are not accurately discerned with the current imaging. Use of sensitive des-gamma-carboxy prothrombin (PIVKA II) assay, and lectin affinity chromatography separating HCC specific subspecies of AFP molecules with a more practical biochemical technique will further improve diagnosis. Early diagnosis and transplantation are the best treatment at the moment, but transplantation is not widely available because of the donor shortage. Despite

  19. Ionizing Radiation Induces Altered Neuronal Differentiation by mGluR1 through PI3K-STAT3 Signaling in C17.2 Mouse Neural Stem-Like Cells.

    PubMed

    Eom, Hyeon Soo; Park, Hae Ran; Jo, Sung Kee; Kim, Young Sang; Moon, Changjong; Kim, Sung-Ho; Jung, Uhee

    2016-01-01

    Most studies of IR effects on neural cells and tissues in the brain are still focused on loss of neural stem cells. On the other hand, the effects of IR on neuronal differentiation and its implication in IR-induced brain damage are not well defined. To investigate the effects of IR on C17.2 mouse neural stem-like cells and mouse primary neural stem cells, neurite outgrowth and expression of neuronal markers and neuronal function-related genes were examined. To understand this process, the signaling pathways including PI3K, STAT3, metabotrophic glutamate receptor 1 (mGluR1) and p53 were investigated. In C17.2 cells, irradiation significantly increased the neurite outgrowth, a morphological hallmark of neuronal differentiation, in a dose-dependent manner. Also, the expression levels of neuronal marker proteins, β-III tubulin were increased by IR. To investigate whether IR-induced differentiation is normal, the expression of neuronal function-related genes including synaptophysin, a synaptic vesicle forming proteins, synaptotagmin1, a calcium ion sensor, γ-aminobutyric acid (GABA) receptors, inhibitory neurotransmitter receptors and glutamate receptors, excitatory neurotransmitter receptors was examined and compared to that of neurotrophin-stimulated differentiation. IR increased the expression of synaptophysin, synaptotagmin1 and GABA receptors mRNA similarly to normal differentiation by stimulation of neurotrophin. Interestingly, the overall expression of glutamate receptors was significantly higher in irradiated group than normal differentiation group, suggesting that the IR-induced neuronal differentiation may cause altered neuronal function in C17.2 cells. Next, the molecular mechanism of the altered neuronal differentiation induced by IR was studied by investigating signaling pathways including p53, mGluR1, STAT3 and PI3K. Increases of neurite outgrowth, neuronal marker and neuronal function-related gene expressions by IR were abolished by inhibition of p53, m

  20. Ionizing Radiation Induces Altered Neuronal Differentiation by mGluR1 through PI3K-STAT3 Signaling in C17.2 Mouse Neural Stem-Like Cells

    PubMed Central

    Eom, Hyeon Soo; Park, Hae Ran; Jo, Sung Kee; Kim, Young Sang; Moon, Changjong; Kim, Sung-Ho; Jung, Uhee

    2016-01-01

    Most studies of IR effects on neural cells and tissues in the brain are still focused on loss of neural stem cells. On the other hand, the effects of IR on neuronal differentiation and its implication in IR-induced brain damage are not well defined. To investigate the effects of IR on C17.2 mouse neural stem-like cells and mouse primary neural stem cells, neurite outgrowth and expression of neuronal markers and neuronal function-related genes were examined. To understand this process, the signaling pathways including PI3K, STAT3, metabotrophic glutamate receptor 1 (mGluR1) and p53 were investigated. In C17.2 cells, irradiation significantly increased the neurite outgrowth, a morphological hallmark of neuronal differentiation, in a dose-dependent manner. Also, the expression levels of neuronal marker proteins, β-III tubulin were increased by IR. To investigate whether IR-induced differentiation is normal, the expression of neuronal function-related genes including synaptophysin, a synaptic vesicle forming proteins, synaptotagmin1, a calcium ion sensor, γ-aminobutyric acid (GABA) receptors, inhibitory neurotransmitter receptors and glutamate receptors, excitatory neurotransmitter receptors was examined and compared to that of neurotrophin-stimulated differentiation. IR increased the expression of synaptophysin, synaptotagmin1 and GABA receptors mRNA similarly to normal differentiation by stimulation of neurotrophin. Interestingly, the overall expression of glutamate receptors was significantly higher in irradiated group than normal differentiation group, suggesting that the IR-induced neuronal differentiation may cause altered neuronal function in C17.2 cells. Next, the molecular mechanism of the altered neuronal differentiation induced by IR was studied by investigating signaling pathways including p53, mGluR1, STAT3 and PI3K. Increases of neurite outgrowth, neuronal marker and neuronal function-related gene expressions by IR were abolished by inhibition of p53, m

  1. Helping Your Child through Early Adolescence -- Helping Your Child Series

    MedlinePlus

    ... CHILD'S ACADEMIC SUCCESS Helping Your Child Through Early Adolescence -- Helping Your Child Series PDF (1 MB) For ... Acknowledgements Tips to Help Your Child through Early Adolescence No Child Left Behind < Previous page | ^ Top ^ | Next ...

  2. Please Help Your Union

    NASA Astrophysics Data System (ADS)

    Killeen, Tim

    2006-03-01

    The continuing success of AGU relies entirely on the volunteer work of members. A major contribution to these efforts comes from the over 40 committees that plan, oversee, and have operational roles in our meetings, publications, finances, elections, awards, education, public information, and public affairs activities. The names of committees are provided in the accompanying text box; their current membership and descriptions can be found on the Web at the AGU site. One of the most important and challenging tasks of the incoming AGU President is to reestablish these committees by appointing hundreds of volunteers. I now solicit your help in staffing these committees. Ideally, participation in these important committees will reflect the overall membership and perspectives of AGU members, so please do consider volunteering yourself. Of course, nominations of others would also be very welcome. I am particularly interested in making sure that the gender balance, age, and geographic representation are appropriate and reflect our changing demographics. Any suggestions you might have will be more helpful if accompanied by a few sentences of background information relevant to the particular committee.

  3. NUT midline carcinomas of the sinonasal tract.

    PubMed

    Bishop, Justin A; Westra, William H

    2012-08-01

    those carcinomas that demonstrate undifferentiated areas. The availability of an immunohistochemical probe has greatly facilitated this analysis and is helping to define the full demographic, morphologic, and immunohistochemical spectrum of sinonasal NMC.

  4. Mucoepidermoid carcinoma of the penis: Case report and literature review

    PubMed Central

    Costa, Márcio Rodrigues; Sugita, Denis Masashi; Vilela, Maria Helena Tavares; da Silva Mendonça, Rodrigo Pastor; de Morais, Danilo Tavares Maranhão; Júnior, Paulo Cézar Ribeiro Gomes; Costa, Théo Rodrigues; Barreira, Bernardo Monteiro Antunes

    2015-01-01

    We describe the fifth case of mucoepidermoid carcinoma. The patient had penile ulcer with bilateral inguinal and pelvic lymphadenopathy and underwent total penectomy. After antibiotic therapy, the patient began outpatient chemotherapy, but the treatment was discontinued due to his intolerance. The patient died due to infectious complications of the inguinal lymphatic fistula 7 months after the histological diagnosis. Notably, the periurethral area was involved in the anatomopathological evaluation of the excised penis. The penile mucoepidermoid carcinoma was aggressive and the perimeatal region was involved. This case helps demystify the origins and prognosis of this rare case. More reports documenting patient characteristics and their evolution with penile mucoepidermoid carcinoma are needed. PMID:25624963

  5. Xeromammographic screening: is it helping

    SciTech Connect

    Hatton, P.D.; Harford, F.J. Jr.; Sheppard, J.R.

    1984-07-01

    A review is presented of the authors' experience with xeromammography over a five-year period in a setting where there is no protocol for mammographic screening. Only 8.9% of breast carcinomas were found by xeromammography alone, a ratio substantially smaller than that found in large screening programs. While 80% of the occult carcinomas were localized, only 47% of women with palpable disease had localized tumors. It appears that screening mammography is underused, and that more localized tumors would be detected if more mammograms were ordered.

  6. Targeted therapy: a new hope for thyroid carcinomas.

    PubMed

    Perri, Francesco; Pezzullo, Luciano; Chiofalo, Maria Grazia; Lastoria, Secondo; Di Gennaro, Francesca; Scarpati, Giuseppina Della Vittoria; Caponigro, Francesco

    2015-04-01

    Thyroid carcinomas are rare and heterogeneous diseases representing less than 1% of all malignancies. The majority of thyroid carcinomas are differentiated entities (papillary and folliculary carcinomas) and are characterized by good prognosis and good response to surgery and radioiodine therapy. Nevertheless, about 10% of differentiated carcinomas recur and become resistant to all therapies. Anaplastic and medullary cancers are rare subtypes of thyroid cancer not suitable for radioiodine therapy. A small percentage of differentiated and all the anaplastic and medullary thyroid carcinomas often recur after primary treatments and are no longer suitable for other therapies. In the last years, several advances have been made in the field of molecular biology and tumorigenesis mechanisms of thyroid carcinomas. Starting from these issues, the targeted therapy may be employed as a new option. The MAP-Kinase pathway has been found often dysregulated in thyroid carcinomas and several upstream signals have been recognized as responsible for this feature. RET/PTC mutations are often discovered both in papillary and in medullary carcinomas, while B-RAF mutation is typical of papillary and anaplastic histologies. Also mTOR disruptions and VEGFR pathway disruption are common features in all advanced thyroid cancers. Some angiogenesis inhibitors and a number of RET/PTC pathway blocking agents are yet present in the clinical armamentarium. Vandetanib, cabozatinib and sorafenib have reached clinical use. A number of other biological compounds have been tested in phase II and III trials. Understanding the biology of thyroid cancers may help us to design a well shaped targeted therapy.

  7. Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines.

    PubMed

    Baharuddin, Puteri; Satar, Nazilah; Fakiruddin, Kamal Shaik; Zakaria, Norashikin; Lim, Moon Nian; Yusoff, Narazah Mohd; Zakaria, Zubaidah; Yahaya, Badrul Hisham

    2016-01-01

    Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10-40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may

  8. Squamous cell carcinoma

    Cancer.gov

    The hallmarks of squamous cell carcinoma are the differentiation features of the squamous epithelium: keratinization and intercellular bridges. Large central masses of keratin, individual cell keratinization, and/or keratin pearls may form. Necrosis of tumor cell nests and accumulation of acute inflammatory cells are frequent features of poorly differentiated squamous cell carcinoma.

  9. [Renal cell carcinoma producing erythrocytosis due to inappropriate production of erythropoietin].

    PubMed

    Villanueva-Gimeno, M M; Vicario-Bermúdez, J M; Fonseca-López, Ch; Caballero-Castro, J P; Zabala-López, S I; Sánchez-Elipe, M A; González-Gómez, N

    2013-01-01

    Erythrocytosis, or polycythaemia, is an increase, in absolute terms, of the erythrocyte mass. The most common solid tumour related to this phenomenon is renal cell carcinoma, which can produce erythrocytosis by increasing erythropoietin production. About 30% of symptomatic renal cell carcinomas are diagnosed due to the appearance of a paraneoplastic syndrome. Polycythaemia is one of these. Surgery, (radical or partial nephrectomy), is the treatment of choice in renal cell carcinoma and helps to keep the erythrocytosis situation under control. PMID:23834980

  10. Mammary Analogue Secretory Carcinoma.

    PubMed

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined. PMID:27575269

  11. We Want to Help!

    NASA Astrophysics Data System (ADS)

    Trombino, D. F.

    1997-05-01

    The D.M.S.O. is the only full-time optical solar observatory in the Sunshine State. Its instruments are made available on a NO CHARGE basis to deserving Central Florida amateur astronomers, undergraduate students at nearby Stetson University and other local colleges. We are privately owned and completely independent of federal funding. Our research is supported through small, individual and corporate donations (mainly equipment) and the voluntary manpower of trained amateur solar observers. The D.M.S.O. is an affiliate of the Museum of Art & Sciences, Daytona Beach, and maintains ties with the Department of Physics and Computer Sciences at Stetson University in DeLand. Daily solar observations are made in while-light, H-alpha and calcium II K-line wavelengths using University grade Day-Star filters in conjunction with a long focus 15cm refractor and two 12 cm refractors. Particular attention is given to the morphology of sunspots, plage, flares, prominence and other features. Our results are reported to the Solar Sections of the B.A.A. (England), A.L.P.O. (U.S.A.) and SONNE, (Germany). Our East coast location enables us to record photospheric and chromospheric activity well in advance of West coast observatories: an obvious advantage. Numerous lakes at our site provides us with exceptional seeing -- at times approaching one arc/sec. Future plans call for high resolution CCD/video solar patrol monitoring, simultaneously in three wavelengths at 15 second intervals. This and other projects, including establishing a web page, will be undertaken in cooperation with the Computer Sciences Institute at Stetson University. We do no have all the answers, but we may have the solution to your problems. We welcome the opportunity to discuss your needs and our future cooperative goals. We need each other and we want to help! Please leave your card and feel free to contact me at the above address. Our E-mail address is NLTsolar@aol.com, if you prefer.

  12. Help Helps, but Only so Much: Research on Help Seeking with Intelligent Tutoring Systems

    ERIC Educational Resources Information Center

    Aleven, Vincent; Roll, Ido; McLaren, Bruce M.; Koedinger, Kenneth R.

    2016-01-01

    Help seeking is an important process in self-regulated learning (SRL). It may influence learning with intelligent tutoring systems (ITSs), because many ITSs provide help, often at the student's request. The Help Tutor was a tutor agent that gave in-context, real-time feedback on students' help-seeking behavior, as they were learning with an ITS.…

  13. Predictors of disease progression in ductal carcinoma in situ of the breast and vascular patterns.

    PubMed

    Adler, Esther H; Sunkara, Jaya L; Patchefsky, Arthur S; Koss, Leopold G; Oktay, Maja H

    2012-04-01

    Breast carcinoma-induced angiogenesis helps meet growing metabolic needs of tumors and progressively increases with malignant transformation of benign ducts to ductal carcinoma in situ (DCIS) and ductal carcinoma in situ to invasive carcinoma. There are conflicting data regarding the difference in angiogenesis in low-, intermediate-, and high-grade ductal carcinoma in situ. If angiogenesis is related to ductal carcinoma in situ progression, the types of ductal carcinoma in situ with more aggressive biologic potential would have different vascular patterns than the less aggressive ones. In this study, we classified 51 cases of ductal carcinoma in situ as low (10-20 years to progression to invasive carcinoma), moderate, or high aggressive (2-5 years to progression to invasive carcinoma), based on criteria outlined by Tsikitis and Chung (Am J Clin Oncol 2006; 29:305), which takes into account nuclear grade, mitotic rate, Ki-67, Her2Neu, P53, estrogen, and progesterone receptor expression. We correlated these 3 groups of ductal carcinoma in situ with the extent of periductal and stromal vascularity and the presence and type of vascular breaks. No association of aggressive biologic behavior of ductal carcinoma in situ with any vascular pattern was found. Moreover, no correlation was found between vascular patterns and classifiers of aggressiveness, microvascular density, or outcome (local recurrence, invasive carcinoma, or metastatic disease). To validate our cohort, we confirmed expected correlations of all measured parameters of aggressiveness by correlating them with each other. In summary, vascular patterns in ductal carcinoma in situ do not correlate with the predictors of aggressive behavior, suggesting that the biologic potential of ductal carcinoma in situ is independent of angiogenesis.

  14. Does Marijuana Help Treat Glaucoma?

    MedlinePlus

    ... Ophthalmologist Patient Stories Español Eye Health / Tips & Prevention Marijuana Sections Does Marijuana Help Treat Glaucoma? Why Eye ... Don't Recommend Marijuana for Glaucoma Infographic Does Marijuana Help Treat Glaucoma? Written by: David Turbert , contributing ...

  15. A subset of prostatic basal cell carcinomas harbor the MYB rearrangement of adenoid cystic carcinoma.

    PubMed

    Bishop, Justin A; Yonescu, Raluca; Epstein, Jonathan I; Westra, William H

    2015-08-01

    Adenoid cystic carcinoma (ACC) is a basaloid tumor consisting of myoepithelial and ductal cells typically arranged in a cribriform pattern. Adenoid cystic carcinoma is generally regarded as a form of salivary gland carcinoma, but it can arise from sites unassociated with salivary tissue. A rare form of prostate carcinoma exhibits ACC-like features; it is no longer regarded as a true ACC but rather as prostatic basal cell carcinoma (PBCC) and within the spectrum of basaloid prostatic proliferations. True ACCs often harbor MYB translocations resulting in the MYB-NFIB fusion protein. MYB analysis could clarify the true nature of prostatic carcinomas that exhibit ACC features and thus help refine the classification of prostatic basaloid proliferations. Twelve PBCCs were identified from the pathology consultation files of Johns Hopkins Hospital. The histopathologic features were reviewed, and break-apart fluorescence in situ hybridization for MYB was performed. All 12 cases exhibited prominent basaloid histology. Four were purely solid, 7 exhibited a cribriform pattern reminiscent of salivary ACC, and 1 had a mixed pattern. The MYB rearrangement was detected in 2 (29%) of 7 ACC-like carcinomas but in none (0%) of the 5 PBCCs with a prominent solid pattern. True ACCs can arise in the prostate as is evidenced by the presence of the characteristic MYB rearrangement. When dealing with malignant basaloid proliferations in the prostate, recommendations to consolidate ACCs with other tumor types may need to be reassessed, particularly in light of the rapidly advancing field of biologic therapy where the identification of tumor-specific genetic alterations presents novel therapeutic targets.

  16. Stages of Adrenocortical Carcinoma

    MedlinePlus

    ... of Childhood Treatment for more information.) Having certain genetic conditions increases the risk of adrenocortical carcinoma. Anything ... can be a sign of disease. CT scan (CAT scan) : A procedure that makes a series of ...

  17. Basal Cell Carcinoma

    PubMed Central

    Lanoue, Julien

    2016-01-01

    Basal cell carcinoma is the most commonly occurring cancer in the world and overall incidence is still on the rise. While typically a slow-growing tumor for which metastases is rare, basal cell carcinoma can be locally destructive and disfiguring. Given the vast prevalence of this disease, there is a significant overall burden on patient well-being and quality of life. The current mainstay of basal cell carcinoma treatment involves surgical modalities, such as electrodessication and curettage, excision, cryosurgery, and Mohs micrographic surgery. Such methods are typically reserved for localized basal cell carcinoma and offer high five-year cure rates, but come with the risk of functional impairment, disfigurement, and scarring. Here, the authors review the evidence and indications for nonsurgical treatment modalities in cases where surgery is impractical, contraindicated, or simply not desired by the patient. PMID:27386043

  18. Unusual Adrenal and Brain Metastases From Follicular Thyroid Carcinoma Revealed by 131I SPECT/CT.

    PubMed

    Zhao, Zhen; Shen, Guo-hua; Liu, Bin; Kuang, An-ren

    2016-01-01

    The adrenal metastasis from differentiated thyroid carcinoma is uncommon. Metastatic involvement of both adrenal and brain in the same patient from differentiated thyroid carcinoma is rare. Here, we described an unusual case with iodine-avid lung, bone, adrenal, liver, and brain metastases from follicular thyroid carcinoma confirmed by 131I SPECT/CT. The utilization of SPECT/CT in thyroid cancer patients can detect the presence of metastases and also exclude potential false-positive lesions. Our case demonstrates that SPECT/CT is helpful in localizing and confirming metastatic lesions from differentiated thyroid carcinoma in rare and unusual sites.

  19. Colorectal carcinoma: Pathologic aspects

    PubMed Central

    Fleming, Matthew; Ravula, Sreelakshmi; Tatishchev, Sergei F.

    2012-01-01

    Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance. PMID:22943008

  20. Cholescintigraphy in gallbladder carcinoma

    SciTech Connect

    Colletti, P.M.; Ralls, P.W.; Siegel, M.E.; Halls, J.M.

    1986-04-01

    Findings on cholescintigraphy in gallbladder carcinoma are described in five patients. Four patients presenting with acute cholecystitis had nonvisualization of the gallbladder with normal hepatoenteric transit time. One of these had a large portal mass and two had liver metastasis as additional findings. The fifth patient was jaundiced, and showed absence of bowel activity compatible with total biliary obstruction. Both the clinical and scintigraphic findings in gallbladder carcinoma are difficult to separate from findings in cholelithiasis and cholecystitis.

  1. [Pulmonary sarcomatoid carcinoma].

    PubMed

    Antoine, Martine; Vieira, Thibault; Fallet, Vincent; Hamard, Cécile; Duruisseaux, Michael; Cadranel, Jacques; Wislez, Marie

    2016-01-01

    Pulmonary sarcomatoid carcinomas are a rare group of tumors accounting for about one percent of non-small cell lung carcinoma (NSCLC). In 2015, the World Health Organization classification united under this name all the carcinomas with sarcomatous-like component with spindle cell or giant cell appearance, or associated with a sarcomatous component sometimes heterologous. There are five subtypes: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma. Clinical characteristics are not specific from the other subtypes of NSCLC. Epithelial to mesenchymal transition pathway may play a key role. Patients, usually tobacco smokers, are frequently symptomatic. Tumors are voluminous more often peripherical than central, with strong fixation on FDG TEP CT. Distant metastases are frequent with atypical visceral locations. These tumors have poorer prognosis than the other NSCLC subtypes because of great aggressivity, and frequent chemoresistance. Here we present pathological description and a review of literature with molecular features in order to better describe these tumors and perhaps introduce new therapeutics.

  2. IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype.

    PubMed

    Kessler, S M; Laggai, S; Barghash, A; Schultheiss, C S; Lederer, E; Artl, M; Helms, V; Haybaeck, J; Kiemer, A K

    2015-01-01

    Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths and commonly develops in inflammatory environments. The IGF2 mRNA-binding protein IMP2-2/IGF2BP2-2/p62 was originally identified as an autoantigen in HCC. Aim of this study was to investigate a potential pathophysiological role of p62 in hepatocarcinogenesis. Human HCC tissue showed overexpression of IMP2, which strongly correlated with the fetal markers AFP and DLK1/Pref-1/FA-1 and was particularly elevated in tumors with stem-like features and hypervascularization. Molecular classification of IMP2-overexpressing tumors revealed an aggressive phenotype. Livers of mice overexpressing the IMP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood. p62 was oncogenic: diethylnitrosamine (DEN)-treated p62 transgenic mice exhibited a higher tumor incidence and multiplicity than wild types. Tumors of transgenics showed a more aggressive and stem-like phenotype and displayed more oncogenic chromosomal aberrations determined with aCGH analysis. DEN-treated p62 transgenic mice exhibited distinct signs of inflammation, such as inflammatory cytokine expression and oxidative stress markers, that is, thiobarbituric acid-reactive substance (TBARS) levels. Reactive oxygen species (ROS) production was elevated in HepG2 cells, which either overexpressed p62 or were treated with DLK1. p62 induced this ROS production by a DLK1-dependent induction and activation of the small Rho-GTPase RAC1, activating NADPH oxidase and being overexpressed in human HCC. Our data indicate that p62/IMP2 promotes hepatocarcinogenesis by an amplification of inflammation. PMID:26426686

  3. IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype

    PubMed Central

    Kessler, S M; Laggai, S; Barghash, A; Schultheiss, C S; Lederer, E; Artl, M; Helms, V; Haybaeck, J; Kiemer, A K

    2015-01-01

    Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths and commonly develops in inflammatory environments. The IGF2 mRNA-binding protein IMP2-2/IGF2BP2-2/p62 was originally identified as an autoantigen in HCC. Aim of this study was to investigate a potential pathophysiological role of p62 in hepatocarcinogenesis. Human HCC tissue showed overexpression of IMP2, which strongly correlated with the fetal markers AFP and DLK1/Pref-1/FA-1 and was particularly elevated in tumors with stem-like features and hypervascularization. Molecular classification of IMP2-overexpressing tumors revealed an aggressive phenotype. Livers of mice overexpressing the IMP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood. p62 was oncogenic: diethylnitrosamine (DEN)-treated p62 transgenic mice exhibited a higher tumor incidence and multiplicity than wild types. Tumors of transgenics showed a more aggressive and stem-like phenotype and displayed more oncogenic chromosomal aberrations determined with aCGH analysis. DEN-treated p62 transgenic mice exhibited distinct signs of inflammation, such as inflammatory cytokine expression and oxidative stress markers, that is, thiobarbituric acid-reactive substance (TBARS) levels. Reactive oxygen species (ROS) production was elevated in HepG2 cells, which either overexpressed p62 or were treated with DLK1. p62 induced this ROS production by a DLK1-dependent induction and activation of the small Rho-GTPase RAC1, activating NADPH oxidase and being overexpressed in human HCC. Our data indicate that p62/IMP2 promotes hepatocarcinogenesis by an amplification of inflammation. PMID:26426686

  4. Ameloblastic carcinoma (secondary type) with extensive squamous differentiation areas and dedifferentiated regions.

    PubMed

    Fonseca, Felipe Paiva; de Almeida, Oslei Paes; Vargas, Pablo Agustin; Gonçalves, Fábio; Corrêa Pontes, Flávia Sirotheau; Rebelo Pontes, Hélder Antônio

    2016-06-01

    Ameloblastic carcinoma is rare, accounting for 1.5%-2.0% of all odontogenic tumors. Few small series are available, but data on its clinicopathologic characteristics derive mainly from single case reports; therefore, descriptions of new cases may help to better understand the biological characteristics of this rare odontogenic malignancy. In the current report we describe an ameloblastic carcinoma affecting a 27-year-old female patient who had a previous diagnosis of ameloblastoma 7 years before. The carcinoma featured extensive areas of squamous differentiation resembling a primary intraosseous squamous cell carcinoma, as well as areas of dedifferentiation, a poorly documented histologic characteristic of ameloblastic carcinoma. This case provides new insights on the microscopic spectrum of ameloblastic carcinoma, permitting a critical discussion of the current World Health Organization classification of this odontogenic tumor. PMID:26768075

  5. To Help Substance Abusers, We Must First Help Ourselves.

    ERIC Educational Resources Information Center

    Educational Leadership, 1988

    1988-01-01

    Administrator recounts experience growing up in alcoholic home, hoping to inspire other school professionals helping young people with substance abuse problems. Although helping others seems natural for adult children of alcoholics, certain unconsciously held attitudes and behaviors can impede school prevention and recovery programs. Organizations…

  6. The Chandra HelpDesk

    NASA Astrophysics Data System (ADS)

    Galle, Elizabeth C.

    2008-03-01

    The Chandra X-ray Center (CXC) HelpDesk has answered hundreds of user questions over the course of the Chandra mission, ranging from basic syntax errors to advanced analysis questions. This talk gives an introduction to the HelpDesk system and staff, presents a sample of recent HelpDesk requests, and discusses how user-submitted questions improve the software and documentation.

  7. [Merkel cell skin carcinoma].

    PubMed

    Krejcí, K; Zadrazil, J; Tichý, T; Horák, P; Ciferská, H; Hodulová, M; Zezulová, M; Zlevorová, M

    2010-01-01

    Merkel cell carcinoma is a rare tumour of the skin. It affects predominantly elderly Caucasian males on sun-exposed areas of the skin. Distinctively more frequent and at significantly lower age, its incidence is higher in immunocompromised patients. In these patients we often observe the highly aggressive course of Merkel cell carcinoma and a fatal outcome. The incidence of Merkel cell carcinoma has been rising in recent years and is more dramatic than the increased incidence of cutaneous melanoma. More than one-third of Merkel cell carcinoma patients will die from this cancer, making it twice as lethal as melanoma. The malignant transformation of Merkel cells is currently thought to be related to an infection with Merkel cell polyomavirus. In the early stage the discreet clinical picture may be contrary to extensive microscopic invasion and this seemingly benign appearance can delay diagnosis or increase the risk of insufficient tumour excision. The diagnosis is definitely confirmed by histological evaluation and immunohistochemical tests. A typical feature is the tendency of Merkel cell carcinoma to frequent local recurrence and early metastasizing into regional lymph nodes with subsequent tumour generalization. The mainstay of therapy is radical excision of the tumour and adjuvant radiotherapy targeted at the site of primary incidence and local draining lymph nodes. The efficacy of different chemotherapy protocols in Merkel cell carcinoma is limited and the median survival rate is measured in months. In the future, prophylaxis with vaccination against Merkel cell polyomavirus will hopefully be possible in high-risk patients, as well as therapeutic usage of antisense oligonucleotides or microRNAs, eventually complete Merkel cell carcinoma elimination by affecting the tumour suppressor gene Atonal homolog 1 expression. The staging of the tumour at time of diagnosis is the most important prognostic factor. In this respect, the importance of preventative skin

  8. Genetic profile of clear cell odontogenic carcinoma.

    PubMed

    Carinci, Francesco; Volinia, Stefano; Rubini, Corrado; Fioroni, Massimiliano; Francioso, Francesca; Arcelli, Diego; Pezzetti, Furio; Piattelli, Adriano

    2003-05-01

    In the head and neck region, clear cell tumors are usually derived from salivary glands, odontogenic tissues, and metastasis. The World Health Organization has classified clear cell odontogenic tumor among benign tumors, but it is now recognized as a more sinister lesion, and current opinion is that it should be designated as a carcinoma. It is characterized by aggressive growth, recurrences, and metastasis. By using complementary DNA microarrays, several genes in clear cell odontogenic tumor were identified that are differentially regulated when compared with non-tumor tissue. In conclusion, the first genetic profiling of clear odontogenic carcinoma is reported. DNA microarrays can potentially help in identifying some genes whose products could be disease-specific targets for cancer therapy as well as a tool for better classifying odontogenic tumor.

  9. Chyluria associated with bronchial carcinoma

    PubMed Central

    Morice, A. H.; Wood, J. R.

    1981-01-01

    Chylous pleural effusion, though not chyluria, is a recognized association of carcinoma of the bronchus. A case of chyluria associated with squamous bronchial carcinoma is reported. Chyluria in this patient was successfully treated by dietary modification. PMID:7329888

  10. Helping a Learning Group Mature.

    ERIC Educational Resources Information Center

    Parsons, Jerry

    The ultimate goal of a learning group is to help learners achieve their goals and objectives and to help them learn to live in a rapidly changing and evolving society. Within the context of social change, the author examines how internal dynamics can be used to aid a teacher in developing an effective learning group. Drawing from psychology,…

  11. p63 immunohistochemistry differentiates salivary gland oncocytoma and oncocytic carcinoma from metastatic renal cell carcinoma.

    PubMed

    McHugh, Jonathan B; Hoschar, Aaron P; Dvorakova, Mari; Parwani, Anil V; Barnes, E Leon; Seethala, Raja R

    2007-12-01

    Metastatic renal cell carcinoma (RCC) can pose diagnostic challenges in the head and neck often resembling benign and malignant oncocytic lesions. Immunohistochemical panels have been reported to help with this differential but are not entirely specific or sensitive. We have noticed that p63 routinely stains salivary gland oncocytomas but not metastatic RCC. Nineteen oncocytomas, 9 cases of oncocytosis, 9 oncocytic carcinomas and 16 head and neck metastatic RCC were studied. Morphologic features evaluated were cytoplasmic character (clear versus oncocytic), Fuhrman nuclear grade, mitotic rate, growth pattern, presence of lumens/blood lakes and stromal characteristics. Tumors were stained with antibodies to p63, renal cell carcinoma marker (RCCm), CD10, and vimentin. Eight benign oncocytic tumors (29%) had clear cell features while 6 metastatic RCC (37%) had oncocytic features. Median Fuhrman nuclear grade was 2 in oncocytoma and oncocytosis and 3 both oncocytic carcinoma and metastatic RCC. Mitotic rates were only significantly different between benign oncocytic tumors and metastatic RCC. All oncocytomas had lumina compared to half of metastatic RCC, all of which also demonstrated blood lakes. Seven benign oncocytic tumors (25%) and 5 oncocytic carcinomas (56%) had RCC-like vascular stroma. All primary salivary gland tumors were positive for p63, predominately in basal cell-type distribution. None of the metastatic RCC was positive. RCCm was entirely specific but lacked sensitivity for metastatic RCC while CD10 and vimentin showed variable sensitivity and specificity. While clinical history and morphology usually are adequate, demonstration of p63 staining can definitively exclude metastatic RCC from the differential diagnosis of similar appearing tumors in salivary glands, namely oncocytoma and oncocytic carcinoma, with 100% specificity and sensitivity. While RCCm, CD10, and vimentin performed adequately, they were significantly less reliable than p63 with both

  12. Collective helping and bystander effects in coevolving helping networks

    NASA Astrophysics Data System (ADS)

    Jo, Hang-Hyun; Lee, Hyun Keun; Park, Hyunggyu

    2010-06-01

    We study collective helping behavior and bystander effects in a coevolving helping network model. A node and a link of the network represents an agent who renders or receives help and a friendly relation between agents, respectively. A helping trial of an agent depends on relations with other involved agents and its result (success or failure) updates the relation between the helper and the recipient. We study the network link dynamics and its steady states analytically and numerically. The full phase diagram is presented with various kinds of active and inactive phases and the nature of phase transitions are explored. We find various interesting bystander effects, consistent with the field study results, of which the underlying mechanism is proposed.

  13. Nonfunctional parathyroid carcinoma.

    PubMed Central

    Giessler, G. A.; Beech, D. J.

    2001-01-01

    Parathyroid carcinoma is a rare entity accounting for 0.5% to 5% of parathyroid neoplasia. Most of these malignancies present as functional hormone-producing masses with elevated serum levels of parathormone and calcium. These tumors may also be nonfunctional. Clinical detection of nonfunctioning parathyroid malignancies preoperatively is primarily based on symptoms of an expanding neck mass. This ominous complaint is typically accompanied with an advanced stage of the disease at initial diagnosis. Because there is a paucity of data in the literature regarding nonfunctioning parathyroid carcinoma, prognosis can not be readily assessed. In both functional and nonfunctional parathyroid carcinoma, early surgery has proven to be the only curative treatment approach whereas both chemotherapy and radiation therapy fail to produce systemic or regional benefit when used alone. Hence, parathyroid cancer should be considered in every patient evaluated for a neck mass regardless of the blood calcium and blood parathormone level. PMID:11491274

  14. Pure Lymphoepithelioma-Like Carcinoma Originating from the Urinary Bladder

    PubMed Central

    Nagai, Takashi; Naiki, Taku; Kawai, Noriyasu; Iida, Keitaro; Etani, Toshiki; Ando, Ryosuke; Hamamoto, Shuzo; Sugiyama, Yosuke; Okada, Atsushi; Mizuno, Kentaro; Umemoto, Yukihiro; Yasui, Takahiro

    2016-01-01

    Lymphoepithelioma-like carcinoma of the urinary bladder (LELCB) is a rare variant of infiltrating urothelial carcinoma. We report a case of LELCB in a 43-year-old man. Ultrasonography and cystoscopy revealed two bladder tumors, one on the left side of the trigone and the other on the right side of the trigone. Transurethral resection of the bladder tumors was performed and pathological analysis revealed undifferentiated carcinoma. We therefore performed radical cystectomy and urinary diversion. Immunohistochemically the tumor cells were positive for cytokeratin, but negative for Epstein-Barr virus-encoded small RNA in situ hybridization as found for previous cases of LELCB. The final pathological diagnosis was a lymphoepithelioma-like variant of urothelial carcinoma with perivesical soft tissue invasion. For adjuvant systemic chemotherapy, three courses of cisplatin were administered. The patient subsequently became free of cancer 72 months postoperatively. Based on the literature, pure or predominant LELCB types show favorable prognoses due to their sensitivity to chemotherapy or radiotherapy. An analysis of the apparent diffusion coefficient (ADC) values of bladder tumors examined in our institution revealed that the ADC value measured for this LELCB was relatively low compared to conventional urothelial carcinomas. This suggests that measuring the ADC value of a lymphoepithelioma-like carcinoma prior to operation may be helpful in predicting LELCB. PMID:27099604

  15. Primary pulmonary cavitating carcinomas

    PubMed Central

    Chaudhuri, M. Ray

    1973-01-01

    A primary lung cancer can produce a cavity in three ways. The first is `cavitary necrosis' due to breakdown of the growth itself. The second is `stenotic abscess' due to infection and breakdown of the lung parenchyma distal to bronchial obstruction caused by the growth. The third type is `spill-over abscess'. In the present series, necrosis and cavitation were observed in 100 cases out of a total of 632 primary bronchial carcinomas seen at the London Chest Hospital from July 1967 to June 1970. There were 91 males and nine females with an average age of 58·45 years. All except one smoked very heavily and had considerable symptoms. The size of the cavities ranged from 1 to 10 cm and their wall thickness from 0·5 to 3 cm. They were single in 92 cases and multiple (up to four) in eight. In 42 cases, the cancerous cavitation was central, in 38 intermediate, and in 20 peripheral. The segments most frequently affected were the apicoposterior segment of the left upper lobe and the superior segment of the left lower lobe. For descriptive purposes, these cavitating carcinomas were also divided into six broad groups on the basis of radiological and pathological correlations. Neoplastic cells in the sputum were found in 64 cases. Bronchoscopy revealed growth in 42 cases and biopsy was positive in 48. The main microscopic feature was vascular invasion of medium-sized muscular arteries and veins found in the vicinity of every cavitating bronchial carcinoma. Invasion along with tumour plugging of the vessels was observed in 75 cases and thrombosis alone in 55 cases. There were 82 squamous-cell carcinomas, 11 undifferentiated carcinomas of large polygonal-cell type, and seven adeno-alveolar cell carcinomas. The single most important and noteworthy feature in the present series was that oat-cell carcinoma hardly ever undergoes necrosis. Out of a total of 95 cases observed, only three showed necrosis, and this was minimal and characteristically devoid of cavitation. In oat

  16. Maxillary sinus carcinoma

    SciTech Connect

    Lee, F.; Ogura, J.H.

    1981-01-01

    Primary site control, anatomical site of failure, survival, and complications of treatment were determined in a retrospective review of primary maxillary sinus carcinoma. Sixty-one patients were treated by radiation followed by surgery and 35 by radiation alone. Primary tumor control was achieved in 69% of patients receiving combined treatment, 14% of patients treated with radiation alone, and 49% of all patients. Local control did not differ with histological type. Virtually all epidermoid and undifferentiated carcinoma recurrences occurred within 2 years, but 27% of adenocarcinomas recurred after 2 years.

  17. Technology Helps Students Learn Grammar.

    ERIC Educational Resources Information Center

    Bowen, Candace Perkins

    1999-01-01

    Describes several recent approaches on college campuses that use technology (including both Web sites and CD-ROM virtual environments) to help journalism students learn grammar. Notes successes and problems. (SR)

  18. Going Local to Find Help

    MedlinePlus

    ... Home Current Issue Past Issues Cover Story: Traumatic Brain Injury Going Local to Find Help Past Issues / Fall ... the time. From the MedlinePlus page on Traumatic Brain Injury, you can use Go Local to find specific ...

  19. Upper urinary tract urothelial carcinoma with intratubular spread

    PubMed Central

    Sarungbam, Judy; Kurtis, Boaz; Phillips, John; Cai, Dongming; Zhang, David; Humayun, Islam; Yang, Ximing; Zhong, Minghao

    2014-01-01

    Upper urinary tract urothelial cell carcinomas (UUT-UCs) are uncommon and are defined as urothelial carcinoma involving the urinary tract from the renal calyces, renal pelvis to the distal ureter. One well-known an peculiar histopathological finding in UUT-UC is urothelial carcinoma with intratubular spread (retrograde spread within renal tubules). However, this special feature has not been systematically studied. We therefore collected a total of 53 consecutive cases of upper urinary tract urothelial carcinomas (UUT-UCs), and studied the clinical and pathological features of intratubular spread (IS). A cocktail stain comprised of antibodies PAX8 and p63 together with PAS was validated and employed to facilitate the study of intratubular spread. Seventeen cases (31.5%) showed intratubular spread demonstrated by either H&E stain and/or the cocktail stain. All of the 17 cases wit intratubular spread had tumor involvement of the renal calyx; the majority of these (14/17, 82.4%) were high grade urothelial carcinoma and the remainder (3/17, 17.6%) were low grade. 4 of 17cases (23.5%) were non-invasive. We classified intratubular spread into 4 different types, based on histopathological patterns: pagetoid, typical, florid, and secondary invasion from intratubular spread. In conclusion, study shows intratubular spread of urothelial carcinoma is fairly common phenomenon in UUT-UC and is associated with a variety of clinical-pathological features. High grade UUT-UC tends to have more extensive intratubular spread and secondary invasion into renal parenchyma. Distinct morphological characteristics as well as the staining pattern from a unique cocktail stain help to identify and evaluate intratubular spread of urothelial carcinoma. Recognizing these different types of intratubular spreading (IS) is crucial for accurate staging of some upper urinary tract urothelial carcinomas (UUT-UCs). PMID:25374911

  20. Racing to help: racial bias in high emergency helping situations.

    PubMed

    Kunstman, Jonathan W; Plant, E Ashby

    2008-12-01

    The present work explored the influence of emergency severity on racial bias in helping behavior. Three studies placed participants in staged emergencies and measured differences in the speed and quantity of help offered to Black and White victims. Consistent with predictions, as the level of emergency increased, the speed and quality of help White participants offered to Black victims relative to White victims decreased. In line with the authors' predictions based on an integration of aversive racism theory and the arousal: cost-reward perspective on prosocial behavior, severe emergencies with Black victims elicited high levels of aversion from White helpers, and these high levels of aversion were directly related to the slower help offered to Black victims but not to White victims (Study 1). In addition, the bias was related to White individuals' interpretation of the emergency as less severe and themselves as less responsible to help Black victims rather than White victims (Studies 2 and 3). Study 3 also illustrated that emergency racial bias is unique to White individuals' responses to Black victims and not evinced by Black helpers.

  1. Helping Teachers Help Themselves: Professional Development That Makes a Difference

    ERIC Educational Resources Information Center

    Patton, Kevin; Parker, Melissa; Tannehill, Deborah

    2015-01-01

    For school administrators to facilitate impactful teacher professional development, a shift in thinking that goes beyond the acquisition of new skills and knowledge to helping teachers rethink their practice is required. Based on review of the professional development literature and our own continued observations of professional development, this…

  2. Helping Schools Help Children. Research Report No. 2.

    ERIC Educational Resources Information Center

    National Inst. of Mental Health (DHEW), Bethesda, MD. Center for Studies of Crime and Delinquency.

    This pamphlet briefly reports on an experimental program designed to help the underachieving student whose academic and behavioral problems keep him in trouble with school officials. The project is based on the following premises: (1) children who learn basic academic skills and appropriate behaviors will be less vulnerable to future problems; (2)…

  3. [Merkel cell carcinoma (trabecular carcinoma) of the skin].

    PubMed

    Zala, L; Armagni, C; Krebs, A

    1983-04-01

    The Merkel cell carcinoma was first designated some years ago by the descriptive term trabecular carcinoma. Both names refer to a skin tumor occurring in elderly patients. This is another example where ultrastructural differentiating criteria are necessary for a definite diagnosis i.e., identification of so-called neurosecretory-like granules by electron microscopy. We report clinical, histological, ultrastructural, and histogenetic aspects of such a disease in a woman suffering from a metastasizing Merkel cell carcinoma. PMID:6853165

  4. Fallacious Carcinoma- Spindle Cell Variant of Squamous Cell Carcinoma.

    PubMed

    Bavle, Radhika M; Govinda, Girish; Venkataramanaiah, Padmalatha Gundappanayakanahalli; Muniswamappa, Sudhakara; Venugopal, Reshma

    2016-07-01

    Spindle cell carcinoma is a unique, rare and peculiar biphasic tumour of head and neck which is not frequently observed in the oral cavity. This variant of squamous cell carcinoma although of monophasic epithelial origin, simulates a sarcoma and is an aggressive carcinoma with high frequency of recurrence and metastasis. A correct and timely diagnosis is of paramount importance. Most of the tumours require an Immunohistochemistry (IHC) panel for confirmation or diagnosis. We report a case of spindle cell carcinoma with varied histopathological morphology and clinical presentation in a middle aged female with a brief review of literature. PMID:27630965

  5. Fallacious Carcinoma- Spindle Cell Variant of Squamous Cell Carcinoma

    PubMed Central

    Bavle, Radhika M; Govinda, Girish; Muniswamappa, Sudhakara; Venugopal, Reshma

    2016-01-01

    Spindle cell carcinoma is a unique, rare and peculiar biphasic tumour of head and neck which is not frequently observed in the oral cavity. This variant of squamous cell carcinoma although of monophasic epithelial origin, simulates a sarcoma and is an aggressive carcinoma with high frequency of recurrence and metastasis. A correct and timely diagnosis is of paramount importance. Most of the tumours require an Immunohistochemistry (IHC) panel for confirmation or diagnosis. We report a case of spindle cell carcinoma with varied histopathological morphology and clinical presentation in a middle aged female with a brief review of literature.

  6. Fallacious Carcinoma- Spindle Cell Variant of Squamous Cell Carcinoma

    PubMed Central

    Bavle, Radhika M; Govinda, Girish; Muniswamappa, Sudhakara; Venugopal, Reshma

    2016-01-01

    Spindle cell carcinoma is a unique, rare and peculiar biphasic tumour of head and neck which is not frequently observed in the oral cavity. This variant of squamous cell carcinoma although of monophasic epithelial origin, simulates a sarcoma and is an aggressive carcinoma with high frequency of recurrence and metastasis. A correct and timely diagnosis is of paramount importance. Most of the tumours require an Immunohistochemistry (IHC) panel for confirmation or diagnosis. We report a case of spindle cell carcinoma with varied histopathological morphology and clinical presentation in a middle aged female with a brief review of literature. PMID:27630965

  7. Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective.

    PubMed

    Lee, Anne W M; Ma, Brigette B Y; Ng, Wai Tong; Chan, Anthony T C

    2015-10-10

    Nasopharyngeal carcinoma of the undifferentiated subtype is endemic to southern China, and patient prognosis has improved significantly over the past three decades because of advances in disease management, diagnostic imaging, radiotherapy technology, and broader application of systemic therapy. Despite the excellent local control with modern radiotherapy, distant failure remains a key challenge. Advances in molecular technology have helped to decipher the molecular pathogenesis of nasopharyngeal carcinoma as well as its etiologic association with the Epstein-Barr virus. This in turn has led to the discovery of novel biomarkers and drug targets, rendering this cancer site a current focus for new drug development. This article reviews and appraises the key literature on the current management of nasopharyngeal carcinoma and future directions in clinical research.

  8. Motivational Maturity and Helping Behavior

    ERIC Educational Resources Information Center

    Haymes, Michael; Green, Logan

    1977-01-01

    Maturity in conative development (type of motivation included in Maslow's needs hierarchy) was found to be predictive of helping behavior in middle class white male college students. The effects of safety and esteem needs were compared, and the acceptance of responsibility was also investigated. (GDC)

  9. Help for Finding Missing Children.

    ERIC Educational Resources Information Center

    McCormick, Kathleen

    1984-01-01

    Efforts to locate missing children have expanded from a federal law allowing for entry of information into an F.B.I. computer system to companion bills before Congress for establishing a national missing child clearinghouse and a Justice Department center to help in conducting searches. Private organizations are also involved. (KS)

  10. Competitive helping in online giving.

    PubMed

    Raihani, Nichola J; Smith, Sarah

    2015-05-01

    Unconditional generosity in humans is a puzzle. One possibility is that individuals benefit from being seen as generous if there is competition for access to partners and if generosity is a costly-and therefore reliable-signal of partner quality [1-3]. The "competitive helping" hypothesis predicts that people will compete to be the most generous, particularly in the presence of attractive potential partners [1]. However, this key prediction has not been directly tested. Using data from online fundraising pages, we demonstrate competitive helping in the real world. Donations to fundraising pages are public and made sequentially. Donors can therefore respond to the behavior of previous donors, creating a potential generosity tournament. Our test of the competitive helping hypothesis focuses on the response to large, visible donations. We show that male donors show significantly stronger responses (by donating more) when they are donating to an attractive female fundraiser and responding to a large donation made by another male donor. The responses for this condition are around four times greater than when males give to less-attractive female (or male) fundraisers or when they respond to a large donation made by a female donor. Unlike males, females do not compete in donations when giving to attractive male fundraisers. These data suggest that males use competitive helping displays in the presence of attractive females and suggest a role for sexual selection in explaining unconditional generosity.

  11. Helping Schools Be More Sustainable

    ERIC Educational Resources Information Center

    Peters, Henricus

    2009-01-01

    How do children relate to and interact with their natural and built environments? What opportunities in science are schools and other groups offering children to help their environmental encounters to be a positive and healthy--even enjoyable--experience? These are questions raised by the concept of "environmental education"--the approach using…

  12. Helping Children with Reading Disability.

    ERIC Educational Resources Information Center

    Edgington, Ruth; And Others

    Intended for parents helping their children with reading disabilities, the book describes specific activities in eight areas. The eight areas include general suggestions for the study period, hand and eye coordination activities, phonics training, ear training, reading, relaxation activities, muscle memory, writing, and spelling. Thirteen…

  13. Grief: Helping Young Children Cope

    ERIC Educational Resources Information Center

    Wood, Frances B.

    2008-01-01

    In their role as caregivers supporting the children they teach, it is important for teachers to understand the grieving process and recognize symptoms of grief. The author explains Elisabeth Kubler-Ross's five stages of grief and offers 10 classroom strategies to help young children cope with their feelings.

  14. Enlisting Parents' Help with Mathematics.

    ERIC Educational Resources Information Center

    Kahn, Ann P.

    1989-01-01

    A new national PTA kit, "Math Matters; Kids Are Counting on You," can help all parents make a difference in their children's education. Suggested home activities include doubling cookie recipes, surveying and graphing family ice cream flavor preferences, filling in football "stat" charts, and other tasks easily performed on a calculator. (MLH)

  15. Helping Your Child to Read.

    ERIC Educational Resources Information Center

    Foust, Betty Jean

    This booklet provides suggestions for parents in helping their children to learn how to read. The first section provides 34 suggestions and activities for parents to use with preschool children, such as reciting nursery rhymes, reading aloud, respecting the child's mood, and playing listening games. The second section offers 25 suggestions and…

  16. Helping Young Children Overcome Shyness.

    ERIC Educational Resources Information Center

    Malouff, John

    This paper examines shyness--its causes and its impact on children--and presents several strategies based on social learning theory for parents and teachers to help young children overcome shyness. The paper also describes a personal application of these strategies on a young girl. The strategies presented for parents and teachers are: (1) tell…

  17. Getting the Help We Need

    ERIC Educational Resources Information Center

    Haertel, Edward

    2013-01-01

    In validating uses of testing, it is helpful to distinguish those that rely directly on the information provided by scores or score distributions ("direct" uses and consequences) versus those that instead capitalize on the motivational effects of testing, or use testing and test reporting to shape public opinion ("indirect" uses and consequences).…

  18. Helping Students Cope with Death.

    ERIC Educational Resources Information Center

    Rodabough, Tillman

    1980-01-01

    Classroom teachers need to understand the broad differences that exist between a child's perception of death and that of an adult and should be prepared to confront and cope with the effects of death and grief upon students. Children's perceptions of death and ways in which the teacher can help the child with his grief are described. (JN)

  19. Helping Students Design an Education

    ERIC Educational Resources Information Center

    Guertin, Elizabeth

    2015-01-01

    Most students embrace the incorporation of diverse disciplines into their educational plan when advisers and faculty members help them understand the added value of these courses in achieving their unique goals and how adding breadth can enhance their education and preparation. Individual advising is key to students gaining this perspective on…

  20. Will You Help Me Lead?

    ERIC Educational Resources Information Center

    Wade, Carolann; Ferriter, Bill

    2007-01-01

    Board certified teachers Wade and Ferriter each describe how established teacher leaders helped them break through hesitancy about accepting leadership roles early in their careers. Ferriter was interested in working on education advocacy and school reform, but found only traditional leadership roles like mentoring and running school committees in…

  1. Scholarship can help ideas flourish.

    PubMed

    Pearce, Lynne

    2016-03-01

    Scholarships from the Florence Nightingale Foundation are providing nurses with the financial means to put innovative ideas into practice. Nurses from all four countries of the UK can apply for leadership, travel and research scholarships to support their career development and help improve patient care. PMID:26959448

  2. Here's How You Can Help

    ERIC Educational Resources Information Center

    Afterschool Alliance, 2007

    2007-01-01

    This "Afterschool Action Kit" contains tips on what the community can do to support afterschool programs. The kit is a useful tool for parents, community members or practitioners, and gives advice on finding or starting a quality program, identifying program needs and what resources to tap for help. The kit notes that Americans agree that…

  3. Helping Children Cope with Disaster.

    ERIC Educational Resources Information Center

    Federal Emergency Management Agency, Washington, DC.

    Noting that the most assistance adults can provide to a child during a disaster is to be calm, honest, and caring, this brochure provides suggestions for helping children cope with natural and other disasters. The brochure details how children's typical reactions vary with their age, describes how families can prepare for disasters, and suggests…

  4. Technology to Help Struggling Students

    ERIC Educational Resources Information Center

    Silver-Pacuilla, Heidi; Fleischman, Steve

    2006-01-01

    Many technology features that were originally developed to help people with specific sensory impairments are now widely in use. Research is beginning to show the benefits of giving all students access to these capabilities. As such, educators should not hesitate to integrate technology features into instruction for students who struggle with…

  5. Some Ways of Helping Underachievers.

    ERIC Educational Resources Information Center

    Willings, David; Greenwood, Bill

    1990-01-01

    A program of intervention called therapeutic tutoring to help underachievers is described. Intervention centers around students' loci of control, through a process of identifying areas in which students feel empowered and relating academic experiences to these areas. Academic exercises based on Monopoly, cricket, rugby, soap operas, field hockey,…

  6. HELP: Healthy Early Literacy Program

    ERIC Educational Resources Information Center

    Rader, Laura A.

    2008-01-01

    A daily intensive supplemental reading and writing program was developed to assist students who were: 1. identified with a language disability and 2. identified as at-risk for reading failure in an urban elementary school. The purpose of the program was to help these students understand and develop the connection between oral and written language…

  7. Helping SBH Pupils with Handwriting.

    ERIC Educational Resources Information Center

    Anderson, Elizabeth

    1979-01-01

    The article describes two cases of children (7- and 8 1/2-years-old) with spina bifida and hydrocephalus who participated in a research project to discover whether such children could make significant improvements in writing given appropriate help, and to produce an advisory booklet for teachers. (SBH)

  8. Ah!Help: A generalized on-line help facility

    NASA Technical Reports Server (NTRS)

    Yu, Wong Nai; Mantooth, Charmiane; Soulahakil, Alex

    1986-01-01

    The idea behind the help facility discussed is relatively simple. It is made unique by the fact that it is written in Ada and uses aspects of the language which make information retrieval rapid and simple. Specifically, the DIRECT IO facility allows for random access into the help files. It is necessary to discuss the advantages of random access over sequential access. The mere fact that the program in written in Ada implies a saving in terms of lines of code. This introduces the possibility of eventually adapting the program to run at the microcomputer level, a major consideration . Additionally, since the program uses only standard Ada generics, it is portable to other systems. This is another aspect which must always be taken into consideration in writting any software package in the modern day world of computer programming.

  9. FPIA helps expand contraceptive services.

    PubMed

    Groot, H

    1984-01-01

    Since the beginning in 1971 of the Planned Parenthood Federation of America's international program, Family Planning International Assistance (FPIA), US$54 million has been contributed in direct financial support for the operation of over 300 family planning programs in 51 countries; over 3000 institutions in 115 countries have been supplied with family planning commodities, including over 600 million condoms, 120 cycles of oral contraceptives, and 4 million IUD; and about 1 million contraceptive clients were served by FPIA funded projects in 1982 aone. Since 1971, however, the world's population has increased from 3.7 billion to around 4.7 billion people. About 85 million people are added to the world each year. There is consensus that without organized family planning programs, today's world population would be even higher. FPIA measures its progress in terms of expanding the availability of contraceptive services in devloping countries. FPIA supported projects have helped make services available in areas previously lacking them, and has helped involve a wide variety of organizations, such as women's groups, youth organizations, and Red Cross Societies, in family planning services. A prime concern of FPIA, which has limited resources, is what happens to projects once FPIA support is terminated. FPIA has been paying attention to local income generation to help projects become more self-supporting and to increas staff members' management skills. The more successful income-generating schemes appear to be directly related to family planning, selling contraceptives and locally produced educational materials, and charging fees for family planning and related medical services and tuition for training courses. FPIA funded to projects use management by objectives (MBO) to help improve management skills. MBO helps grantees improve their ability to set objectives, plan, monitor, report, and do day-to-day project management.

  10. Independent bilateral primary bronchial carcinomas

    PubMed Central

    Chaudhuri, M. Ray

    1971-01-01

    Independent bilateral primary bronchial carcinomas are not common. Since Beyreuther's description in 1924, 16 well-documented cases of independent primary bronchial carcinomas of different histology have been described. From 1965 to 1970, eight cases were seen at the London Chest Hospital. In order to make the diagnosis of a second primary bronchial carcinoma, each tumour should be malignant and neither should be a metastasis from the other. To meet this last criterion, the histopathological features of the two tumours must be different. Many cases have been described in the literature as double primary bronchial carcinomas where the second primary had the same histological features as the first. Images PMID:4327711

  11. Primary biliary carcinoma: CT evaluation

    SciTech Connect

    Thorsen, M.K.; Quiroz, F.; Lawson, T.L.; Smith, D.F.; Foley, W.D.; Steward, E.T.

    1984-08-01

    Fifty-three patients with documented primary biliary carcinoma were studied with computed tomography. Twenty-six patients had gallbladder carcinoma and 27 patients had carcinoma of the biliary ductal system. Ninety percent of patients with gallbladder cancer had an intraluminal mass. Local invasion into the liver was common. The majority of patients with biliary ductal carcinoma had dilated bile ducts, while only 50% of patients with gallbladder cancer had biliary ductal dilatation. The most common location of tumor involving the extrahepatic biliary ductal system was the distal common bile duct. This occurred in eight patients out of 27, or 30% of the cases.

  12. Merkel cell carcinoma

    PubMed Central

    Koljonen, Virve

    2006-01-01

    Background Merkel cell carcinoma (MCC) is an unusual primary neuroendocrine carcinoma of the skin. MCC is a fatal disease, and patients have a poor chance of survival. Moreover, MCC lacks distinguishing clinical features, and thus by the time the diagnosis is made, the tumour usually have metastasized. MCC mainly affects sun-exposed areas of elderly persons. Half of the tumours are located in the head and neck region. Methods MCC was first described in 1972. Since then, most of the cases reported, have been in small series of patients. Most of the reports concern single cases or epidemiological studies. The present study reviews the world literature on MCC. The purpose of this article is to shed light on this unknown neuroendocrine carcinoma and provide the latest information on prognostic markers and treatment options. Results The epidemiological studies have revealed that large tumour size, male sex, truncal site, nodal/distant disease at presentation, and duration of disease before presentation, are poor prognostic factors. The recommended initial treatment is extensive local excision. Adjuvant radiation therapy has recently been shown to improve survival. Thus far, no chemotherapy protocol have achieved the same objective. Conclusion Although rare, the fatality of this malignancy makes is important to understand the etiology and pathophysiology. During the last few years, the research on MCC has produced prognostic markers, which can be translated into clinical patient care. PMID:16466578

  13. Primary duodenal carcinoma.

    PubMed Central

    Adedeji, O. A.; Trescoli-Serrano, C.; Garcia-Zarco, M.

    1995-01-01

    Eight cases of primary duodenal carcinoma in a district general hospital are presented. The cases highlight the advanced state of the disease at presentation, the difficulty in diagnosis, and its poor prognosis. Duodenal carcinoma occurs in both sexes worldwide with no predisposing factors in the majority of cases. There is an increased risk in patients with familial adenomatous polyposis and adenomas of the duodenum. Duodenal carcinoma occurs about 22 years from the diagnosis of familial adenomatous polyposis in about 2% of patients, forming over 50% of upper gastrointestinal cancers occurring in these patients. Carcinomatous changes occur in 30 to 60% of duodenal villous adenomas and much less in tubulo-villous and tubular adenomas. These categories of patients should be screened and adequately followed up. Aggressive and radical surgery, even in the presence of locally advanced disease and lymph node involvement, gives a better outcome. When curative surgery is not possible, chemotherapy must accompany palliation with or without radiotherapy. Pre-operative chemotherapy may facilitate a curative radical resection. The general five-year survival is 17-33% but some centres have achieved a five-year survival of 40-60% with aggressive management of these patients. PMID:7644397

  14. Help for health decision challenges.

    PubMed

    Doty, L

    1997-01-01

    Medical care is becoming more technically challenging and community-based. The majority of patients and family health gatekeepers (the family member who regulates health care services for the family unit) are female, while the majority of physicians are male. Therefore, differences in female versus male methods of decision making add to the difficulty in making health choices. The female patient and family health gatekeeper may need new knowledge, skills and time to help them deal with difficult medical choices. They may benefit from a multidisciplinary, unbiased group of experts in the form of a Community Healthcare Committee. Trained to be responsible for the general health of the community, the primary care practitioner is ideal to take a leadership role in developing such a committee. A Community Healthcare Committee that understands different methods of health decision making could serve as a resource by providing community health education and private case reviews intended to help individuals with health care decisions. PMID:9379165

  15. New Help for the Handicapped

    NASA Technical Reports Server (NTRS)

    1984-01-01

    L & M Electronics, Inc.'s telemetry system is used to measure degree and location of abnormal muscle activity. This telemetry was originally used to monitor astronauts vital functions. Leg sensors send wireless signals to computer which develops pictures of gait patterns. System records, measures and analyzes muscle activities in limbs and spine. Computer developed pictures of gait patterns help physicians determine potential of corrective surgery, evaluate various types of braces, or decide whether physical therapy may improve motor functions.

  16. Why humans might help strangers

    PubMed Central

    Raihani, Nichola J.; Bshary, Redouan

    2015-01-01

    Humans regularly help strangers, even when interactions are apparently unobserved and unlikely to be repeated. Such situations have been simulated in the laboratory using anonymous one-shot games (e.g., prisoner’s dilemma) where the payoff matrices used make helping biologically altruistic. As in real-life, participants often cooperate in the lab in these one-shot games with non-relatives, despite that fact that helping is under negative selection under these circumstances. Two broad explanations for such behavior prevail. The “big mistake” or “mismatch” theorists argue that behavior is constrained by psychological mechanisms that evolved predominantly in the context of repeated interactions with known individuals. In contrast, the cultural group selection theorists posit that humans have been selected to cooperate in anonymous one-shot interactions due to strong between-group competition, which creates interdependence among in-group members. We present these two hypotheses before discussing alternative routes by which humans could increase their direct fitness by cooperating with strangers under natural conditions. In doing so, we explain why the standard lab games do not capture real-life in various important aspects. First, asymmetries in the cost of perceptual errors regarding the context of the interaction (one-shot vs. repeated; anonymous vs. public) might have selected for strategies that minimize the chance of making costly behavioral errors. Second, helping strangers might be a successful strategy for identifying other cooperative individuals in the population, where partner choice can turn strangers into interaction partners. Third, in contrast to the assumptions of the prisoner’s dilemma model, it is possible that benefits of cooperation follow a non-linear function of investment. Non-linear benefits result in negative frequency dependence even in one-shot games. Finally, in many real-world situations individuals are able to parcel

  17. Motivational maturity and helping behavior.

    PubMed

    Haymes, M; Green, L

    1977-12-01

    This study was undertaken to examine the independent influences of conative development (the Maslow needs hierarchy) upon behavioral aspects of prosocial orientations. It provides a behavioral demonstration of conative effects in a helping paradigm, among college-age men. A comparison of the conative data across the ages of 15-22 provided a cross-sectional view of conative development itself. Conative maturity was found to be predictive of greater helping among college-age men. Situational demands were demonstrated which tended to mask, but not override, these predispositional influences on helping. The cross-sectional data on conative development point to probable movement to early esteem concerns among high school men who have reached the conative level of love and belonging. On the other hand, the stability across the years of 15-22 of proportion of safety concerns suggests fixation of such concerns in those exhibiting them in high school. Results are discussed in terms of conative growth for development of prosocial orientations.

  18. Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component.

    PubMed

    Yasui, Mariko; Morikawa, Teppei; Nakagawa, Tohru; Miyakawa, Jimpei; Maeda, Daichi; Homma, Yukio; Fukayama, Masashi

    2016-09-01

    Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary.

  19. Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component.

    PubMed

    Yasui, Mariko; Morikawa, Teppei; Nakagawa, Tohru; Miyakawa, Jimpei; Maeda, Daichi; Homma, Yukio; Fukayama, Masashi

    2016-09-01

    Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary. PMID:27461832

  20. Macrofollicular variant of papillary thyroid carcinoma with extensive lymph node metastases.

    PubMed

    Yeo, Min-kyung; Bae, Ja Seong; Oh, Woo Jin; Park, Gyeong Sin; Jung, Chan Kwon

    2014-09-01

    The macrofollicular variant of papillary thyroid carcinoma is a rare subtype of the follicular variant of papillary thyroid carcinoma and is usually characterized by an indolent clinical course. The tumors are prone to be misdiagnosed as benign due to their macrofollicular architecture and bland cytologic features. We report a rare case of the macrofollicular variant of papillary thyroid carcinoma with extensive lymph node metastases. The patient was a 48-year-old female with a right thyroid nodule and multiple enlarged lymph nodes in the right neck. It was not possible to make a definitive diagnosis of malignancy on fine-needle aspiration cytology and intraoperative frozen section. She underwent total thyroidectomy with right modified radical neck dissection. The surgical specimen showed a 2.5 × 1.5 × 10 cm, well-circumscribed macrofollicular variant of papillary thyroid carcinoma in the right lobe and multiple central and right lateral neck lymph node metastases. Molecular testing for BRAF, NRAS, HRAS, and KRAS was all negative. We then reviewed the demographic and clinicopathologic characteristics of 71 patients with the macrofollicular variant of papillary thyroid carcinoma. The cytologic or histopathologic diagnosis of macrofollicular variant of papillary thyroid carcinoma can be difficult. Extensive lymph node metastases caused by the macrofollicular variant of papillary thyroid carcinoma may occur even in the absence of capsular or lymphovascular invasion. This review will help to better understand the nature of the macrofollicular variant of papillary thyroid carcinoma.

  1. Pattern of oestrogen, progesterone and Her2neu receptors expression in a heterogeneous carcinoma of the breast in a lactating woman.

    PubMed

    Naim, Mohammed; Kumar, Amit; Gaur, Kavita; John, Vanesa T

    2010-11-23

    Oestrogen-progestrone-Her2neu receptor status was studied in various loci/foci of heterogeneous carcinoma of the breast and its metastatic secretory component in the lymph node in a lactating woman. All the carcinoma variants were negative for the trio markers except tumour components evolved to secretory or lactating carcinoma, which showed focal positivity. Findings showed that oestrogenic receptors, progesterone receptors and Her2neu negative primitive carcinoma in a heterogenous breast cancer may evolve into oestrogen receptor, progesterone receptor and Her2neu positive secretory/lactating carcinoma alongside other receptor negative carcinoma variants. Focal marker positivity/negativity underlined the fact that a diagnostic/prognostic marker status report may account for the tumour area included in the section/sample only. Study of the immune marker expression/status in various loci may help identification of the components, morphogenesis and dynamics of heterogeneous carcinoma of the breast.

  2. Lobomycosis and squamous cell carcinoma*

    PubMed Central

    Nogueira, Lisiane; Rodrigues, Luciana; Rodrigues, Carlos Alberto Chirano; Santos, Mônica; Talhari, Sinésio; Talhari, Carolina

    2013-01-01

    The occurence of squamous cell carcinoma on long-lasting ulcers is classic. Malignant transformation may occur on burn scars and chronic ulcers of varying etiology, including infectious agents. Transformation of old lobomycosis lesion scars into squamous cell carcinoma has been rarely reported. Careful and long-term follow-up of such patients is important to avoid carcinomatous transformation. PMID:23739701

  3. Experienced help for the environment

    SciTech Connect

    Benjamin, T.

    1995-08-01

    How can communities draw on the life experience and professional skills of one of their most precious and underutilized natural resources to help solve environmental problems at the local level? Get senior citizens involved. Founded in January 1992 by a partnership of environmental, government, and senior volunteer organizations, the Environmental Alliance for Senior Involvement (EASI) identifies ways to foster senior involvement in environmental issues. The members of EASI have developed an extensive network of environmental, senior volunteer projects across the country. These projects include everything from recycling to monitoring Superfund sites.

  4. Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

    PubMed Central

    Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

    2016-01-01

    The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID:27125498

  5. USP16 Downregulation by Carboxyl-terminal Truncated HBx Promotes the Growth of Hepatocellular Carcinoma Cells.

    PubMed

    Qian, Yu; Wang, Boshi; Ma, Aihui; Zhang, Li; Xu, Guiqin; Ding, Qi; Jing, Tiantian; Wu, Lin; Liu, Yun; Yang, Zhaojuan; Liu, Yongzhong

    2016-01-01

    Hepatitis B virus (HBV) infection is a major factor that contributes to the development of hepatocellular carcinoma (HCC). HBV X protein (HBx) has been shown to accelerate HCC progression by promoting tumour growth and metastasis. In the clinic, carboxyl-terminal truncated HBx (Ct-HBx) proteins are frequently present in HCC tumour tissues, but not in non-tumorous tissues. In this study, we analysed deubiquitinase expression profiles in cells with or without ectopic expression of the Ct-HBx proteins and observed that the expression of ubiquitin specific peptidase 16 (USP16) was substantially inhibited by Ct-HBx proteins. Liver tumour cells with forced down-regulation of USP16 exhibited increased capabilities for colony formation and tumour growth in vivo. In addition, USP16 inhibition promoted stem-like properties in tumour cells, as evidenced by their spheroid formation and chemo-responsiveness. Furthermore, ectopic expression of USP16 in tumour cells significantly abrogated the tumour promoting activities of the Ct-HBx proteins (HBxΔ35), leading to decreased tumour cell viability and tumour growth. In human HCCs, USP16 was frequently downregulated, and the decreased expression of USP16 was correlated with high tumour stages and poor differentiation status. Taken together, our study suggests that USP16 downregulation is a critical event in Ct-HBx-mediated promotion of HCC tumorigenicity and malignancy. PMID:27633997

  6. USP16 Downregulation by Carboxyl-terminal Truncated HBx Promotes the Growth of Hepatocellular Carcinoma Cells

    PubMed Central

    Qian, Yu; Wang, Boshi; Ma, Aihui; Zhang, Li; Xu, Guiqin; Ding, Qi; Jing, Tiantian; Wu, Lin; Liu, Yun; Yang, Zhaojuan; Liu, Yongzhong

    2016-01-01

    Hepatitis B virus (HBV) infection is a major factor that contributes to the development of hepatocellular carcinoma (HCC). HBV X protein (HBx) has been shown to accelerate HCC progression by promoting tumour growth and metastasis. In the clinic, carboxyl-terminal truncated HBx (Ct-HBx) proteins are frequently present in HCC tumour tissues, but not in non-tumorous tissues. In this study, we analysed deubiquitinase expression profiles in cells with or without ectopic expression of the Ct-HBx proteins and observed that the expression of ubiquitin specific peptidase 16 (USP16) was substantially inhibited by Ct-HBx proteins. Liver tumour cells with forced down-regulation of USP16 exhibited increased capabilities for colony formation and tumour growth in vivo. In addition, USP16 inhibition promoted stem-like properties in tumour cells, as evidenced by their spheroid formation and chemo-responsiveness. Furthermore, ectopic expression of USP16 in tumour cells significantly abrogated the tumour promoting activities of the Ct-HBx proteins (HBxΔ35), leading to decreased tumour cell viability and tumour growth. In human HCCs, USP16 was frequently downregulated, and the decreased expression of USP16 was correlated with high tumour stages and poor differentiation status. Taken together, our study suggests that USP16 downregulation is a critical event in Ct-HBx-mediated promotion of HCC tumorigenicity and malignancy. PMID:27633997

  7. Basal cell carcinoma

    PubMed Central

    2010-01-01

    Introduction Basal cell carcinoma (BCC) is the most common form of skin cancer, predominantly affecting the head and neck, and can be diagnosed clinically in most cases. Metastasis of BCC is rare, but localised tissue invasion and destruction can lead to morbidity. Incidence of BCC increases markedly after the age of 40 years, but incidence in younger people is rising, possibly as a result of increased sun exposure. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions on treatment response/recurrence (within 1 year of therapy) in people with basal cell carcinoma? What are the effects of interventions on long-term recurrence (a minimum of 2 years after treatment) in people with basal cell carcinoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: cryotherapy/cryosurgery, curettage and cautery/electrodesiccation, fluorouracil, imiquimod 5% cream, photodynamic therapy, and surgery (conventional or Mohs' micrographic surgery). PMID:21718567

  8. Helping parents with sex education.

    PubMed

    Wakley, Gill

    2011-01-01

    Health visitors, school nurses and other community nurses are sometimes asked for advice by parents and carers on the emerging sexuality of their children. Parents often lack knowledge about sexual development and are confused about whether to talk to their children about sex. They may have been brought up in a family where sex was not mentioned. They are worried that they do not have the skills or the knowledge to help their children. They do not know whether to leave it all to the school or not allow their children to have any information. All the evidence shows that children who have had their questions answered and who know about sex and relationships start sexual activity later, use contraception more reliably and are less likely to cause or have an unwanted pregnancy. Sex education should be part of the ordinary information and moral guidance that parents normally give and should start as early as possible. The type of advice to give to parents and carers is split into age ranges that they might find helpful. Examples of language and the level of information required are given. A list of resources for further guidance is included.

  9. Perianal Basal Cell Carcinoma

    PubMed Central

    Bulur, Isil; Boyuk, Emine; Saracoglu, Zeynep Nurhan; Arik, Deniz

    2015-01-01

    Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer. Exposure to ultraviolet light is an important risk factor for BCC development and the disorder therefore develops commonly on body areas that are more exposed to sunlight, such as the face and neck. It is uncommon in the closed area of the body and quite rare in the perianal and genital regions. Herein, we report a 34-year-old patient with perianal BCC who had no additional risk factors. PMID:25848349

  10. Carcinoma Adenomatodes Cervicis Uteri

    PubMed Central

    Spencer, Herbert R.

    1926-01-01

    The case is one of carcinoma adenomatodes (adenoma malignum) cervicis uteri, which occurred in a patient, aged 49. Vaginal hysterectomy was performed with the Pacquelin cautery, and the patient remains well after 22 years. Attention is drawn to the rarity of the disease, and the point is emphasized that in true cases of the disease the glandular epithelium is nowhere proliferated, and therefore reliance on microscopic examination alone for the diagnosis may lead to serious error. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:19985105

  11. Do Dogs Provide Information Helpfully?

    PubMed

    Piotti, Patrizia; Kaminski, Juliane

    2016-01-01

    Dogs are particularly skilful during communicative interactions with humans. Dogs' abilities to use human communicative cues in cooperative contexts outcompete those of other species, and might be the result of selection pressures during domestication. Dogs also produce signals to direct the attention of humans towards outside entities, a behaviour often referred to as showing behaviour. This showing behaviour in dogs is thought to be something dogs use intentionally and referentially. However, there is currently no evidence that dogs communicate helpfully, i.e. to inform an ignorant human about a target that is of interest to the human but not to the dog. Communicating with a helpful motive is particularly interesting because it might suggest that dogs understand the human's goals and need for information. In study 1, we assessed whether dogs would abandon an object that they find interesting in favour of an object useful for their human partner, a random novel distractor, or an empty container. Results showed that it was mainly self-interest that was driving the dogs' behaviour. The dogs mainly directed their behaviour towards the object they had an interest in, but dogs were more persistent when showing the object relevant to the human, suggesting that to some extent they took the humans interest into account. Another possibility is that dogs' behaviour was driven by an egocentric motivation to interact with novel targets and that the dogs' neophila might have masked their helpful tendencies. Therefore, in study 2 the dogs had initial access to both objects, and were expected to indicate only one (relevant or distractor). The human partner interacted with the dog using vocal communication in half of the trials, and remaining silent in the other half. Dogs from both experimental groups, i.e. indicating the relevant object or indicating the distractor, established joint attention with the human. However, the human's vocal communication and the presence of the

  12. Do Dogs Provide Information Helpfully?

    PubMed Central

    Piotti, Patrizia; Kaminski, Juliane

    2016-01-01

    Dogs are particularly skilful during communicative interactions with humans. Dogs’ abilities to use human communicative cues in cooperative contexts outcompete those of other species, and might be the result of selection pressures during domestication. Dogs also produce signals to direct the attention of humans towards outside entities, a behaviour often referred to as showing behaviour. This showing behaviour in dogs is thought to be something dogs use intentionally and referentially. However, there is currently no evidence that dogs communicate helpfully, i.e. to inform an ignorant human about a target that is of interest to the human but not to the dog. Communicating with a helpful motive is particularly interesting because it might suggest that dogs understand the human’s goals and need for information. In study 1, we assessed whether dogs would abandon an object that they find interesting in favour of an object useful for their human partner, a random novel distractor, or an empty container. Results showed that it was mainly self-interest that was driving the dogs’ behaviour. The dogs mainly directed their behaviour towards the object they had an interest in, but dogs were more persistent when showing the object relevant to the human, suggesting that to some extent they took the humans interest into account. Another possibility is that dogs’ behaviour was driven by an egocentric motivation to interact with novel targets and that the dogs’ neophila might have masked their helpful tendencies. Therefore, in study 2 the dogs had initial access to both objects, and were expected to indicate only one (relevant or distractor). The human partner interacted with the dog using vocal communication in half of the trials, and remaining silent in the other half. Dogs from both experimental groups, i.e. indicating the relevant object or indicating the distractor, established joint attention with the human. However, the human’s vocal communication and the presence

  13. Music Therapy Helps Preemie Babies Thrive

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_160627.html Music Therapy Helps Preemie Babies Thrive Mom's singing helps ... of over a dozen clinical trials, found that music therapy helped stabilize premature newborns' breathing rate during ...

  14. Prenatal Surgery: Helping Babies Before Birth

    MedlinePlus

    ... About Zika & Pregnancy Prenatal Surgery: Helping Babies Before Birth KidsHealth > For Parents > Prenatal Surgery: Helping Babies Before ... A Text Size Prenatal Surgery: Helping Babies Before Birth Operating on a baby before birth may seem ...

  15. Immunotherapy of pancreatic carcinoma.

    PubMed

    Märten, Angela

    2008-05-01

    Patients with carcinoma of the exocrine pancreas have especially poor prognosis with a five-year survival rate of <1% and a median survival of 4-6 months. Pancreatic carcinoma is a systemic disease, insensitive to radiotherapy and mostly to chemotherapy. Accordingly, new treatment modalities are worth being investigated. One of the promising approaches is immunotherapy. Several phase I/II trials that have been published show interesting results, whereupon antibody-based strategies seem to fail and unspecific stimulation or vaccination with peptides look encouraging. Furthermore, phase II trials dealing with combination therapies are highly promising. One of them, a combination of chemoradiotherapy plus interferon-alpha is currently tested in a randomized phase III trial. As most of the trials had enrolled only limited numbers of patients and most of the trials were not conducted and/or reported according to the new standards it is difficult to draw final conclusions from the discussed trials. Immuno-monitoring was performed only in 40% of the discussed publications. In all cases immune responses were observed and correlation with the clinical outcome is discussed. Immunotherapy of pancreatic adenocarcinoma and especially combination therapies including immunotherapy is an up-and-coming approach and needs to be investigated in well conducted phase III randomized controlled trials accompanied by appropriate immuno-monitoring.

  16. Clear cell odontogenic carcinoma.

    PubMed

    Iezzi, G; Rubini, C; Fioroni, M; Piattelli, A

    2002-02-01

    Clear cell tumours, in the head and neck region, are usually derived from salivary or odontogenic tissues, or may be metastatic. A few clear cells may be present in odontogenic cysts, while, odontogenic neoplasms composed predominantly of clear cells are quite rare. They include calcifying epithelial odontogenic tumours (CEOT), ameloblastoma and odontogenic carcinoma. Clear cell odontogenic tumour (CCOT) has been classified in the last WHO classification as a benign tumour, but it is now recognized as a more sinister lesion and current opinion is that CCOT should be designated as a carcinoma. These tumours are characterized by aggressive growth, recurrences, and metastatic disease. A recent review of the literature has yielded 30 cases of tumours with similar characteristics. These tumours have a peak incidence in the 5th-7th decades, with a female predilection. The anterior portions of the jaws, especially the mandible, are most frequently affected. The aggressive potential of these neoplasms is well documented by the extensive invasion of adjacent tissues, multiple recurrences and regional or distant metastases.

  17. Carcinoma of endocrine organs: results of the RARECARE project.

    PubMed

    van der Zwan, Jan Maarten; Mallone, Sandra; van Dijk, Boukje; Bielska-Lasota, Magdalena; Otter, Renée; Foschi, Roberto; Baudin, Eric; Links, Thera P

    2012-09-01

    The rarity or the asymptomatic character of endocrine tumours results in a lack of epidemiological studies on their incidence and survival patterns. The aim of this study was to describe the incidence, prevalence and survival of endocrine tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002, registered in 89 population-based cancer registries (CRs) with follow-up until 31st December 2003. These data give an unique overview of the burden of endocrine carcinomas in Europe. A list of tumour entities based on the third International Classification of Diseases for Oncology was provided by the project Surveillance of rare cancer in Europe (RARECARE) project. Over 33,594 cases of endocrine carcinomas were analysed in this study. Incidence rates increased with age and were highest in patients 65 years of age or older. In 2003, more than 315,000 persons in the EU (27 countries) were alive with a past diagnosis of a carcinoma of endocrine organs. The incidence of pituitary carcinoma equalled four per 1,000,000 person years and showed the strongest decline in survival with increasing age. Thyroid cancer showed the highest crude incidence rates (four per 100,000 person years) and was the only entity with a gender difference: (female-to-male ratio: 2:9). Parathyroid carcinoma was the rarest endocrine entity with two new cases per 10,000,000 person years. For adrenal carcinoma, the most remarkable observations were a higher survival for women compared to men (40% compared to 32%, respectively) and a particularly low relative survival of 24% in patients 65 years of age or older. More high quality studies on rare cancers, with additional information, e.g. on stage and therapeutic approach, are needed and may be of help in partly explaining the observed variation in survival.

  18. Etiopathogenesis of Differentiated Thyroid Carcinomas

    PubMed Central

    Makazlieva, Tanja; Vaskova, Olivija; Majstorov, Venjamin

    2016-01-01

    INTRODUCTION: Thyroid malignomas are a heterogeneous group of neoplasm consisting of most frequent differentiated encountered carcinomas, papillary and follicular thyroid carcinoma, then medullary thyroid carcinoma originating from neuroendocrine calcitonin-producing C-cells and rare forms of thyroid lymphomas arising from intrathyroidal lymphatic tissue, thyroid sarcomas and poorly differentiated anaplastic thyroid carcinoma. There are increasing numbers of epidemiological studies and publications that have suggested increased incidence rate of thyroid carcinomas. We have read, analysed and compare available reviews and original articles investigating different etiological factors in the development of thyroid carcinomas through Google Scholar and PubMed Database. DISCUSSION: Aetiology involved in the development of thyroid carcinomas is multifactorial and includes external influences, as well as constitutional predispositions and genetic etiological factors. The actual effect of environmental and constitutional factors is on promoting genetic and epigenetic alterations which result in cell proliferation and oncogenesis. Until now are identified numerous genetic alterations, assumed to have an important role in oncogenesis, with MAPK and PI3K-AKT as crucial signalling networks regulating growth, proliferation, differentiation and cell survival/apoptosis. CONCLUSION: This new molecular insight could have a crucial impact on diagnosis and also on improving and selecting an appropriate treatment to the patients with thyroid malignancies. PMID:27703585

  19. [DNA methylation in thyroid carcinoma].

    PubMed

    Song, Xianyun; Shang, Xiaoling; Zhang, Yutuo

    2015-03-01

    Cancer has become clear that not merely gene variations but also epigenetic modifications may contribute to it. Epigenetic changes refer to stable alterations in gene expression with unrelated to changes in the underlying genetic sequence,resulting in heritable. DNA methylation is one of the common epigenetic changes. It control the gene expression through changing DNA conformation and stability, chromatin structer, DNA-protein interaction. The reversal of dysregulated DNA methylation has emerged as a potential strategy for the treatment of thyroid carcinoma. The artical will provide an overview of how DNA methylation contribute to thyroid carcinoma dissemination,invasion and metastasis and we will summarize the latest epigenetic therapies for thyroid carcinoma.

  20. Correlative imaging in gallbladder carcinoma.

    PubMed

    Willekens, I; Goethals, L R; Brussaard, C; Verdries, D; de Mey, J

    2014-01-01

    Gallbladder carcinoma is a relatively rare malignant epithelial neoplasm, arising from gallbladder mucosa. It is the fifth most common gastrointestinal malignancy and the most common biliary tract cancer. Early diagnosis remains difficult, because clinical symptoms are sparse and non-specific, often resulting in advanced stage disease at the time of diagnosis. The most common feature of gallbladder carcinoma on different imaging modalities is focal wall thickening, associated with a large eccentric tumor mass. In this case we report the imaging characteristics of gallbladder carcinoma on ultrasound, MDCT and 18F-FDG PET/CT.

  1. Myoepithelial carcinoma with contralateral invasive micropapillary carcinoma of the breast.

    PubMed

    Kwon, Sun Young; Bae, Young Kyung; Cho, Jihyong; Kang, Sun Hee

    2011-09-01

    Adenomyoepithelioma (AME) is a rare benign tumor composed of myoepithelial cells (MECs) which are located beneath the epithelial cells of exocrine glands, especially in breast and salivary glands. These tumor cells show biphasic proliferation of epithelial and MECs. Malignant AME is characterized by distant metastasis, local recurrence, cytologic atypia, high mitotic activity and infiltrating tumor margins. A 51-year-old woman presented with an 8 months growth in the left breast. She underwent core-needle biopsy and consecutively mammotome assisted biopsy at a local clinic. After resection, she complained about re-growing remnant lesion and a newly developed solid mass in the right breast. Finally, the remnant mass in the left breast was diagnosed with myoepithelial carcinoma. Concurrently, contralateral breast mass was diagnosed with invasive micropapillary carcinoma. Herein we report an unusual case of synchronous myoepithelial carcinoma and invasive micropapillary carcinoma of the breast with a review of literatures.

  2. Botswana's self-help community.

    PubMed

    Endrst, J

    1979-09-01

    Gaborone, the new capital of Botswana, has grown rapidly from 600 inhabitants in 1966 to 30,000 currently. People squatted in what was to have been a temporary labor camp zoned for industrial development. The Naledi camp was illegal until 1975 when the government dropped its zoning category and, with aid from the Canadian International Development Agency, began laying plans for turning 116 hectares of squatter land into 2000 individual plots housing 10,000 people. Naledi is now a suburban housing development that combines modern toilet facilities, street lighting, 2 primary schools, a health clinic, and a community center with traditional Tswana culture. A Certificate of Rights must be obtained for a plot of ground. The owner must construct a house within 12 months and pay a levy for road maintenance, water supply, and trash pickup. The Self-Help Housing Agency provides loans for building materials, payable in 15 years. The first thing a Naledi house-owner does is have it blessed by a minister of 1 of some 40 African churches in the settlement. The community is in the formative stages of organization. There is no single headman and no police. Elders are sometimes called upon to settle disputes. Naledi residents often view their plot as their second home. Many have their primary dwellings, and their head of cattle, in their native villages, living in Gabarone solely for economic reasons.

  3. Helping Dementia Caregivers Through Technology.

    PubMed

    Fowler, Christianne Nesbitt; Haney, Tina; Lemaster, Margaret

    2016-04-01

    It is estimated there are between 43.5 and 65.7 million caregivers in the United States who provide unpaid care for older adults. Although the number of informal caregivers is expected to continue to increase, few programs have been established in home healthcare agencies to support these caregivers. This article describes a project that used a unique Web site to connect caregivers of people with dementia in a geographic region with an interprofessional group of healthcare providers and caregiver peers. Virtual Healthcare Neighborhood (VHN) was developed and maintained by an interprofessional group of healthcare providers from nursing, physical therapy, clinical counseling, and dental hygiene. The VHN provided weekly information on topics relevant to caring for a loved one with dementia at home as well as Question and Answer and Social Support Blogging sections for use by participants. This project was viewed as a positive and helpful method to provide support for caregivers of homebound older adults that could be easily replicated by home healthcare agencies.

  4. Standing alone with prosodic help*

    PubMed Central

    Frazier, Lyn; Clifton, Charles; Carlson, Katy; Harris, Jesse A.

    2013-01-01

    Two partially independent issues are addressed in two auditory rating studies: under what circumstances is a sub-string of a sentence identified as a stand-alone sentence, and under what circumstances do globally ill-formed but ‘locally coherent’ analyses (Tabor, Galantucci, & Richardson., 2004) emerge? A new type of locally coherent structure is established in Experiment 1, where a that-less complement clause is at least temporarily analyzed as a stand-alone sentence when it corresponds to a prosodic phrase. In Experiment 2, reduced relative clause structures like those in Tabor et al. were investigated. As in Experiment 1, the root sentence (mis-)analyses emerged most frequently when the locally coherent clause corresponded to a prosodic phrase. However, a substantial number of locally coherent analyses emerged even without prosodic help, especially in examples with for-datives (which do not grammatically permit a reduced relative clause structure for some speakers). Overall, the results suggest that prosodic grouping of constituents encourages analysis of a sub-string as a root sentence, and raise the question of whether all local coherence structures involve analysis of an utterance-final sub-string as a root sentence. PMID:24729648

  5. Helping Dementia Caregivers Through Technology.

    PubMed

    Fowler, Christianne Nesbitt; Haney, Tina; Lemaster, Margaret

    2016-04-01

    It is estimated there are between 43.5 and 65.7 million caregivers in the United States who provide unpaid care for older adults. Although the number of informal caregivers is expected to continue to increase, few programs have been established in home healthcare agencies to support these caregivers. This article describes a project that used a unique Web site to connect caregivers of people with dementia in a geographic region with an interprofessional group of healthcare providers and caregiver peers. Virtual Healthcare Neighborhood (VHN) was developed and maintained by an interprofessional group of healthcare providers from nursing, physical therapy, clinical counseling, and dental hygiene. The VHN provided weekly information on topics relevant to caring for a loved one with dementia at home as well as Question and Answer and Social Support Blogging sections for use by participants. This project was viewed as a positive and helpful method to provide support for caregivers of homebound older adults that could be easily replicated by home healthcare agencies. PMID:27023296

  6. Helping Those in Need: Human Service Workers

    ERIC Educational Resources Information Center

    Moffat, Colleen Teixeira

    2011-01-01

    Many people experience hardship and need help. This help is provided by a network of agencies and organizations, both public and private. Staffed by human service workers, this network, and the kinds of help it offers, is as varied as the clients it serves. Human service workers help clients become more self-sufficient. The first section of this…

  7. Help Seeking in English Language Learning

    ERIC Educational Resources Information Center

    Skinner, Barbara; Madden, Mary Catherine

    2010-01-01

    An examination of literature on the issue of help seeking (HS) has revealed a common theme: students will not always ask for help, even when they are aware that help is needed. The purpose of this action research study was to examine HS and help avoidance in the context of setting tasks in two types of English language-learning environment: a…

  8. Hepatocellular Carcinoma (HCC)

    NASA Astrophysics Data System (ADS)

    Helmberger, Thomas K.

    Hepatocellular carcinoma (HCC) is considered to be one of the most common malignancies worldwide, and the most common one in Africa and Asia. Over the last decade, a rising incidence of up to 10-15/100,000 per population has been seen in the Western world, with an estimate of 250,000 deaths and more than a million worldwide per year. By the year 2010, the World Health Organization expects that HCC will be the leading cause of cancer mortality surpassing lung cancer. This increasing incidence is most likely related to an increasing prevalence of chronic hepatitis C (HC) and B (HB) virus infections and other diseases inducing chronic inflammation (Befeler and Di Bisceglie 2002; Llovet et al. 2003).

  9. Prevention of Hepatocellular Carcinoma

    PubMed Central

    Schütte, Kerstin; Balbisi, Fathi; Malfertheiner, Peter

    2016-01-01

    The epidemiology of hepatocellular carcinoma (HCC) has significantly changed throughout the past decade and will continue to do so in the future as a consequence of effective primary prevention and treatment of virus-related liver diseases. However, other risk factors for HCC are constantly on the rise, including alcoholic liver disease and nonalcoholic fatty liver disease. The knowledge on these and further risk factors associated with an increased risk of HCC provide the opportunity and chance for the development and implementation of successful preventive strategies to decrease the worldwide burden of HCC. This mini-review gives a short overview on current strategies in primary, secondary, and tertiary prevention of HCC. PMID:27722155

  10. Salivary gland myoepithelial carcinoma.

    PubMed

    Vilar-González, S; Bradley, K; Rico-Pérez, J; Vogiatzis, P; Golka, D; Nigam, A; Sivaramalingam, M; Kazmi, S

    2015-11-01

    Salivary gland myoepithelial carcinoma (MC) or malignant myoepithelioma is a rare entity. MC usually presents as a slow-growing painless mass arising in the parotid gland, but may involve other salivary glands. This tumour may be particularly locally aggressive, but its clinical and biological features are not yet fully understood. MC may arise from pre-existing benign lesions, such as pleomorphic adenomas or benign myoepitheliomas, or may arise de novo. It usually affects patients over 50 years old, with no gender preference. Because it is often asymptomatic, the presentation and diagnosis can be delayed by months, even years. The current WHO classification considers MC to be an intermediate- to high-grade malignancy. Other published data suggest it is likely to be a high-grade neoplasm, consistent with its aggressive behaviour. Its epidemiology, histopathological features, immunohistochemical profile, clinical behaviour and optimal management are not well understood. Following review of the current literature we aim to address these.

  11. Duodenal bleeding from metastatic renal cell carcinoma.

    PubMed

    Rustagi, Tarun; Rangasamy, Priya; Versland, Mark

    2011-04-20

    Massive upper gastrointestinal bleeding due to malignancy is relatively uncommon and the duodenum is the least frequently involved site. Duodenal metastasis is rare in renal cell carcinoma (RCC) and early detection, especially in case of a solitary mass, helps in planning further therapy. We report a case of intractable upper gastrointestinal bleeding from metastatic RCC to the duodenum. The patient presented with melena and anemia, 13 years after nephrectomy for RCC. On esophagogastroduodenoscopy, a submucosal mass was noted in the duodenum, biopsies of which revealed metastatic RCC. In conclusion, metastasis from RCC should be considered in nephrectomized patients presenting with gastrointestinal symptoms and a complete evaluation, especially endoscopic examination followed by biopsy, is suggested.

  12. Duodenal Bleeding from Metastatic Renal Cell Carcinoma

    PubMed Central

    Rustagi, Tarun; Rangasamy, Priya; Versland, Mark

    2011-01-01

    Massive upper gastrointestinal bleeding due to malignancy is relatively uncommon and the duodenum is the least frequently involved site. Duodenal metastasis is rare in renal cell carcinoma (RCC) and early detection, especially in case of a solitary mass, helps in planning further therapy. We report a case of intractable upper gastrointestinal bleeding from metastatic RCC to the duodenum. The patient presented with melena and anemia, 13 years after nephrectomy for RCC. On esophagogastroduodenoscopy, a submucosal mass was noted in the duodenum, biopsies of which revealed metastatic RCC. In conclusion, metastasis from RCC should be considered in nephrectomized patients presenting with gastrointestinal symptoms and a complete evaluation, especially endoscopic examination followed by biopsy, is suggested. PMID:21577373

  13. Treatment Option Overview (Adrenocortical Carcinoma)

    MedlinePlus

    ... of Childhood Treatment for more information.) Having certain genetic conditions increases the risk of adrenocortical carcinoma. Anything ... can be a sign of disease. CT scan (CAT scan) : A procedure that makes a series of ...

  14. Stages of Merkel Cell Carcinoma

    MedlinePlus

    ... other organs . Sun exposure and having a weak immune system can affect the risk of Merkel cell carcinoma. ... ultraviolet A (PUVA) therapy for psoriasis . Having an immune system weakened by disease, such as chronic lymphocytic leukemia ...

  15. Onychocytic carcinoma: a new entity.

    PubMed

    Perrin, Christophe; Langbein, Lutz; Ambrossetti, Damien; Erfan, Nouran; Schweizer, Jürgen; Michiels, Jean-François

    2013-08-01

    We have recently described a new nail tumor known as onychocytic matricoma. Herein, we describe its malignant counterpart. Clinically, the tumor simulates onychomatricoma (OM). Histologically, this in situ malignant epithelial tumor exhibits a distinct picture of onychocytic differentiation with signs of both nail matrical differentiation and nail plate differentiation. We have proposed the name onychocytic carcinoma for this singular adnexal neoplasm. Given the peculiar thickening of the nail plate observed in OM, onychocytic matricoma, and onychocytic carcinoma, the clinical individualization of a new type of nail band pattern could be proposed. It presents as an acquired localized (monodactylous) longitudinal pachyonychia. Such longitudinal pachyonychia allow the recognition of the matrical nail tumor, which has a limited etiological spectrum. Xantholeucopachyonychia suggests mainly OM and rarely onychocytic carcinoma. Pachymelanonychia suggests onychocytic matricoma and rarely pigmented OM or onychocytic carcinoma. PMID:23518638

  16. Cutaneous metastases of hepatocellular carcinoma.

    PubMed

    Lazaro, M; Serrano, M L; Allende, I; Ratón, J A; Acebo, E; Diaz-Perez, J L

    2009-12-01

    Cutaneous metastases are an unusual finding that may present as the first sign of an internal neoplasia. A case of cutaneous metastases of hepatocellular carcinoma, which may often involve other organs but very rarely metastases to the skin, is reported.

  17. Nevoid basal cell carcinoma syndrome

    MedlinePlus

    ... radiation. Exposure to radiation can lead to skin cancers. ... DG, Farndon PA. Nevoid basal cell carcinoma syndrome. 2002 Jun 20 ... al. eds. Cancer of the Skin. 2nd ed. Philadelphia, PA: Elsevier ...

  18. Neuroendocrine carcinoma of the tongue.

    PubMed

    Esmati, Ebrahim; Babaei, Mohammad; Matini, Amirhassan; Ashtiani, Monir Sadat Mirai; Hamed, Ehsan Akbari; Nosrati, Hassan; Razi, Farideh; Ganjalikhani, Maryam

    2015-01-01

    Neuroendocrine carcinoma usually originates from lung. Few data exist in the literature regarding neuroendocrine carcinoma of the tongue. Patient data including history, surgical procedure, histology, and radiology investigations were collected and summarized. A 40-year-old woman was referred after partial glossectomy. Squamous mucosa with neoplasm and cells with round nuclei and light cytoplasm was reported in the tongue biopsy. Immunohistochemistry (IHC) staining was positive for cytokeratin, neuron specific enolase, synaptophysin and chromogranin and negative for leukocyte common antigen. This case showed a high proliferative activity (Ki-67 labeling index were 60%). These IHC findings were in favor of poorly differentiated neuroendocrine carcinoma. After surgery, she received chemotherapy and chemoradiation. The diagnosis of neuroendocrine tumors in the present case is based on immunohistochemical markers and cellular shapes. Postoperative chemoradiotherapy is a critical element of therapy for head and neck high-grade neuroendocrine carcinomas, our patient received this treatment after surgery. PMID:26458666

  19. [Bronchial mucoepidermoid carcinoma].

    PubMed

    Bregante, J I; Rituerto, B; Font de Mora, F; Alonso, F; Andreu, M J; Figuerola, J; Mulet, J F

    1998-07-01

    We submit the case of a child afflicted with a mucoepidermoid bronchial tumor. The patient is a boy, aged seven, who after undergoing antibiotic treatment for six weeks because of a fever and atelectasia-condensation in the right lower lobe showed no signs of clinical improvement and was sent to our department to undergo further study and treatment. A bronchoscopy performed shows a polypoid mass that partially blocks the main bronchial tube a few milimiters under the access to the right upper lobe. A biopsy is carried out and the anatomopathological test shows there is a low degree epidermoid carcinoma. We decide to perform a lobectomy which for the tumor location and the lung condition has to be medium and lower right. We proceed to remove the adenopaty of hilium not affected by the tumor. The postoperative period develops without incidents. A check-up bronchoscopy performed three months later shows two polypoid masses in the right bronchial tube which, once a biopsy is performed, proved to be granulation tissue. Twelve months after undergoing surgery, the patient's condition is good, there is no evidence of tumor relapse and the breathing capacity is adequate, though there is an obstructive restrictive pattern in the espirometry. Even taking into consideration that lung tumors are extremely unusual, the epidermoid carcinoma is the one which most frequently occurs. The tumor's low malignancy is a sign that points to a good prognosis. Performing conservative surgery by means of bronchoplasty should be taken into account so as to keep the sequelae on the lung condition to a minimum, even though in this case the tumor location made it impossible. PMID:12602035

  20. Carcinoma of the gastroesophageal junction in Chinese patients

    PubMed Central

    Huang, Qin

    2012-01-01

    Carcinoma of the gastroesophageal junction (GEJ) is defined as carcinoma that crosses the GEJ line, irrespective of where the tumor epicenter is located. This group of cancer is rare but controversial. Based on study results from the majority of epidemiologic and clinicopathologic investigations carried out in Western countries, this cancer is believed to arise from Barrett’s esophagus (BE) and includes both distal esophageal and proximal gastric carcinomas because of similar characteristics in epidemiology, clinicopathology, and molecular pathobiology in relation to BE. As such, the most recent American Joint Committee on Cancer staging manual requires staging all GEJ carcinomas with the rule for esophageal adenocarcinoma (EA). This mandate has been challenged recently by the data from several studies carried out mainly in Chinese patients. The emerging evidence derived from those studies suggests: (1) both BE and EA are uncommon in the Chinese population; (2) almost all GEJ cancers in Chinese arise in the proximal stomach and show the features of proximal gastric cancer, not those of EA; (3) application of the new cancer staging rule to GEJ cancer of Chinese patients cannot stratify patients’ prognosis effectively; and (4) prognostic factors of GEJ cancer in Chinese are similar, but not identical, to those of EA. In conclusion, the recent evidence suggests that GEJ cancer in Chinese shows distinct clinicopathologic characteristics that are different from EA. Further investigations in molecular pathology may help illustrate the underlying pathogenesis mechanisms of this cancer in Chinese patients and better manage patients with this fatal disease. PMID:23326117

  1. Carcinoma of the gastroesophageal junction in Chinese patients.

    PubMed

    Huang, Qin

    2012-12-28

    Carcinoma of the gastroesophageal junction (GEJ) is defined as carcinoma that crosses the GEJ line, irrespective of where the tumor epicenter is located. This group of cancer is rare but controversial. Based on study results from the majority of epidemiologic and clinicopathologic investigations carried out in Western countries, this cancer is believed to arise from Barrett's esophagus (BE) and includes both distal esophageal and proximal gastric carcinomas because of similar characteristics in epidemiology, clinicopathology, and molecular pathobiology in relation to BE. As such, the most recent American Joint Committee on Cancer staging manual requires staging all GEJ carcinomas with the rule for esophageal adenocarcinoma (EA). This mandate has been challenged recently by the data from several studies carried out mainly in Chinese patients. The emerging evidence derived from those studies suggests: (1) both BE and EA are uncommon in the Chinese population; (2) almost all GEJ cancers in Chinese arise in the proximal stomach and show the features of proximal gastric cancer, not those of EA; (3) application of the new cancer staging rule to GEJ cancer of Chinese patients cannot stratify patients' prognosis effectively; and (4) prognostic factors of GEJ cancer in Chinese are similar, but not identical, to those of EA. In conclusion, the recent evidence suggests that GEJ cancer in Chinese shows distinct clinicopathologic characteristics that are different from EA. Further investigations in molecular pathology may help illustrate the underlying pathogenesis mechanisms of this cancer in Chinese patients and better manage patients with this fatal disease.

  2. Cholangiographic evaluation of bile duct carcinoma

    SciTech Connect

    Nichols, D.A.; MacCarty, R.L.; Gaffey, T.A.

    1983-12-01

    Cholangiograms and clinical histories of 82 patients with biopsy-proved bile duct carcinoma were reviewed. The carcinomas were classified according to morphologic findings and clinical outcome. Ulcerative colitis and antecedent inflammatory disease of the biliary tree, particularly primary sclerosing cholangitis, seem to predispose to the development of bile duct carcinoma. Focal stenotic lesions were the most common morphologic type (62/82). Polypoid carcinomas and diffuse sclerosing carcinomas were less common and of about equal frequency. Prognosis was best for patients with polypoid carcinomas and worst for those with diffuse sclerosing carcinomas. In 69 cases (84%), the tumors involved the intrahepatic or proximal extrahepatic ducts, makin curative resection difficult or impossible. Patients with carcinomas limited to the more distal extrahepatic bile ducts had a longer average survival and a higher probability of surgical cure. Proper management of patients with bile duct carcinoma requires a complete and accurate cholangiographic evaluation of the morphology, location, and extent of the disease.

  3. Simultaneous Renal Cell Carcinoma and Giant Retroperitoneal Liposarcoma Involving Small Intestine

    PubMed Central

    2016-01-01

    Background. The concomitant occurrence of a renal cell carcinoma and retroperitoneal sarcoma is extremely rare with only few cases being reported. Methods. We present a case of simultaneous renal cell carcinoma and exceptionally large size retroperitoneal sarcoma involving small intestine. Surgical resection of retroperitoneal sarcoma and simultaneous right nephrectomy were performed. Results. Patient developed recurrent and metastatic disease and underwent debulking surgery following by chemotherapy. Despite aggressive behavior of the retroperitoneal sarcomas, patient is currently (7 years after simultaneous resection and nephrectomy) recurrence-free. Conclusions. Complete surgical resection is the mainstay of therapy for both renal cell carcinoma and retroperitoneal sarcoma. We present a case of simultaneous renal cell carcinoma and exceptionally large size retroperitoneal sarcoma. Debulking surgery and chemotherapy were helpful in our case. PMID:27595033

  4. Simultaneous Renal Cell Carcinoma and Giant Retroperitoneal Liposarcoma Involving Small Intestine.

    PubMed

    Reznichenko, Aleksandr A

    2016-01-01

    Background. The concomitant occurrence of a renal cell carcinoma and retroperitoneal sarcoma is extremely rare with only few cases being reported. Methods. We present a case of simultaneous renal cell carcinoma and exceptionally large size retroperitoneal sarcoma involving small intestine. Surgical resection of retroperitoneal sarcoma and simultaneous right nephrectomy were performed. Results. Patient developed recurrent and metastatic disease and underwent debulking surgery following by chemotherapy. Despite aggressive behavior of the retroperitoneal sarcomas, patient is currently (7 years after simultaneous resection and nephrectomy) recurrence-free. Conclusions. Complete surgical resection is the mainstay of therapy for both renal cell carcinoma and retroperitoneal sarcoma. We present a case of simultaneous renal cell carcinoma and exceptionally large size retroperitoneal sarcoma. Debulking surgery and chemotherapy were helpful in our case. PMID:27595033

  5. Congenital extrahepatic portosystemic shunt complicated by the development of hepatocellular carcinoma.

    PubMed

    Sharma, Ruchi; Suddle, Abid; Quaglia, Alberto; Peddu, Praveen; Karani, John; Satyadas, Thomas; Heaton, Nigel

    2015-10-01

    Congenital extrahepatic portosystemic shunt, also known as Abernethy malformation, is a rare congenital malformation. It causes shunting of blood through a communication between the portal and systemic veins such as a patent ductus venous. We report 3 cases of Abernethy malformation complicated by the development of hepatocellular carcinoma. Additionally, we comprehensively reviewed all previously reported cases and highlighted common features that may help in early diagnosis and appropriate management. Patients with Abernethy malformation may have an increased propensity to develop hepatocellular carcinoma. All 5 previously reported cases, plus the three of our patients, have a type 1 (complete) shunt suggesting a role for absent portal blood flow in the pathogenesis of hepatocellular carcinoma. Congenital extrahepatic portosystemic shunt should be sought for in cases with raised serum ammonia, hepatic encephalopathy or hepatocellular carcinoma in the absence of cirrhosis. PMID:26459734

  6. A pure primary transitional cell carcinoma of the ovary: A rare case report with literature review.

    PubMed

    Chandanwale, Shirish S; Kamble, Tushar; Mishra, Neha; Kumar, Harsh; Jadhav, Rahul

    2016-01-01

    Primary transitional cell carcinoma (TCC) of the ovary is a rare and recently recognized subtype of ovarian surface epithelial-stromal cancer. Pure forms of the TCC ovary account for only 1% of surface epithelial carcinomas. The clinical presentation is indistinguishable from other types of ovarian cancers. They have a favorable response to chemotherapy than other surface epithelial cancers. We report a case of 55-year-old woman who presented with a hard mass in the abdomen. Computed tomography-diagnosed it as a carcinoma of the ovary. Tumor was immunoreactive with Wilms' tumor protein-1 and nonreactive with cytokeratin 7 (CK7) and CK20. Histopathology diagnosis of primary TCC of the ovary was made. These tumors are needed to be differentiated from metastatic TCC from other sites and undifferentiated carcinomas of ovaries. Clinical features and immunohistochemistry are helpful. Surgical resection is the primary therapeutic approach followed by standardized chemotherapy. PMID:27127747

  7. Primary Cutaneous Lymphoma-Associated Pseudoepitheliomatous Hyperplasia Masquerading as Squamous Cell Carcinoma in a Young Adult.

    PubMed

    Ansari, Mahsa; Azmoodeh Ardalan, Farid; Najafi, Masoumeh; Goodarzi, Azadeh; Ghanadan, Alireza

    2015-12-01

    Primary cutaneous anaplastic large cell lymphoma is a T-cell malignancy with atypical CD30 positive lymphocytes. Pseudoepitheliomatous hyperplasia is an uncommon finding in primary cutaneous anaplastic large cell lymphoma, and may mimic squamous cell carcinoma as pseudomalignancy. Careful attention of a pathologist to correct diagnosis of pseudoepitheliomatous hyperplasia and its underlying causes will help physicians to avoid inappropriate management. Here, we present a 22-year-old man referred to our hospital with a solitary nodule persistent on his forearm which was diagnosed as squamous cell carcinoma in the first biopsy. The lesion recurred after two months and histopathologic and immunohistochemistry examination revealed anaplastic large cell lymphoma with florid pseudoepitheliomatous hyperplasia which masquerading as well-differentiated squamous cell carcinoma. Diagnosis of pseudoepitheliomatous hyperplasia must guide the pathologist to search for underlying causes, such as primary cutaneous lymphoma. Pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and this can result in inappropriate diagnosis and management. PMID:26749237

  8. Microvascular invasion in hepatocellular carcinoma

    PubMed Central

    Ünal, Emre; İdilman, İlkay Sedakat; Akata, Deniz; Özmen, Mustafa Nasuh; Karçaaltıncaba, Muşturay

    2016-01-01

    Microvascular invasion is a crucial histopathologic prognostic factor for hepatocellular carcinoma. We reviewed the literature and aimed to draw attention to clinicopathologic and imaging findings that may predict the presence of microvascular invasion in hepatocellular carcinoma. Imaging findings suggesting microvascular invasion are disruption of capsule, irregular tumor margin, peritumoral enhancement, multifocal tumor, increased tumor size, and increased glucose metabolism on positron emission tomography-computed tomography. In the presence of typical findings, microvascular invasion may be predicted. PMID:26782155

  9. Gene therapy and nasopharyngeal carcinoma.

    PubMed

    Hughes, J; Alusi, G; Wang, Y

    2012-06-01

    In 2003, a non-replicating adenoviral gene therapy product received the world`s first government licence for the treatment of head and neck cancer. Two years later approval was granted to a replication-selective adenovirus for the treatment of nasopharyngeal carcinoma in combination with chemotherapy. This review introduces the reader to gene therapy as an emerging treatment modality, and outlines its application to the management of nasopharyngeal carcinoma by examining recent pre-clinical and clinical research.

  10. Multiple oncocytomas and renal carcinoma

    SciTech Connect

    Velasquez, G.; Glass, T.A.; D'Souza, V.J.; Formanek, A.G.

    1984-01-01

    Renal oncocytoma, although rare, is being diagnosed more frequently, and criteria to differentiate it from other tumors have been described. Multiple oncocytomas have been reported, but an association between multiple oncocytomas and renal carcinoma in the same kidney has not been described. The authors report a case with two oncocytomas and a renal carcinoma in the right kidney as well as a right adrenal adenoma.

  11. [Adenosquamous carcinoma of the palate].

    PubMed

    Mancusi, G; Susani, M; Kornfehl, J; Girsch, W; Kautzky, M

    2002-08-01

    A rare case of adenosquamous carcinoma in a 74 year-old man is reported. Presenting as a nodule on the soft palate, diagnosis was prolonged because of the benign macroscopic aspect. CT-scan and MR-tomography showed an encapsulated lesion but biopsy and histologic examination revealed the typical features of adenosquamous carcinoma. The tumour consisted of adenocarcinoma and squamous cell carcinoma in close proximity to minor salivary glands of which the tumour seemed to have its origin. This entity, although rare in the head and neck region has been documented to be very aggressive with early regional and hematogenic metastasis. Therefore it has to be distinguished from other tumours, especially from mucoepidermoid carcinomas of the salivary glands, which have a better prognosis. Adenosquamous carcinoma is considered to have poor radiosensitivity and chemotherapeutic approaches have also not been successful in the literature. In our case radical surgical therapy was performed by excision of the whole soft palate and bilateral neck dissection. This resulted in total removal of the tumour but revealed bilateral lymph node metastases. Vital functions were saved by reconstruction of the palate with a free vascularized tensor-fasciae-latae-perforator-flap. For the first time in a case of adenosquamous carcinoma carcinoembryonic antigen in serum was monitored. A pretherapeutical 29-fold elevation resulted in a marked decrease after surgery, but supranormal values indicated remaining tumour burden which was found in metastases in the lung. Because of the limitations in therapy, early histologic diagnosis is most important in this highly malignant tumour.

  12. Boswellic acid activity against glioblastoma stem-like cells

    PubMed Central

    SCHNEIDER, HANNAH; WELLER, MICHAEL

    2016-01-01

    Boswellic acids (BAs) have long been considered as useful adjunct pharmacological agents for the treatment of patients with malignant brain tumors, notably glioblastoma. Two principal modes of action associated with BAs have been postulated: i) Anti-inflammatory properties, which are useful for containing edema formation, and ii) intrinsic antitumor cell properties, with a hitherto ill-defined mode of action. The present study assessed the effects of various BA derivatives on the viability and clonogenicity of a panel of nine long-term glioma cell lines and five glioma-initiating cell lines, studied cell cycle progression and the mode of cell death induction, and explored potential synergy with temozolomide (TMZ) or irradiation. BA induced the concentration-dependent loss of viability and clonogenicity that was independent of tumor protein 53 status and O6-methylguanine DNA methyltransferase expression. The treatment of glioma cells with BA resulted in cell death induction, prior to or upon S phase entry, and exhibited features of apoptotic cell death. Synergy with irradiation or TMZ was detected at certain concentrations; however, the inhibitory effects were mostly additive, and never antagonistic. While the intrinsic cytotoxic properties of BA at low micromolecular concentrations were confirmed and the potential synergy with irradiation and TMZ was identified, the proximate pharmacodynamic target of BA remains to be identified. PMID:27313764

  13. Lymphoepithelial carcinoma of the minor salivary gland.

    PubMed

    Worley, N K; Daroca, P J

    1997-06-01

    Undifferentiated carcinoma of the minor salivary glands has been rarely reported in the world literature. Lymphoepithelial carcinoma, which is a variant of undifferentiated carcinoma, is distinguished from small cell and large cell undifferentiated carcinoma by its association with benign lymphoepithelial lesions. We report a case of a lymphoepithelial carcinoma developing in a minor salivary gland of the oral cavity in a 69-year-old woman. To our knowledge, this is the first reported case of a lymphoepithelial carcinoma arising from a minor salivary gland.

  14. Inflammatory Breast Carcinoma Presenting with Two Different Patterns of Cutaneous Metastases: Carcinoma Telangiectaticum and Carcinoma Erysipeloides

    PubMed Central

    Yaghoobi, Reza; Talaizade, Abdolhasan; Lal, Karan; Ranjbari, Nastaran; Sohrabiaan, Nasibe

    2015-01-01

    Cutaneous metastases can have many different clinical presentations. They are seen in patients with advanced malignant disease; however, they can be the initial manifestation of undetected malignancies. Inflammatory breast carcinoma is a rare and aggressive form of breast cancer that has a nonspecific appearance mimicking many benign conditions including mastitis, breast abscesses, and/or dermatitis. The authors report the case of a 40-year-old woman with inflammatory breast carcinoma presenting with violaceous papulovesicular lesions resembling lymphangioma circumscriptum and erythematous patches resembling erysipelas. These lesions represent two different types of cutaneous metastases, both of which were the initial signs of inflammatory breast carcinoma in the patient described herein. Skin biopsy of lesions confirmed invasive breast cancer and further prompted a work up for inflammatory breast carcinoma. This case demonstrates the importance of follow-up for all breast lesions, even those considered to be of benign nature, for they can be presenting signs of metastatic breast cancer. PMID:26345728

  15. Activating BRAF Mutations Detected in Mixed Hürthle Cell Carcinoma and Multifocal Papillary Carcinoma of the Thyroid Gland: Report of an Unusual Case and Review of the Literature.

    PubMed

    Sinno, Sara; Choucair, Mahmoud; Nasrallah, Mona; Wadi, Lara; Jabbour, Mark N; Nassif, Samer

    2016-09-01

    Despite the increase in the incidence of thyroid carcinomas, the occurrence of collision tumors in the thyroid remains a rare event. We present the case of a 69-year-old female who presented to the emergency department with a chief complaint of painful neck swelling. Imaging revealed a large right hemithyroid mass and a left hemithyroid nodule. Fine needle aspiration of the lesions and subsequent total thyroidectomy revealed a Hürthle cell carcinoma in the right lobe and bilateral multicentric papillary carcinoma foci, including 2 foci with a classical pattern and 1 encapsulated follicular variant in the isthmus. BRAF gene mutation analysis revealed V600E gene mutation in the classical variants of papillary carcinoma and in the Hürthle cell carcinoma. The focus of follicular variant of papillary carcinoma in the isthmus and a sample from normal thyroid tissue did not harbor BRAF mutations. This case is remarkable in being an unusual report of a follicular Hürthle cell carcinoma harboring the BRAF V600E mutation and occurring in collision with multifocal papillary carcinoma. Documentation of such cases is important as it helps better understand the pathogenesis, clinical behavior, and radiologic findings of such rare lesions and to determine the optimal treatment modalities.

  16. Would Weaker Beer Help Reduce Alcohol's Harms?

    MedlinePlus

    ... medlineplus.gov/news/fullstory_160387.html Would Weaker Beer Help Reduce Alcohol's Harms? Researchers say drinkers wouldn' ... 2016 (HealthDay News) -- Lowering the alcohol content in beer and other drinks may help reduce their harmful ...

  17. Help your teen cope with stress

    MedlinePlus

    Adolescents - stress; Anxiety - cope with stress ... American Academy of Child and Adolescent Psychology. Helping teenagers deal with stress. Updated May 2012. www.aacap.org/app_themes/aacap/docs/facts_for_families/66_helping_ ...

  18. Spindle cell carcinoma of the mandible: Clinicopathological and immunohistochemical characteristics.

    PubMed

    Al-Bayaty, Haytham; Balkaran, Ramaa L

    2016-01-01

    Spindle cell carcinoma, a rare variant of squamous cell carcinoma, has propensity to occur in the upper aero digestive tract, including the oral mucosa. In this oral pathology communication, we report the occurrence of this neoplasm in the left mandible as a large fleshy growth with destruction of bone in a 73-year-old Afro-Trinidadian female. The distinction of this tumor from other malignant spindle cell mesenchymal tumors is important. Selective sampling of this specimen for possible transitional areas of squamous and spindle cell appearance, immunohistochemical staining for cytokeratin, vimentin, and S-100 protein are helpful in establishing the diagnosis. According to the patient's insistence, debulking of the tumor was performed under general anesthesia. Eight months later the patient succumbed to the disease.

  19. Endoscopic Therapy of Early Carcinoma of the Oesophagus

    PubMed Central

    Knabe, Mate; May, Andrea; Ell, Christian

    2015-01-01

    Summary Background Oesophageal cancer is a comparatively rare disease in the Western world. Prognosis is highly dependent on the choice of treatment. Early stages can be treated by endoscopic resection, whereas surgery needs to be performed in the case of advanced carcinomas. Technical progress has enabled high-definition endoscopes and technical add-ons which help the endoscopist in finding fine irregularities in the oesophageal mucosa, though interpretation still remains challenging. Methods In this review, we discuss both novel and old diagnostic procedures and their value, as well as the current recommendations for the diagnosis and treatment of early oesophageal carcinomas. The database of PubMed and Medline was searched and analysed to provide all relevant literature for this review. Results and Conclusion Endoscopic resection is the therapy of choice in early oesophageal cancer. In case of adenocarcinoma it is mandatory to perform subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions. PMID:26989386

  20. Aggressive Extraocular Sebaceous Carcinoma Recurring after Mohs Micrographic Surgery

    PubMed Central

    Grigoryan, Konstantin V.; Leithauser, Laurel; Gloster, Hugh M.

    2015-01-01

    Sebaceous carcinomas (SC) are rare adnexal tumors with possible aggressive behavior usually arising in the head and neck region of adults in the seventh decade of life. Treatment has traditionally been with surgical excision with 5-6 mm wide margins but Mohs micrographic surgery (MMS) has also been reported as an effective treatment modality. We present a case of a Caucasian female renal transplant patient with a rapidly enlarging nodule on the left preauricular cheek that was excised with MMS with negative margins. The tumor recurred rapidly and metastasized ultimately leading to the death of the patient. There was some disagreement amongst pathologists as to the possible nature of the diagnosis with the original biopsy being labeled as a poorly differentiated carcinoma. We aim to highlight the potential aggressive nature of SC and review the features of the neoplasm including histological features that help in making the diagnosis. PMID:25685571

  1. Nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome)

    PubMed Central

    Kiran, N. K.; Tilak Raj, T. N.; Mukunda, K. S.; Rajashekar Reddy, V.

    2012-01-01

    The Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS), is an infrequent multisystemic disease inherited in a dominant autosomal way, which shows a high level of penetrance and variable expressiveness. It is characterized by odontogenic keratocysts in the jaw, multiple basal cell nevi carcinomas and skeletal abnormalities. This syndrome may be diagnosed early by a dentist by routine radiographic exams in the first decade of life, since the odontogenic keratocysts are usually one of the first manifestations of the syndrome. This case report presents a patient diagnosed as NBCCS by clinical, radiographic and histological findings in a 13-year-old boy. This paper highlights the importance of early diagnosis of NBCCS which can help in preventive multidisciplinary approach to provide a better prognosis for the patient. PMID:23633824

  2. Current Issues in the Diagnosis and Treatment of Endometrial Carcinoma

    PubMed Central

    Stubert, J.; Gerber, B.

    2016-01-01

    Endometrial carcinoma is the most common carcinoma of the female genital tract. Its most important clinical sign is postmenopausal bleeding. An endometrial biopsy is essential for diagnosis. Treatment decisions are governed by tumour risk assessment and patient comorbidity, which is often present. Pelvic and paraaortic lymph node dissection is unnecessary in low risk cases (definition: pT1 a, G1/2) and adjuvant radiotherapy and systemic treatments are usually avoidable. Treatment of high-risk patients (G3 and/or pT1b) and palliative cases is difficult and not well standardised. New molecular-based subtype classification may help treatment decision making in future. PMID:26941450

  3. Treatment Options for Thymoma and Thymic Carcinoma

    MedlinePlus

    ... symptoms of thymoma and thymic carcinoma include a cough and chest pain. Thymoma and thymic carcinoma may ... if you have any of the following: A cough that doesn't go away. Chest pain. Trouble ...

  4. Stages of Thymoma and Thymic Carcinoma

    MedlinePlus

    ... symptoms of thymoma and thymic carcinoma include a cough and chest pain. Thymoma and thymic carcinoma may ... if you have any of the following: A cough that doesn't go away. Chest pain. Trouble ...

  5. General Information about Merkel Cell Carcinoma

    MedlinePlus

    ... Merkel Cell Carcinoma Treatment (PDQ®)–Patient Version General Information About Merkel Cell Carcinoma Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  6. General Information about Thymoma and Thymic Carcinoma

    MedlinePlus

    ... and Thymic Carcinoma Treatment (PDQ®)–Patient Version General Information About Thymoma and Thymic Carcinoma Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  7. Potential targets for lung squamous cell carcinoma

    Cancer.gov

    Researchers have identified potential therapeutic targets in lung squamous cell carcinoma, the second most common form of lung cancer. The Cancer Genome Atlas (TCGA) Research Network study comprehensively characterized the lung squamous cell carcinoma gen

  8. Hepatocellular carcinoma in India.

    PubMed

    Bhattacharyya, Gouri Shankar; Babu, K Govind; Malhotra, Hemant; Ranade, Anantbhushan A; Murshed, Shaiqua; Datta, Debasis

    2013-12-01

    Cancers of the liver are one of the commonest cancers that occur in the world, the commonest of which is the hepatocellular carcinoma (HCC). It is considered to be the 5th commonest cancer in the world. In the areas that are endemic for hepatitis B and C, it is extremely common. Unfortunately, India which is an endemic zone for hepatitis B, there has been no comprehensive analyzed data for HCC. Incidence of HCC in India occurs at two peaks, one at a young age between 40 to 55 years and another above 60 years. Eighty per cent of all HCCs occurring in India occur with cirrhosis of liver in the background and 60% of all these cases are hepatitis B positive carriers. Symptoms are reflective of late presentation with advanced disease. Surgery, the only curative modulus available, unfortunately is not possible in 95% of HCC patients. Majority of the patients are treated with palliative and supportive care and life spans are limited. Sorafenib is used in a small section of patients. Characterization of HCC with molecular sub-typing is the need of the hour.

  9. Epidemiology of bronchioloalveolar carcinoma.

    PubMed

    Falk, R T; Pickle, L W; Fontham, E T; Greenberg, S D; Jacobs, H L; Correa, P; Fraumeni, J F

    1992-01-01

    Descriptive features of bronchioloalveolar carcinoma (BAC) are presented using Surveillance, Epidemiology and End Results Program population-based incidence data from 1973 through 1987, along with risk factors from histologically confirmed cases of BAC identified in a hospital-based case-control study conducted in Louisiana between 1979 and 1982. Compared to the rising incidence of lung cancer overall, BAC rates have remained relatively constant, accounting for less than 3% of all lung cancer. BAC incidence rates were higher in males, yet it explained proportionately more of the total lung cancer incidence in females. In the case-control study, 21 of the 33 cases originally ascertained from hospital pathology records were histologically confirmed as BAC. Most cases smoked cigarettes, with a 4-fold risk for ever smoking. Risks tended to increase with smoking intensity (reaching 10-fold for more than 1.5 packs/day) and duration (reaching 5-fold for more than 45 years of smoking). Following 10 or more years of employment, there was a 4-fold risk associated with motor freight occupations, along with nonsignificant excesses among construction workers, petroleum manufacturers, and sugar cane farmers. Cases were more likely than controls to have had emphysema or to have had a close family member with lung cancer. Although based on small numbers, this study suggests that BAC shares many of the epidemiological characteristics of lung adenocarcinoma.

  10. Anticipated Guilt for Not Helping and Anticipated Warm Glow for Helping Are Differently Impacted by Personal Responsibility to Help

    PubMed Central

    Erlandsson, Arvid; Jungstrand, Amanda Å.; Västfjäll, Daniel

    2016-01-01

    One important motivation for people behaving prosocially is that they want to avoid negative and obtain positive emotions. In the prosocial behavior literature however, the motivations to avoid negative emotions (e.g., guilt) and to approach positive emotions (e.g., warm glow) are rarely separated, and sometimes even aggregated into a single mood-management construct. The aim of this study was to investigate whether anticipated guilt if not helping and anticipated warm glow if helping are influenced similarly or differently when varying situational factors related to personal responsibility to help. Helping scenarios were created and pilot tests established that each helping scenario could be formulated both in a high-responsibility version and in a low-responsibility version. In Study 1 participants read high-responsibility and low-responsibility helping scenarios, and rated either their anticipated guilt if not helping or their anticipated warm glow if helping (i.e., separate evaluation). Study 2 was similar but here participants rated both their anticipated guilt if not helping and their anticipated warm glow if helping (i.e., joint evaluation). Anticipated guilt was clearly higher in the high-responsibility versions, but anticipated warm glow was unaffected (in Studies 1a and 1b), or even higher in the low-responsibility versions (Study 2). In Studies 3 (where anticipated guilt and warm glow were evaluated separately) and 4 (where they were evaluated jointly), personal responsibility to help was manipulated within-subjects. Anticipated guilt was again constantly higher in the high-responsibility versions but for many types of responsibility-manipulations, anticipated warm glow was higher in the low-responsibility versions. The results suggest that we anticipate guilt if not fulfilling our responsibility but that we anticipate warm glow primarily when doing over and beyond our responsibility. We argue that future studies investigating motivations for helping

  11. Harried Principals Aren't Helpful Principals

    ERIC Educational Resources Information Center

    Connolly, Mike

    2007-01-01

    A harried leader is not a helpful leader. Schools need calm, well-balanced, helpful leaders as much as they need visionary ones. In fact, in this era of frenetic change in schools, principals should devote at least as much time to helping teachers be more focused and less frantic as they do to formulating new visions for the school or embarking on…

  12. Help Options in CALL: A Systematic Review

    ERIC Educational Resources Information Center

    Cardenas-Claros, Monica S.; Gruba, Paul A.

    2009-01-01

    This paper is a systematic review of research investigating help options in the different language skills in computer-assisted language learning (CALL). In this review, emerging themes along with is-sues affecting help option research are identified and discussed. We argue that help options in CALL are application resources that do not only seem…

  13. Medical Errors: Tips to Help Prevent Them

    MedlinePlus

    ... to Web version Medical Errors: Tips to Help Prevent Them Medical Errors: Tips to Help Prevent Them Medical errors are one of the nation's ... single most important way you can help to prevent errors is to be an active member of ...

  14. [External radiotherapy for hepatocellular carcinoma].

    PubMed

    Girard, N; Mornex, F

    2011-02-01

    For a long time radiotherapy has been excluded from the therapeutic strategy for hepatocellular carcinoma, given its significant toxicity on the non-tumoral liver parenchyma. Conformal radiation is a recent advance in the field of radiotherapy, allowing dose escalation and combination with other therapeutic options for hepatocellular carcinoma, including trans-arterial chemo-embolization. Conformal radiotherapy is associated with interesting features, especially in cirrhotic patients: wide availability, non-invasiveness, possibility to target multiple localizations anywhere within the liver parenchyma, and favorable tolerance profile even in patients with cirrhosis and/or in a poor medical condition. Recently, radiation delivery has been optimized through several technical developments: respiratory gating and intensity-modulated radiotherapy, which allow a better focalization of the ballistics, stereotactic techniques and proton-beam radiotherapy, whose availability is currently limited in Europe. Given the high response rates of hepatocellular carcinoma to radiation, conformal radiotherapy may be regarded as a curative-intent treatment for hepatocellular carcinoma, similar to surgery and per-cutaneous techniques. Yet the impact of radiotherapy has to be evaluated in randomized trials to better integrate in the complex therapeutic algorithm of hepatocellular carcinoma.

  15. Helping Each Other: The Effects of Cost, Need and Contextual Features Upon Preschoolers' Helping Behavior.

    ERIC Educational Resources Information Center

    Rodd, Jillian

    1988-01-01

    Investigated effects of variation of personal cost to the helper and perceived neediness of the person helped upon the helping behavior of 96 children of 43-67 months. Data indicated that the helping stimulus, the absence of behavior by the person helped, and cost contributed to the prediction of helping response type. (RJC)

  16. College Students' Intentions to Seek Help for Suicidal Ideation: Accounting for the Help-Negation Effect

    ERIC Educational Resources Information Center

    Yakunina, Elena S.; Rogers, James R.; Waehler, Charles A.; Werth, James L., Jr.

    2010-01-01

    Prior research has identified a negative association between suicidal ideation and help-seeking, a phenomenon called "help-negation." Help-negation has been documented to occur for both professional and nonprofessional sources of help. In this study help-seeking attitudes, stigma concerns, and perceptions of social support were examined as…

  17. Akt Inhibitor MK2206 in Treating Patients With Progressive, Recurrent, or Metastatic Adenoid Cyst Carcinoma

    ClinicalTrials.gov

    2016-06-14

    Recurrent Oral Cavity Adenoid Cystic Carcinoma; Recurrent Salivary Gland Carcinoma; Salivary Gland Adenoid Cystic Carcinoma; Stage IVA Major Salivary Gland Carcinoma; Stage IVA Oral Cavity Adenoid Cystic Carcinoma; Stage IVB Major Salivary Gland Carcinoma; Stage IVB Oral Cavity Adenoid Cystic Carcinoma; Stage IVC Major Salivary Gland Carcinoma; Stage IVC Oral Cavity Adenoid Cystic Carcinoma

  18. Transitional cell bladder carcinoma with presentation mimicking ovarian carcinoma.

    PubMed

    Erickson, D R; Dabbs, D J; Olt, G J

    1996-05-01

    In the case described here, the patient's initial presentation suggested ovarian carcinoma. She had recurrent ascites, a pelvic mass, elevated CA-125, and extensive peritoneal carcinomatosis with transitional cell histology. The presence of hematuria prompted a cystoscopy, which revealed the true site of origin to be the urinary bladder rather than ovaries. This presentation is extremely rare for bladder cancer. Since transitional cell tumors from the bladder have a much worse prognosis than those of ovarian origin, it is important to identify the primary site correctly. Therefore, cystoscopy is essential for patients with hematuria, and should be considered in cases of apparent primary peritoneal carcinoma with transitional cell histology.

  19. Combination of cetuximab and PP242 synergistically suppress the progression of wild-type KRAS colorectal carcinoma.

    PubMed

    Cheng, Lei; Xia, Zuguang; Bian, Xinyu; Li, Guangchao; Hu, Jing; Cao, Ya; Wang, Qing; Qian, Xiaoping

    2015-01-01

    Mammalian target of rapamycin (mTOR) has been shown to be overactive in human colorectal cancer, but the first-generation mTOR inhibitor, rapamycin, has failed to show clinical efficacy against colorectal cancer. On the other hand, although the second-generation mTOR inhibitor, PP242, has exerted substantial efficacy, it was revealed that independent inhibition by PP242 was transient, which could lead to positive-feedback loop to EGFR. Using wild-type KRAS colorectal cancer cells as models, we investigate the treatment efficacy of a widely used anti-EGFR monoclonal antibody, cetuximab, and PP242, alone or in combination in vitro and in vivo. Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of Caco-2 and HT-29 cells. Moreover, the ability of cancer-cell invasion and proliferation was also significantly inhibited by the combination therapy when compared with cetuximab or PP242 alone. Interestingly, the percentage of CD44-positive cancer cells was substantially decreased by the combination therapy in comparison with PP242 alone through fluorescence-activated cell sorting. The growth of cancer stem-like cell spheres in vitro was also maximally inhibited by combination therapy, in terms of either diameter or number. More importantly, the efficacy of combination therapy was more prominent than either drug alone in established tumor xenografts. These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas.

  20. Transplant benefit for patients with hepatocellular carcinoma.

    PubMed

    Vitale, Alessandro; Volk, Michael; Cillo, Umberto

    2013-12-28

    Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma (HCC), it is limited by the realities of perioperative complications, and the shortage of donor organs. Furthermore, in many cases there are available alternative treatments such as resection or locoregional therapy. Deciding upon the best option for a patient with HCC is complicated, involving numerous ethical principles including: urgency, utility, intention-to-treat survival, transplant benefit, harm to candidates on waiting list, and harm to living donors. The potential contrast between different principles is particularly relevant for patients with HCC for several reasons: (1) HCC candidates to liver transplantation are increasing; (2) the great prognostic heterogeneity within the HCC population; (3) in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome; and (4) effective alternative therapies are often available for HCC candidates to liver transplantation. In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles, and also introduce equity between patients with HCC and nonmalignant liver disease. We also propose a triangular equipoise model to help decide between deceased donor liver transplantation, living donor liver transplantation, or alternative therapies. PMID:24409046

  1. Treatment of thyroid follicular carcinoma.

    PubMed

    Ríos, Antonio; Rodríguez, José M; Parrilla, Pascual

    2015-12-01

    Differentiated thyroid carcinoma includes 2 different tumor types, papillary (PC) and follicular carcinoma (FC), and although similar, their prognosis is different. FC is uncommon, and this has led to it often being analyzed together with PC, and therefore the true reality of this tumor is difficult to know. As a result, the diagnostic and therapeutic management and the prognostic factors in differentiated carcinoma are more predictive of PC than FC. In this review we analyze the current state of many of the therapeutic aspects of this pathology. The best surgical technique and the usefulness of associated lymphadenectomy is also analyzed. Regarding post-surgical ablation with 131I, the indications, doses and usefulness are discussed. For the remaining therapies we analyze the few indications for radiotherapy and chemotherapy, and of new drugs such as tyrosine kinase inhibitors.

  2. Genetic heterogeneity of hepatocellular carcinoma

    SciTech Connect

    Unsal, H.; Isselbacher, K.J. ); Yakicier, C.; Marcais, C.; Ozturk, M. ); Kew, M. ); Volkmann, M. ); Zentgraf, H. )

    1994-01-18

    The authors studied 80 hepatocellular carcinomas from three continents for p53 gene (TP53) mutations and hepatitis B virus (HBV) sequences. p53 mutations were frequent in tumors from Mozambique but not in tumors from South Africa, China, and Germany. Independent of geographic origin, most tumors were positive for HBV sequences. X gene coding sequences of HBV were detected in 78% of tumors, whereas viral sequences in the surface antigen- and core antigen-encoding regions were present in less than 35% of tumors. These observations indicate that hepatocellular carcinomas are genetically heterogeneous. Mozambican-types of hepatocellular carcinomas are characterized by a high incidence of p53 mutations related to aflatoxins. In other tumors, the rarity of p53 mutations combined with the frequent presence of viral X gene coding sequences suggests a possible interference of HBV with the wild-type p53 function.

  3. Radioimmune localization of occult carcinoma

    SciTech Connect

    Duda, R.B.; Zimmer, A.M.; Rosen, S.T.; Gilyon, K.A.; Webber, D.; Spies, S.; Spies, W.; Merchant, B. )

    1990-07-01

    Patients with a rising serum carcinoembryonic antigen level and no clinical or roentgenographic evidence of recurrent or metastatic cancer present a treatment dilemma. Eleven such patients, 10 with a previously treated colorectal carcinoma and 1 with a previously treated breast carcinoma, received an injection of the anticarcinoembryonic antigen monoclonal antibody ZCE-025 labeled with the radioisotope indium 111. Nuclear scintigraphy was performed on days 3 and 5 through 7 to detect potential sites of tumor recurrence. The monoclonal antibody scan accurately predicted the presence or absence of occult malignancy in 7 (64%) patients. Second-look laparotomy confirmed the monoclonal antibody scan results in the patients with colorectal cancer, and magnetic resonance imaging confirmed metastatic breast cancer. This study demonstrates that In-ZCE-025 can localize occult carcinoma and may assist the surgeon in facilitating the operative exploration. In-ZCE-025 assisted in the initiation of adjuvant therapy for the patient with breast cancer.

  4. Current management of pancreatic carcinoma.

    PubMed Central

    Lillemoe, K D

    1995-01-01

    OBJECTIVE: The author seeks to provide an update on the current management of pancreatic carcinoma, including diagnosis and staging, surgical resection and adjuvant therapy for curative intent, and palliation. SUMMARY BACKGROUND DATA: During the 1960s and 1970s, the operative mortality and long-term survival after pancreaticoduodenectomy for pancreatic carcinoma was so poor that some authors advocated abandoning the procedure. Several recent series have reported a marked improvement in perioperative results with 5-year survival in excess of 20%. Significant advances also have been made in areas of preoperative evaluation and palliation for advanced disease. CONCLUSION: Although carcinoma of the pancreas remains a disease with a poor prognosis, advances in the last decade have led to improvements in the overall management of this disease. Resection for curative intent currently should be accomplished with minimal perioperative mortality. Surgical palliation also may provide the optimal management of selected patients. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 7. PMID:7531966

  5. Mucoepidermoid carcinoma of the liver.

    PubMed

    Katsuda, S; Nakanishi, I; Kajikawa, K; Takabatake, S

    1984-01-01

    An autopsy case of mucoepidermoid carcinoma of the liver associated with congenital cysts in a 78-year-old man was reported. The liver weighed 1,900 g, and there was a massive tumor of 11 X 10 X 6.5 cm in the left lobe with multiple sero-mucinous cysts. Histologically, the tumor cells consisted of four types of cells: mucus-secreting cells, squamous cells, intermediate cells, and oxyphilic cells. The variety of tumor cells quite resembled that of mucoepidermoid carcinoma of the salivary gland. The sero-mucinous cysts were lined with a single layer of cuboidal or columnar cells and were not communicated with the biliary ducts. Part of the cysts with benign lining cells was in continuity with tumor cells of the intermediate type. Discussion was made on the histogenesis of hepatic mucoepidermoid carcinoma in particular emphasis on the association of the congenital cysts.

  6. Parathyroid carcinoma in tertiary hyperparathyroidism.

    PubMed

    Kim, Byung Seup; Ryu, Han Suk; Kang, Kyung Ho; Park, Sung Jun

    2016-10-01

    Parathyroid carcinoma is a rare disease of unknown etiology. This study presents a case of parathyroid carcinoma in a patient with tertiary hyperparathyroidism. Despite a successful kidney transplantation, the intact parathyroid hormone (iPTH) level of the patient was elevated consistently and could not be controlled by medical therapy. Due to the development of tertiary hyperparathyroidism with bone pain and osteoporosis, subtotal parathyroidectomy was performed 4 months after the kidney transplantation. Histological evaluation revealed that one of four parathyroid lesions was a parathyroid carcinoma, while the others were diffuse hyperplasia. Postoperative laboratory studies indicated a decreased level of iPTH. A positron emission tomography-computed tomography performed 6 months after the operation revealed no evidence of local recurrence or distant metastasis. PMID:27664600

  7. Screening for hepatocellular carcinoma.

    PubMed

    Merican, I

    1996-03-01

    Hepatocellular carcinoma (HCC) is one of the commonest cancers in Asian males. In Malaysia, it is one of the ten most common cancers amongst the male population. Most of our patients with HCC present to us rather late and almost all die within 4 months of diagnosis. HCC occurs more commonly in patients with cirrhosis associated with hepatitis B and C infections. Screening for HCC can lead to early detection of small tumours (< 5 cm) that are more amenable to surgical resection, resulting in improved survival rates. The average 5-year survival rate for those who have undergone surgical resection is 68% (range, 22-73%). Better results are obtained with the smaller tumours (< 2 cm in diameter). Patients with chronic hepatitis B and C infection especially those who are > 45 years of age, who have concomitant cirrhosis or have a family history of HCC should be examined every 3-6 months with periodic serum alpha-fetoprotein (AFP) measurements and abdominal ultrasound examinations. Abdominal ultrasound is useful in the detection of small tumours. While mass screening for HCC is not cost-effective in countries of low incidence of HCC, screening of high risk groups may be justified in countries with a high endemicity of HBV infection. Screening for HCC in Japan, Taiwan and China appears to yield better results than those in the West. Nonetheless, primary prevention with mass hepatitis B vaccination and blood donor screening for anti-HCV is expected to make a much greater impact in the control of HCC in the years to come.

  8. [Medullary thyroid carcinoma].

    PubMed

    Niccoli-Sire, P; Conte-Devolx, B

    2007-10-01

    Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT). MTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Diagnosis is usually made by a solitary nodule often associated to nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form and in about 30% of case as a familial form as a part of multiple endocrine neoplasia syndrome, an hereditary dominant inherited disease related to germline mutation of the proto-oncogene RET. Both biological (CT) and genetic (RET) markers allows the optimal diagnosis and treatment of MTC; the former allows screening and early diagnosis of MTC by routinely CT measurements in nodular thyroid diseases that make the adequate and complete surgery required to be performed. The former leads to diagnose familial MTC and to identify at risk subjects in whom early or prophylactic surgery may be performed. Treatment of MTC is based on the complete surgical resection: total thyroidectomy associated to central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be associated to other systemic treatments: as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appears as possible valuable therapeutic options for the future. Prognosis of MTC is mainly related to both the stage of the disease and the extend of the initial surgery. Ten-year survival is about 80% when the patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery. PMID:17572372

  9. Hepatocellular carcinoma: a review

    PubMed Central

    Balogh, Julius; Victor, David; Asham, Emad H; Burroughs, Sherilyn Gordon; Boktour, Maha; Saharia, Ashish; Li, Xian; Ghobrial, R Mark; Monsour, Howard P

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated

  10. Non-invasive diagnostic techniques in the diagnosis of squamous cell carcinoma.

    PubMed

    Warszawik-Hendzel, Olga; Olszewska, Małgorzata; Maj, Małgorzata; Rakowska, Adriana; Czuwara, Joanna; Rudnicka, Lidia

    2015-12-31

    Squamous cell carcinoma is the second most common cutaneous malignancy after basal cell carcinoma. Although the gold standard of diagnosis for squamous cell carcinoma is biopsy followed by histopathology evaluation, optical non-invasive diagnostic tools have obtained increased attention. Dermoscopy has become one of the basic diagnostic methods in clinical practice. The most common dermoscopic features of squamous cell carcinoma include clustered vascular pattern, glomerular vessels and hyperkeratosis. Under reflectance confocal microscopy, squamous cell carcinoma shows an atypical honeycomb or disarranged pattern of the spinous-granular layer of the epidermis, round nucleated bright cells in the epidermis and round vessels in the dermis. High frequency ultrasound and optical coherence tomography may be helpful in predominantly in pre-surgical evaluation of tumor size. Emerging non-invasive or minimal invasive techniques with possible application in the diagnosis of squamous cell carcinoma of the skin, lip, oral mucosa, vulva or other tissues include high-definition optical coherence tomography, in vivo multiphoton tomography, direct oral microscopy, electrical impedance spectroscopy, fluorescence spectroscopy, Raman spectroscopy, elastic scattering spectroscopy, differential path-length spectroscopy, nuclear magnetic resonance spectroscopy, and angle-resolved low coherence interferometry.

  11. Primary multiple clear cell variant urothelial carcinomas of urinary bladder: a rare case report

    PubMed Central

    Zhang, Yutao; Huang, Jun; Feng, Hao; Tang, Yun

    2014-01-01

    Clear cell variant urothelial carcinoma of urinary bladder was very rare. There were only 6 report articles included by Pubmed and total 8 cases had been described till now. All of the past reports described single tumor of urinary bladder, but multiple carcinomas had not been reported. Here we reported a 65-years-old Chinese man who complained of intermittent gross hematuria and odynuria for more than 2 months in January 2013. Only one cauliflower-like tumor was detected approximately in the left wall of the urinary bladder with cystoscopy and the biopsy specimen was diagnosed as “urothelial carcinoma, high grade”. However, three tumors were found in anterior wall (×2) near neck of urinary bladder and posterior wall (×1) of the urinary bladder during transurethral resection of the bladder tumor. Typical urothelial carcinoma with partial clear cell appearance made it difficult to make a precise pathological diagnosis and immunohistochemical stain helped to diagnose the case as clear cell variant urothelial carcinoma, but not metastasis of the renal cell carcinoma. Finally, computerized tomographic scanning confirmed that there was no primary tumor in the kidney. The clinical and pathological characteristic had not been identified for the limited reports. More work should be done to know this kind of tumor well for guiding clinical therapy. PMID:25031765

  12. Non-invasive diagnostic techniques in the diagnosis of squamous cell carcinoma.

    PubMed

    Warszawik-Hendzel, Olga; Olszewska, Małgorzata; Maj, Małgorzata; Rakowska, Adriana; Czuwara, Joanna; Rudnicka, Lidia

    2015-12-31

    Squamous cell carcinoma is the second most common cutaneous malignancy after basal cell carcinoma. Although the gold standard of diagnosis for squamous cell carcinoma is biopsy followed by histopathology evaluation, optical non-invasive diagnostic tools have obtained increased attention. Dermoscopy has become one of the basic diagnostic methods in clinical practice. The most common dermoscopic features of squamous cell carcinoma include clustered vascular pattern, glomerular vessels and hyperkeratosis. Under reflectance confocal microscopy, squamous cell carcinoma shows an atypical honeycomb or disarranged pattern of the spinous-granular layer of the epidermis, round nucleated bright cells in the epidermis and round vessels in the dermis. High frequency ultrasound and optical coherence tomography may be helpful in predominantly in pre-surgical evaluation of tumor size. Emerging non-invasive or minimal invasive techniques with possible application in the diagnosis of squamous cell carcinoma of the skin, lip, oral mucosa, vulva or other tissues include high-definition optical coherence tomography, in vivo multiphoton tomography, direct oral microscopy, electrical impedance spectroscopy, fluorescence spectroscopy, Raman spectroscopy, elastic scattering spectroscopy, differential path-length spectroscopy, nuclear magnetic resonance spectroscopy, and angle-resolved low coherence interferometry. PMID:26848316

  13. Intergrin gene expression profiles of humanhepatocellular carcinoma

    PubMed Central

    Liu, Lian-Xin; Jiang, Hong-Chi; Liu, Zhi-Hua; Zhou, Jing; Zhang, Wei-Hui; Zhu, An-Long; Wang, Xiu-Qin; Wu, Min

    2002-01-01

    AIM: To investigate gene expression profiles of intergrin genes in hepatocellular carcinoma (HCC) through the usage of Atlas Human Cancer Array membranes, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Northern blot. METHODS: Hybridization of cDNA array membrane was performed with α 32P-labeled cDNA probes synthesized from RNA isolated from hepatocellular carcinoma and adjacent non-cirrhotic liver. AtlasImage, which is a software specific to array, was used to analyze the result. RT-PCR of 24 pairs specimen and Northern blot of 4 pairs specimen were used to confirm the expression pattern of some intergrin genes identified by Atlas arrays hybridization. RESULTS: Among 588 genes spotted in membrane, 17 genes were related to intergrin. Four genes were up-regulated, such as intergrin alpha8, beta1, beta7 and beta8 in HCC. Whereas there were no genes down-regulated in HCC. RT-PCR and Northern blot analysis of intergrin beta1 gene gave results consistent with cDNA array findings. CONCLUSION: Investigation of these intergrin genes should help to disclose the molecular mechanism of the cell adhesion, invasive and metastasis of HCC. A few genes are reported to have changed in HCC for the first time. The quick and high-throughout method of profiling gene expression by cDNA array provides us overview of key factors that may involved in HCC, and may find the clue of the study of HCC metastasis and molecular targets of anti-metastasis therapy. The precise relationship between the altered genes and HCC is a matter of further investigation. PMID:12174369

  14. Merkel cell carcinoma and chronic arsenicism.

    PubMed

    Lien, H C; Tsai, T F; Lee, Y Y; Hsiao, C H

    1999-10-01

    Arsenic is a well-documented human carcinogen. Bowen's disease, squamous cell carcinoma, and basal cell carcinoma are the most common skin cancers found in patients exposed to arsenic over the long term. Merkel cell carcinoma has been documented in Taiwanese patients who resided in an endemic area of black foot disease, another condition found in patients with chronic arsenicism. We collected all cases of Merkel cell carcinoma diagnosed at two medical centers in Taiwan (N = 11) to find a possible association between chronic arsenicism and Merkel cell carcinoma. In our study 6 of the 11 patients were residents of the endemic areas for chronic arsenicism.

  15. Thyroid carcinoma, version 2.2014.

    PubMed

    Tuttle, R Michael; Haddad, Robert I; Ball, Douglas W; Byrd, David; Dickson, Paxton; Duh, Quan-Yang; Ehya, Hormoz; Haymart, Megan; Hoh, Carl; Hunt, Jason P; Iagaru, Andrei; Kandeel, Fouad; Kopp, Peter; Lamonica, Dominick M; Lydiatt, William M; McCaffrey, Judith; Moley, Jeffrey F; Parks, Lee; Raeburn, Christopher D; Ridge, John A; Ringel, Matthew D; Scheri, Randall P; Shah, Jatin P; Sherman, Steven I; Sturgeon, Cord; Waguespack, Steven G; Wang, Thomas N; Wirth, Lori J; Hoffmann, Karin G; Hughes, Miranda

    2014-12-01

    These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.

  16. Papillary thyroid carcinoma in children and adolescents.

    PubMed

    Chung, Bo Mi; Park, Sung Hee; Kim, Soo Jin; Seo, Jae Seung; Kim, Yang Soo; Shim, Hyung Jin; Lee, Jong Beum

    2014-09-01

    Differentiated thyroid carcinoma is uncommon in children and constitutes 0.5% to 3% of all pediatric malignancies. Few studies have reported imaging findings of childhood papillary thyroid carcinomas. We report 3 cases of papillary thyroid carcinomas in children. Among the 3 patients, the youngest was a 7-year-old girl. In the current report, we describe 2 cases of classic papillary thyroid carcinoma and 1 case of pediatric diffuse sclerosing variant of papillary thyroid carcinoma. The ultrasonographic features and diagnostic procedures in these pediatric patients are similar to those in adults.

  17. [Lactobacilli and colon carcinoma--A review].

    PubMed

    Wang, Shumei; Zhang, Lanwei; Shan, Yujuan

    2015-06-01

    Epidemiological studies showed that incidence of colon carcinoma is increased in the world. There are many difficulties to inhibit colon carcinoma because the causes of inducing colon carcinoma were various and interactive each other. Previous evidence supported the balance of the colonic microflora was critical in inhibiting colon carcinoma and the protection by colonic microflora could be improved by ingesting lactobacilli. Therefore, the biological functions and anticancer effects of lactobacilli attract attention of researchers. In this review we discussed the causes of colon carcinoma; the anticancer mechanisms of lactobacilli on the basis of our own studies. Eventually, we summarized the effects of anticancer of different components and metabolic products extracted from lactobacilli.

  18. Tubulocystic carcinoma of kidney associated with papillary renal cell carcinoma.

    PubMed

    Deshmukh, Mahesh; Shet, Tanuja; Bakshi, Ganesh; Desai, Sangeeta

    2011-01-01

    Tubulocystic renal cell carcinoma (TCRCC) is a rare variant of renal cell carcinoma, which has distinct histology but there is some controversy about its association with papillary renal cell carcinoma (PRCC) and cell of origin in literature. We report an 18-year-old girl with the rare TCRCC of kidney associated with PRCC with metastases to the para-aortic nodes. The patient presented with hematuria and a right renal mass with enlarged regional nodes for which a radical nephrectomy with retroperitoneal lymph node dissection was done. On gross examination, a solid cystic lesion involving the lower pole and middle pole of the kidney measuring 12x9x9 cm was seen along with an additional cystic lesion in upper pole of kidney. Microscopically the main tumor showed the typical histology of a tubulocystic carcinoma with multiple cysts filled with secretions lined by variably flattened epithelium with hobnailing of cells. The mass in the upper pole was a high-grade PRCC and the nodal metastases had morphology similar to this component. To conclude, at least a small but definite subset of TCRCC is associated with PRCC, and cases associated with PRCC do seem to have a higher propensity for nodal metastasis as in the case we report.

  19. [Clinical-biological differences between invasive ductal carcinomas and breast lobular carcinomas. Preliminary results].

    PubMed

    Ruibal, A; Núñez, M I; del Río, M f; Arias, J; Martínez, M I; Rabadán, J; Tejerina, A

    1999-01-01

    In order to know the biological differences between both histological types, we have analyzed some clinical and biological parameters in tissues of women having infiltrating carcinomas (247 ductal (IDCs) 17 and lobular (ILCs) of the breast. Our preliminary results led us to suggest the following. 1) In negative axillary lymph node involvement (N-) patients, ILCs were more frequently associated with diploidy and the existence of multiple foci; likewise, they had higher pS2 cytosolic levels than IDC; 2) in N+ patients, ILC were associated with multicentricity and had higher concentrations of progesterone receptors and 3) these findings could help to explain us the clinical and biological peculiarities, as well as, the clinical outcome of both histological types. PMID:10352319

  20. Integrating self-help books into psychotherapy.

    PubMed

    Campbell, Linda F; Smith, Thomas P

    2003-02-01

    This article describes a systematic and integral method of incorporating self-help books into psychotherapy as a collaborative function. We address the distinctions between self-help and bibliotherapy, consider bibliotherapy as adjunctive or integrative to psychotherapy, and outline the multiple uses of bibliotherapy for clinical purposes. How to apply self-help books in psychotherapy and ways to select books are illustrated by a case example. Indications and contraindications for bibliotherapy in therapy are outlined.

  1. Xenotransplanted human prostate carcinoma (DU145) cells develop into carcinomas and cribriform carcinomas: ultrastructural aspects.

    PubMed

    Gilloteaux, Jacques; Jamison, James M; Neal, Deborah R; Summers, Jack L; Taper, Henryk S

    2012-10-01

    Androgen-independent, human prostate carcinoma cells (DU145) develop into solid, carcinomatous xenotransplants on the diaphragm of nu/nu mice. Tumors encompass at least two poorly differentiated cell types: a rapidly dividing, eosinophilic cell comprises the main cell population and a few, but large basophilic cells able to invade the peritoneal stroma, the muscular tissue, lymph vessels. Poor cell contacts, intracytoplasmic lumina, and signet cells are noted. Lysosomal activities are reflected by entoses and programmed cell deaths forming cribriform carcinomas. In large tumors, degraded cells may align with others to facilitate formation of blood supply routes. Malignant cells would spread via ascites and through lymphatics.

  2. Postpartum depression and help-seeking behavior.

    PubMed

    McGarry, Joanne; Kim, Han; Sheng, Xiaoming; Egger, Marlene; Baksh, Laurie

    2009-01-01

    The objective of this analysis was to investigate the demographic differences between women who report postpartum depression symptoms (PPDS) and seek help versus those who report symptoms but who do not seek help, using data from the Utah Pregnancy Risk Assessment Monitoring System (PRAMS) 2004 dataset. Overall, 14.7% of Utah women reported experiencing PPDS in 2004. Sixty percent of the women who reported having PPDS did not seek help. Seeking help for depression during pregnancy was associated with help-seeking behavior postpartum (adjusted odds ratio [aOR] = 0.1; 95% confidence interval [CI], 0.04-0.2). Other factors associated with seeking help included having an infant admitted to the intensive care unit (aOR = 0.4; 95% CI, 0.2-0.9) and rural residency (aOR = 0.3; 95% CI, 0.2-0.7). Nonwhite women were 12.1 times (95% CI, 3.0-48.5) more likely to not seek help for depression compared to white women. Further, Hispanic women (aOR = 3.2; 95% CI, 1.3-8.1) and women who experienced emotional abuse had increased odds of not seeking help (aOR = 2.9; 95% CI, 1.3-6.2). Nearly 15% of Utah women in this study reported PPDS, yet fewer than half sought help. Target populations, such as nonwhite, Hispanic, emotionally abused, and urban women, have been identified for public health interventions.

  3. Can Instructors Help Learners Overcome Math Anxiety?

    ERIC Educational Resources Information Center

    Preis, Christy; Biggs, Bobbie T.

    2001-01-01

    Defines math anxiety and discusses some of its sources. Suggests methods for instructors in postsecondary institutions to help learners become successful in mathematics. (Contains 33 references.) (JOW)

  4. Helping You Choose Quality Behavioral Health Care

    MedlinePlus

    Helping You Choose Quality Behavioral Health Care Selecting quality behavioral health care services for yourself, a relative or friend requires special thought and attention. The Joint Commission on ...

  5. Helping You Identify Quality Laboratory Services

    MedlinePlus

    Helping You Identify Quality Laboratory Services Selecting quality health care services for yourself, a relative or friend requires special thought and attention. The Joint Commission has prepared ...

  6. 18F-fluorodeoxyglucose positron emission tomography/computed tomography comparison of gastric lymphoma and gastric carcinoma

    PubMed Central

    Li, Xiao-Feng; Fu, Qiang; Dong, You-Wen; Liu, Jian-Jing; Song, Xiu-Yu; Dai, Dong; Zuo, Cong; Xu, Wen-Gui

    2016-01-01

    AIM To compare 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) features in gastric lymphoma and gastric carcinoma. METHODS Patients with newly diagnosed gastric lymphoma or gastric carcinoma who underwent 18F-FDG PET/CT prior to treatment were included in this study. We reviewed and analyzed the PET/CT features of gastric wall lesions, including FDG avidity, pattern (focal/diffuse), and intensity [maximal standard uptake value: (SUVmax)]. The correlation of SUVmax with gastric clinicopathological variables was investigated by χ2 test, and receiver-operating characteristic (ROC) curve analysis was performed to determine the differential diagnostic value of SUVmax-associated parameters in gastric lymphoma and gastric carcinoma. RESULTS Fifty-two patients with gastric lymphoma and 73 with gastric carcinoma were included in this study. Abnormal gastric FDG accumulation was found in 49 patients (94.23%) with gastric lymphoma and 65 patients (89.04%) with gastric carcinoma. Gastric lymphoma patients predominantly presented with type I and type II lesions, whereas gastric carcinoma patients mainly had type III lesions. The SUVmax (13.39 ± 9.24 vs 8.35 ± 5.80, P < 0.001) and SUVmax/THKmax (maximal thickness) (7.96 ± 4.02 vs 4.88 ± 3.32, P < 0.001) were both higher in patients with gastric lymphoma compared with gastric carcinoma. ROC curve analysis suggested a better performance of SUVmax/THKmax in the evaluation of gastric lesions between gastric lymphoma and gastric carcinoma in comparison with that of SUVmax alone. CONCLUSION PET/CT features differ between gastric lymphoma and carcinoma, which can improve PET/CT evaluation of gastric wall lesions and help differentiate gastric lymphoma from gastric carcinoma. PMID:27678362

  7. 18F-fluorodeoxyglucose positron emission tomography/computed tomography comparison of gastric lymphoma and gastric carcinoma

    PubMed Central

    Li, Xiao-Feng; Fu, Qiang; Dong, You-Wen; Liu, Jian-Jing; Song, Xiu-Yu; Dai, Dong; Zuo, Cong; Xu, Wen-Gui

    2016-01-01

    AIM To compare 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) features in gastric lymphoma and gastric carcinoma. METHODS Patients with newly diagnosed gastric lymphoma or gastric carcinoma who underwent 18F-FDG PET/CT prior to treatment were included in this study. We reviewed and analyzed the PET/CT features of gastric wall lesions, including FDG avidity, pattern (focal/diffuse), and intensity [maximal standard uptake value: (SUVmax)]. The correlation of SUVmax with gastric clinicopathological variables was investigated by χ2 test, and receiver-operating characteristic (ROC) curve analysis was performed to determine the differential diagnostic value of SUVmax-associated parameters in gastric lymphoma and gastric carcinoma. RESULTS Fifty-two patients with gastric lymphoma and 73 with gastric carcinoma were included in this study. Abnormal gastric FDG accumulation was found in 49 patients (94.23%) with gastric lymphoma and 65 patients (89.04%) with gastric carcinoma. Gastric lymphoma patients predominantly presented with type I and type II lesions, whereas gastric carcinoma patients mainly had type III lesions. The SUVmax (13.39 ± 9.24 vs 8.35 ± 5.80, P < 0.001) and SUVmax/THKmax (maximal thickness) (7.96 ± 4.02 vs 4.88 ± 3.32, P < 0.001) were both higher in patients with gastric lymphoma compared with gastric carcinoma. ROC curve analysis suggested a better performance of SUVmax/THKmax in the evaluation of gastric lesions between gastric lymphoma and gastric carcinoma in comparison with that of SUVmax alone. CONCLUSION PET/CT features differ between gastric lymphoma and carcinoma, which can improve PET/CT evaluation of gastric wall lesions and help differentiate gastric lymphoma from gastric carcinoma.

  8. Mitochondriome and Cholangiocellular Carcinoma

    PubMed Central

    Bahitham, Wesam; Liao, Xiaoping; Peng, Fred; Bamforth, Fiona; Chan, Alicia; Mason, Andrew; Stone, Bradley; Stothard, Paul; Sergi, Consolato

    2014-01-01

    Cholangiocellular carcinoma (CCA) of the liver was the target of more interest, recently, due mainly to its increased incidence and possible association to new environmental factors. Somatic mitochondrial DNA (mtDNA) mutations have been found in several cancers. Some of these malignancies contain changes of mtDNA, which are not or, very rarely, found in the mtDNA databases. In terms of evolutionary genetics and oncology, these data are extremely interesting and may be considered a sign of poor fitness, which may conduct in some way to different cellular processes, including carcinogenesis. MitoChip analysis is a strong tool for investigations in experimental oncology and was carried out on three CCA cell lines (HuCCT1, Huh-28 and OZ) with different outcome in human and a Papova-immortalized normal hepatocyte cell line (THLE-3). Real time quantitative PCR, western blot analysis, transmission electron microscopy, confocal laser microscopy, and metabolic assays including L-Lactate and NAD+/NADH assays were meticulously used to identify mtDNA copy number, oxidative phosphorylation (OXPHOS) content, ultrastructural morphology, mitochondrial membrane potential (ΔΨm), and differential composition of metabolites, respectively. Among 102 mtDNA changes observed in the CCA cell lines, 28 were non-synonymous coding region alterations resulting in an amino acid change. Thirty-eight were synonymous and 30 involved ribosomal RNA (rRNA) and transfer RNA (tRNA) regions. We found three new heteroplasmic mutations in two CCA cell lines (HuCCT1 and Huh-28). Interestingly, mtDNA copy number was decreased in all three CCA cell lines, while complexes I and III were decreased with depolarization of mitochondria. L-Lactate and NAD+/NADH assays were increased in all three CCA cell lines. MtDNA alterations seem to be a common event in CCA. This is the first study using MitoChip analysis with comprehensive metabolic studies in CCA cell lines potentially creating a platform for future

  9. Spontaneous regression of hepatocellular carcinoma.

    PubMed Central

    Ayres, R C; Robertson, D A; Dewbury, K C; Millward-Sadler, G H; Smith, C L

    1990-01-01

    A 63 year old white woman presented with abdominal discomfort, anorexia, and weight loss. Investigations showed hepatocellular carcinoma with pulmonary metastases. The primary and secondary tumours resolved without specific treatment. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:2165992

  10. Transrectal Ultrasound of Prostatic Carcinoma

    PubMed Central

    Murray, Daniel J.; Cooperberg, Peter L.; Goldenberg, S. Larry; Toi, Ants

    1991-01-01

    The purpose of this paper is to review the indications for transrectal ultrasound; to briefly describe the sonographic technique; to describe the sonographic findings of prostatic carcinoma; to review the indications for transrectal sonographic-guided biopsy; and to discuss the controversles of routine screening and staging. ImagesFigures 1-3 PMID:21229044

  11. Genomic homogeneity in fibrolamellar carcinomas

    PubMed Central

    Sirivatanauksorn, Y; Sirivatanauksorn, V; Lemoine, N; Williamson, R; Davidson, B

    2001-01-01

    BACKGROUND—Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) with distinctive clinical and histological features. To date there have been few studies on the genotypic aspects of FLC and no previous attempts have been made to use the arbitrarily primed-polymerase chain reaction (AP-PCR) technique to detect genetic alterations in this disease.
AIM—The aim of this study was to assess the degree of genomic heterogeneity of FLC using the AP-PCR technique.
METHODS—A total of 50 tissue samples of primary and metastatic FLCs from seven patients were microdissected. AP-PCR amplification of each genomic DNA sample was carried out using two arbitrary primers.
RESULTS—DNA fingerprints of the primary FLCs and all their metastatic lesions (both synchronous and metachronous disease) were identical in an individual patient. The fingerprints were different between tumours of different patients. No evidence of intratumour heterogeneity was observed.
CONCLUSIONS—Such genomic homogeneity in FLCs may explain their indolent growth. The absence of clonal evolution, which is present in other tumours (particularly HCCs), may explain the distinct behaviour in this tumour. The tumorigenic pathway and degree of somatic genomic changes in this disease may be less complex than in HCC.


Keywords: fibrolamellar carcinoma; hepatocellular carcinoma; DNA fingerprint; arbitrarily primed-polymerase chain reaction; laser capture microdissection PMID:11413114

  12. Radiotherapy T1 glottic carcinoma

    SciTech Connect

    Zablow, A.I.; Erba, P.S.; Sanfillippo, L.J.

    1989-11-01

    From 1970 to 1985, curative radiotherapy was administered to 63 patients with stage I carcinoma of the true vocal cords. Precision radiotherapeutic technique yields cure rates comparable to surgical results. Good voice quality was preserved in a high percentage of patients.

  13. Mandible metastasis of hepatocellular carcinoma.

    PubMed

    Niedzielska, Iwona; Langowska-Adamczyk, Helena; Pajak, Jacek; Kajor, Maciej; Niedzielski, Zbigniew; Gołka, Dariusz

    2004-01-01

    Metastases to oral cavity are very uncommon. We present a case of hepatocellular carcinoma (HCC) metastasis to the jaw. The x-ray examination and clinical picture of the lesion were not characteristic. The gingival metastasis may mimic other benign and malignant conditions which affect jaw and therefore the histopathological examination is necessary to make an ultimate diagnosis.

  14. Children's Recognition of Pride and Guilt as Consequences of Helping and Not Helping.

    ERIC Educational Resources Information Center

    Shorr, David N.; McClelland, Stephen E.

    1998-01-01

    Investigated the relationship between young children's age and their recognition that helping or choosing not to help can cause feelings of pride or guilt. Found age differences in identifying helping-action or inaction as causes, but little support for the hypothesis that identification of guilt as a consequence of not helping would…

  15. Oct4 is a reliable marker of liver tumor propagating cells in hepatocellular carcinoma.

    PubMed

    Wu, Guang; Wilson, George; Zhou, Gang; Hebbard, Lionel; George, Jacob; Qiao, Liang

    2015-10-01

    Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide and the 2nd most common cause of cancer related mortality. The poor prognosis is largely due to the difficulty in early diagnoses and eradication of stem-like cells within HCC, which are termed liver tumor propagating cells (LTPCs). These LTPCs are involved in all stages of tumorigenesis including tumor initiation, progression, and treatment failure. The greatest challenge in understanding these LTPCs is finding effective ways in isolating and characterizing these cells with current methods showing large inter-tumor variability in isolating these cells. Oct4 is a stem cell gene associated with LTPCs and has been shown to be involved in regulating a range of functions in HCC cells associated with LTPC features. In this study we determined the efficacy and reliability in utilizing Oct4 to isolate and characterize LTPCs. We have shown that Oct4 is ubiquitously expressed in all HCC tumors tested whereas other traditional LTPC markers had high intratumor variability in their expression. We then utilized a human Oct4 promoter driving an enhanced green fluorescent protein (EGFP) reporter which showed that Oct4+ cells had all the classic features of LTPCs including increased sphere formation in vitro, tumor forming potential in immunocompromised mice, expression of stemness associated genes, and resistance to Sorafenib which is the major drug used to treat advanced HCC. Based on our findings we have identified Oct4 as a reliable marker of LTPCs and discovered a novel way to isolate and characterize LTPCs. PMID:26562475

  16. A network-based method for identifying prognostic gene modules in lung squamous carcinoma

    PubMed Central

    Zhang, Kaitai; Wang, Guiqi; Zhang, Lei; An, Ning; Cheng, Shujun

    2016-01-01

    Similarities in gene expression between both developing embryonic and precancerous tissues and cancer tissues may help identify much-needed biomarkers and therapeutic targets in lung squamous carcinoma. In this study, human lung samples representing ten successive time points, from embryonic development to carcinogenesis, were used to construct global gene expression profiles. Differentially expressed genes with similar expression in precancerous and cancer samples were identified. Using a network-based greedy searching algorithm to analyze the training cohort (n = 69) and three independent testing cohorts, we successfully identified a significant 22-gene module in which expression levels were correlated with overall survival in lung squamous carcinoma patients. PMID:26919109

  17. Teaching Helping to Adolescents with Autism

    ERIC Educational Resources Information Center

    Day-Watkins, Jessica; Murray, Rachel; Connell, James E.

    2014-01-01

    This study is a replication and extension of Reeve, Reeve, Townsend, and Poulson (2007) evaluating the effects of a treatment package that included multiple-exemplar training, video modeling, prompting, and reinforcement on helping of 3 adolescents with autism. Results demonstrated that all participants acquired the helping responses. Probes…

  18. Helping Students Cope with Fears and Crises.

    ERIC Educational Resources Information Center

    Walz, Garry R., Ed.; Bleuer, Jeanne C., Ed.

    This document consists of two modules extracted from a six-module larger work. Module 1 presents six articles on the topic of "helping students to cope with fears and crises." Module 2 contains 17 articles on "programs and practices for helping students cope with fears and crises." Article titles and authors are as follows: (1) "Worries of…

  19. Causal Indicators Can Help to Interpret Factors

    ERIC Educational Resources Information Center

    Bentler, Peter M.

    2016-01-01

    The latent factor in a causal indicator model is no more than the latent factor of the factor part of the model. However, if the causal indicator variables are well-understood and help to improve the prediction of individuals' factor scores, they can help to interpret the meaning of the latent factor. Aguirre-Urreta, Rönkkö, and Marakas (2016)…

  20. Helping Your Child in Reading in Science.

    ERIC Educational Resources Information Center

    Ediger, Marlow

    Parents can help students learn science in a variety of ways. Taking advantage of children's natural curiosity, parents can take short walks with their child to notice interesting things in the environment. Parents can also help students perform science experiments at home that are related to school science experiments. In addition, parents can…

  1. Helping Your Child Become a Reader

    ERIC Educational Resources Information Center

    US Department of Education, 2008

    2008-01-01

    "Helping Your Child Become a Reader" includes information about why and how to use language skills (talking and listening, reading, and writing) to help young children grow into readers. Everyday activities and a list of resources for parents to encourage children's love of reading and strengthen language skills are also provided. This brochure…

  2. Children in Conflict: Books that Help.

    ERIC Educational Resources Information Center

    Galen, Nancy; Johns, Jerry L.

    Bibliotherapy may be of assistance in helping children cope with problems in the following ways: by helping them learn to analyze their attitudes and behavior; by assisting them in comparing their beliefs with those of others; by offering possible solutions to problems; and by contributing to their socialization. To identify the types of problems…

  3. Helping Your Students Manage Their Time

    ERIC Educational Resources Information Center

    Reese, Susan

    2006-01-01

    This article presents some suggestions for helping students learn how to better manage their time. Much of this advice can help students in the secondary education establish habits that will benefit them in the postsecondary education or in the world of work. Students benefit by using an appointment calendar to keep track of all due dates,…

  4. Helping Young Children in Frightening Times.

    ERIC Educational Resources Information Center

    Young Children, 2001

    2001-01-01

    Presents ways parents and other adults can help young children deal with tragedy and violence in the wake of terrorist attacks on the United States. Suggests giving reassurance and physical comfort, providing structure and stability, expecting a range of reactions, helping children to talk if they are ready, turning off the television, and…

  5. Context-Sensitive "Help" in CALL

    ERIC Educational Resources Information Center

    Heift, Trude

    2006-01-01

    This article discusses design and usability issues pertaining to context-sensitive "help" in computer-assisted language learning (CALL). As part of the discussion, we present a study in which we examined the effects of three independent factors on student usage of context-sensitive "help": feedback, exercise type, and language proficiency. Forty…

  6. Students' Help Seeking during Physical Education

    ERIC Educational Resources Information Center

    Nye, Susan B.

    2008-01-01

    Seeking help with academic tasks has been regarded as an important strategy to enhance student learning (Newman, 1994; Ryan, Gheen, & Midgley, 1998; Zimmerman & Martinez-Pons, 1986). Seeking help is conceptualized as student-initiated efforts to secure task information or solicit advice when a deficiency in their understanding of the content…

  7. Helping Your Child Learn Math. ERIC Digest.

    ERIC Educational Resources Information Center

    Haury, David L.; Milbourne, Linda A.

    This digest informs parents about how to help their child learn mathematics. It discusses what children are learning in mathematics and provides parents with some guidance and World Wide Web resources that can benefit them in assisting their child. Featured topics include setting an example of the usefulness of math, helping children see the math…

  8. Signaling for Help. PAM Repeater, No. 56.

    ERIC Educational Resources Information Center

    Ensign, Arselia S., Ed.

    Signaling devices can help individuals with disabilities call for help, see and feel sound, and monitor what is happening in another room. This pamphlet describes signaling devices within the following categories: emergency, telephone, doorbell, smoke and fire, baby cry and room monitor, light and vibrating, security, wake-up, and child monitor…

  9. Helping tomorrow's retirees manage "distribution phase" risks.

    PubMed

    Daniels, Bill

    2004-01-01

    Much of employers' attention has focused on helping employees manage the accumulation of 401(k) plan assets rather than on helping them manage the distribution phase--the period during which employees begin drawing down their 401(k) savings to meet their retirement needs. Assisting employees in managing the distribution phase can play an important role in helping employers meet a range of workforce planning goals and ensuring a maximum return on the retirement dollars that have been invested by both employees and the company. By implementing a properly structured approach to help employees manage the distribution phase, employers can help them maximize the value of their retirement savings at little or no employer cost, thanks to the leverage of the company's group purchasing power and the tax advantages of employer-sponsored plans.

  10. Insular carcinoma: a distinct de novo entity among follicular carcinomas of the thyroid gland.

    PubMed

    Pilotti, S; Collini, P; Mariani, L; Placucci, M; Bongarzone, I; Vigneri, P; Cipriani, S; Falcetta, F; Miceli, R; Pierotti, M A; Rilke, F

    1997-12-01

    We reclassified 720 nonmedullary invasive thyroid carcinomas diagnosed and treated between 1975 and 1993. Twenty-seven cases met the criteria of insular carcinoma and 29 cases those of widely invasive follicular carcinoma. Comparison of these histotypes with respect to pathologic stage and overall, relative, and visceral metastasis-free survival showed a significant association between histotype and pT and pN categories. In particular, pT4 (p < 0.001) and pN1 (p < 0.001) categories were more frequent in the insular carcinoma histotype. By contrast, no significant differences in overall, relative, or visceral metastasis-free survival were observed between insular carcinoma and widely invasive follicular carcinoma. Molecular analysis by polymerase chain reaction-single-strand conformation polymorphism demonstrated RAS gene family point mutations in five of eight cases analyzed in each of the two histotypes, with a high proportion of CAA-->AAA transversion at codon 61 of the N-RAS gene in insular carcinoma. These findings suggest that insular carcinoma represents a de novo entity distinct from widely invasive follicular carcinoma, that widely invasive follicular carcinoma has biologic characteristics more consistent with poorly differentiated than well-differentiated carcinomas, and that both insular carcinoma and widely invasive follicular carcinoma share similar molecular alterations.

  11. Synchronous invasive ductal carcinoma in encapsulated papillary ductal carcinoma

    PubMed Central

    Regan, J.P.; Casaubon, J.T.; Genelus-Dominique, E.

    2016-01-01

    Encapsulated papillary ductal carcinoma (EPC) of the breast is a rare form of cancer with defining histopathology of encapsulation. These lesions are typically indolent but may rarely have concomitant, synchronous invasive lesions. This report details a 56-year-old black female who presented with a palpable left breast mass. Adenosis with focal fibrous and ductal hyperplasia characteristics were found on core needle biopsy. Excisional biopsy showed EPC with invasive components. A simple mastectomy was performed and a second lesion was identified as invasive ductal carcinoma. EPC typically has good prognosis and a low incidence of invasion. The risk increases in the presence of a second, synchronous lesion as in our case. Management is typically performed with breast conserving methods; however, missing a second lesion is possible. This report provides an overview of the literature and discussion of the role of MRI in preoperative workup. PMID:27562577

  12. Anxiolytic Treatment Impairs Helping Behavior in Rats.

    PubMed

    Ben-Ami Bartal, Inbal; Shan, Haozhe; Molasky, Nora M R; Murray, Teresa M; Williams, Jasper Z; Decety, Jean; Mason, Peggy

    2016-01-01

    Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats' subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat's behavior on one session

  13. Automated Help System For A Supercomputer

    NASA Technical Reports Server (NTRS)

    Callas, George P.; Schulbach, Catherine H.; Younkin, Michael

    1994-01-01

    Expert-system software developed to provide automated system of user-helping displays in supercomputer system at Ames Research Center Advanced Computer Facility. Users located at remote computer terminals connected to supercomputer and each other via gateway computers, local-area networks, telephone lines, and satellite links. Automated help system answers routine user inquiries about how to use services of computer system. Available 24 hours per day and reduces burden on human experts, freeing them to concentrate on helping users with complicated problems.

  14. Anxiolytic Treatment Impairs Helping Behavior in Rats

    PubMed Central

    Ben-Ami Bartal, Inbal; Shan, Haozhe; Molasky, Nora M. R.; Murray, Teresa M.; Williams, Jasper Z.; Decety, Jean; Mason, Peggy

    2016-01-01

    Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats’ subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat’s behavior on one

  15. Two cases of matrix-producing carcinoma showing chondromyxoid matrix in cytological specimens

    PubMed Central

    Tajima, Shogo; Koda, Kenji

    2015-01-01

    Matrix-producing carcinoma (MPC) is extremely rare. Limited reports have described the cytological aspects of MPC. Herein, we present 2 cases of MPC, both of which showed ring-enhancement on magnetic resonance imaging (MRI) and chondromyxoid matrix on cytological specimens. In these cases, the diagnosis of MPC was preoperatively suspected. Recognizing extracellular matrix as chondromyxoid matrix on the cytological specimen is important in making a distinction between MPC and mucinous carcinoma. They share some features on cytology and MRI (ring-enhancement) but have different prognoses and involve different approaches for obtaining histological specimens for neoadjuvant therapy. The reason for the different approaches for obtaining the histological specimens is that tumor cells usually distribute peripherally in MPC in contrast to the relatively uniform distribution of mucinous carcinoma. Therefore, it would be helpful if the diagnosis of MPC can be suspected by examination of the cytological specimen. PMID:26379985

  16. Immunohistochemistry applied to the differential diagnosis between ductal and lobular carcinoma of the breast.

    PubMed

    de Deus Moura, Rafael; Wludarski, Sheila C L; Carvalho, Filomena M; Bacchi, Carlos E

    2013-01-01

    The distinction between classic lobular and ductal carcinoma, both in situ and invasive, has important therapeutic and management implications. Most ductal and lobular carcinomas are distinguished readily on hematoxylin-eosin-stained sections because of distinct histomorphologic features. In cases with ambiguous morphologic features, however, categorization in one or another type can be a challenge. Several immunohistochemical markers, including epithelial cadherin, p120, β-catenin, and low-molecular-weight and high-molecular-weight cytokeratins among others, have been introduced to help better discriminate between lobular neoplasia and ductal carcinoma. In this critical review of the literature, we comment about the usefulness and the limitations of these markers to improve the accuracy in the differential diagnosis of breast pathology.

  17. Renal cell carcinoma: Evolving and emerging subtypes

    PubMed Central

    Crumley, Suzanne M; Divatia, Mukul; Truong, Luan; Shen, Steven; Ayala, Alberto G; Ro, Jae Y

    2013-01-01

    Our knowledge of renal cell carcinoma (RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and defined, and our understanding of the biology and clinical correlates of these tumors is changing. Evolving concepts in Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular cystic clear cell RCC, and carcinoma associated with neuroblastoma are addressed within this review. Tubulocystic carcinoma, thyroid-like follicular carcinoma of kidney, acquired cystic disease-associated RCC, and clear cell papillary RCC are also described. Finally, candidate entities, including RCC with t(6;11) translocation, hybrid oncocytoma/chromophobe RCC, hereditary leiomyomatosis and RCC syndrome, and renal angiomyoadenomatous tumor are reviewed. Knowledge of these new entities is important for diagnosis, treatment and subsequent prognosis. This review provides a targeted summary of new developments in RCC. PMID:24364021

  18. Elderly care recipients’ perceptions of treatment helpfulness for depression and the relationship with help-seeking

    PubMed Central

    Atkins, Joanna; Naismith, Sharon L; Luscombe, Georgina M; Hickie, Ian B

    2015-01-01

    Objective This study aims to examine perceptions of the helpfulness of treatments/interventions for depression held by elderly care recipients, to examine whether these beliefs are related to help-seeking and whether the experience of depression affects beliefs about treatment seeking, and to identify the characteristics of help-seekers. Method One hundred eighteen aged care recipients were surveyed on their beliefs about the helpfulness of a variety of treatments/interventions for depression, on their actual help-seeking behaviors, and on their experience of depression (current and past). Results From the sample, 32.4% of the participants screened positive for depression on the Geriatric Depression Scale, and of these, 24.2% reported receiving treatment. Respondents believed the most helpful treatments for depression were increasing physical activity, counseling, and antidepressant medication. Help-seeking from both professional and informal sources appeared to be related to belief in the helpfulness of counseling and antidepressants; in addition, help-seeking from informal sources was also related to belief in the helpfulness of sleeping tablets and reading self-help books. In univariate analyses, lower levels of cognitive impairment and being in the two lower age tertiles predicted a greater likelihood of help-seeking from professional sources, and female sex and being in the lower two age tertiles predicted greater likelihood of help-seeking from informal sources. In multivariate analyses, only lower levels of cognitive impairment remained a significant predictor of help-seeking from professional sources, whereas both lower age and female sex continued to predict a greater likelihood of help-seeking from informal sources. Conclusion Beliefs in the helpfulness of certain treatments were related to the use of both professional and informal sources of help, indicating the possibility that campaigns or educational programs aimed at changing beliefs about treatments

  19. Photodynamic therapy for basal cell carcinoma.

    PubMed

    Fargnoli, Maria Concetta; Peris, Ketty

    2015-11-01

    Topical photodynamic therapy is an effective and safe noninvasive treatment for low-risk basal cell carcinoma, with the advantage of an excellent cosmetic outcome. Efficacy of photodynamic therapy in basal cell carcinoma is supported by substantial research and clinical trials. In this article, we review the procedure, indications and clinical evidences for the use of photodynamic therapy in the treatment of basal cell carcinoma.

  20. Clear cell carcinoma of the lung.

    PubMed Central

    Edwards, C; Carlile, A

    1985-01-01

    Six tumours of the lung initially classified as clear cell carcinoma, were studied. Examination of further material by light and electron microscopy showed adenocarcinomatous differentiation in three cases and squamous differentiation in two. One case showed the features of a large cell anaplastic carcinoma. The clear appearance of the cytoplasm in paraffin sections was due to accumulations of glycogen that were partially removed during processing. It is concluded that clear cell carcinoma is not a single and separate entity. Images PMID:4031101

  1. Small cell carcinoma of epididymis: multimodal therapy.

    PubMed

    Lima, Guilherme C; Varkarakis, Ioannis M; Allaf, Mohamad E; Fine, Samson W; Kavoussi, Louis R

    2005-08-01

    Extrapulmonary small cell carcinoma is an infrequent tumor that can occur in various organs. Although a few sporadic reports about extrapulmonary small cell carcinoma have been published, much remains to be uncovered about the clinical features, optimal treatment, and natural history. We present a case of small cell carcinoma of the epididymis with retroperitoneal recurrence, an exceedingly rare tumor with behavior and treatment not well characterized. Multimodal therapy with chemotherapy and retroperitoneal lymph node dissection was necessary to manage this aggressive disease.

  2. Long non-coding RNAs and hepatocellular carcinoma.

    PubMed

    Yu, Fu-Jun; Zheng, Jian-Jian; Dong, Pei-Hong; Fan, Xiao-Ming

    2015-01-01

    Recent advances in next-generation sequencing technology in transcriptome analysis have helped identify numerous non-coding RNAs. The long non-coding RNA (lncRNA) is commonly defined as an RNA molecule with a length of 200 bp-100 kbp that lacks protein-coding potential. LncRNAs play a critical role in the regulation of gene expression, including chromatin modification, transcription and post-transcriptional processing. It has been confirmed that dysregulation of lncRNAs is associated with a number of human diseases, particularly tumors. In this study, we focused on the most extensively investigated lncRNAs in hepatocellular carcinoma (HCC). The biological functions and molecular mechanisms of the majority of lncRNAs have yet to be investigated. The improved knowledge on lncRNAs in HCC may help identify lncRNAs that may be used as novel prognostic markers and therapeutic targets.

  3. How to Help a Child Who's Cyberbullied

    MedlinePlus

    ... 25 percent of American children and teens experience cyberbullying, but there are ways parents can help their children, a criminology and bullying expert says. Cyberbullying is intentional harassment, humiliation or ...

  4. Vision Problems: How Teachers Can Help.

    ERIC Educational Resources Information Center

    Desrochers, Joyce

    1999-01-01

    Describes common vision problems in young children such as myopia, strabismus, and amblyopia. Presents suggestions for helping children with vision problems in the early childhood classroom and in outdoor activities. Lists related resources and children's books. (KB)

  5. High Cholesterol: Medicines to Help You

    MedlinePlus

    ... Consumer Information by Audience For Women High Cholesterol--Medicines To Help You Share Tweet Linkedin Pin it ... Test to check your cholesterol (LDL-C) Combination Medicines Brand Name Generic Name Advicor Niacin and Lovastatin ...

  6. Depression--Medicines To Help You

    MedlinePlus

    ... Consumers Consumer Information by Audience For Women Depression--Medicines To Help You Share Tweet Linkedin Pin it ... who take medicines for depression. Important Warnings about Medicines for Depression Children and teens who take antidepressants ...

  7. Family Key to Helping Teens Avoid Obesity

    MedlinePlus

    ... 159681.html Family Key to Helping Teens Avoid Obesity Good relationship with parents, especially between fathers and ... develop healthy habits that may protect them against obesity, a new study suggests. The researchers also found ...

  8. Helping a Child Manage a Chronic Illness

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_160011.html Helping a Child Manage a Chronic Illness Feeling they have control over their ... News) -- Children and teens who feel confident handling a chronic illness on their own appear better able ...

  9. Tips to Help You Get Active

    MedlinePlus

    ... watching your kids, or working out with you. Weather. Wear the right gear . A rain jacket, sunhat ... or winter clothes will help you beat the weather. Find a place to exercise indoors. Walk in ...

  10. Hiring Help at Home: The Basic Facts

    MedlinePlus

    ... usually familiar with community services and know insurance requirements and limitations. It may be helpful to use ... clarify for yourself: n What are your minimum requirements? n What personal qualities are you looking for? ...

  11. How a Healthy Diet Helps You Breastfeed

    MedlinePlus

    ... helps breastfeeding mothers (and everyone else) maintain their energy level, so be sure to get enough of this important mineral in your diet. Lean meats and dark leafy green vegetables are good sources of iron. ...

  12. Parental Money Help to Children and Stepchildren

    PubMed Central

    Henretta, John C.; Van Voorhis, Matthew F.; Soldo, Beth J.

    2013-01-01

    Divorce and remarriage have reshaped the American family giving rise to questions about the place of stepchildren in remarried families. In this article, we examine money transfers from a couple to each of their children. We introduce characteristics of the family and estimate the role of shared family membership affecting all children in the family as well as the difference that stepchild status and other individual characteristics make in transfer flows. Data are from the Health and Retirement Study. There are two central results in the analysis. Overall, provision of financial help from parents to children is a family phenomenon. While help to a particular child is episodic, differences between families in provision of help were much greater than the differences in helping one child versus another within families. Second, stepchild status does differentiate one child from another within a family. Stepchildren are disadvantaged, particularly stepchildren of the wife. PMID:24976667

  13. Folic Acid Helps Prevent Neural Tube Defects

    MedlinePlus

    ... Features Folic Acid Helps Prevent Neural Tube Defects Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir The feature you selected is no longer available. In 10 seconds you will be automatically redirected to the CDC. ...

  14. Strategies That Work to Help Prevent Suicides

    MedlinePlus

    ... fullstory_159314.html Strategies That Work to Help Prevent Suicides Measures include physical barriers and selling fewer ... attempts. There is no single best way to prevent suicide, according to one of the study authors, ...

  15. Who's Most Likely to Seek Infertility Help

    MedlinePlus

    ... fullstory_159678.html Who's Most Likely to Seek Infertility Help They're more likely to be better ... 2016 (HealthDay News) -- Nearly half of people with infertility problems don't seek treatment, according to a ...

  16. Help Protect Babies from Whooping Cough

    MedlinePlus

    ... cough infographic . Keep Your Baby's Whooping Cough Vaccine Current Getting the whooping cough vaccine during pregnancy provides ... this? Submit What's this? Submit Button Past Emails Language: English Español (Spanish) File Formats Help: How do ...

  17. Endometriosis and Infertility: Can Surgery Help?

    MedlinePlus

    ... Website of the American Society for Reproductive Medicine Endometriosis and Infertility: Can Surgery Help? This fact sheet ... with The Society of Reproductive Surgeons What is endometriosis? When tissue like the tissue that that normally ...

  18. Pneumonia Can Be Prevented -- Vaccines Can Help

    MedlinePlus

    ... Past Emails CDC Features Pneumonia Can Be Prevented—Vaccines Can Help Language: English Español (Spanish) Recommend on ... not recommended. Learn more . Lower Your Risk with Vaccines In the United States, there are vaccines that ...

  19. Even Incomplete Steroid Treatment Helps Preemies

    MedlinePlus

    ... medlineplus.gov/news/fullstory_161404.html Even Incomplete Steroid Treatment Helps Preemies: Study Fewer deaths, complications for ... MONDAY, Oct. 10, 2016 (HealthDay News) -- Even partial steroid treatment before birth can improve survival odds for ...

  20. Fruit Flies Help Human Sleep Research

    MedlinePlus

    ... Current Issue Past Issues Fruit Flies Help Human Sleep Research Past Issues / Summer 2007 Table of Contents ... Chiara Cirelli uses experimental fruit flies to study sleep. Although it may be tough to imagine a ...