345 results on '"Davis, Tammy"'
Search Results
302. More Than a Floor.
- Author
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Davis, Tammy
- Subjects
FLOORING - Abstract
The article offers brief profile of flooring products and installation service provider Jack Laurie Group which was established in 1950 and the company has expanded from commercial flooring market to residential flooring after acquisition of carpet manufacturer Carpet Craftsman.
- Published
- 2014
303. ROLLING INTO ROANOKE.
- Author
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Davis, Tammy
- Subjects
AUTOMOBILE exhibitions ,CHARITIES ,AUTOMOBILE auctions - Abstract
The article offers information on the car show, Rolling into Roanoke, to be held on July 19, 2014 in Huntington County, Indiana. Organized by Rick Fischer, owner of Deco Illusions LLC and a board member of the Roanoke Beautification Foundation (RBF), the event will benefit the town of Roanoke. It states that the car show features a unique combination of vehicles on display and ancillary activities like music, shopping and food selling.
- Published
- 2014
304. Intimate Secrets.
- Author
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Davis, Tammy
- Subjects
BRIDES ,WEDDINGS ,UNDERWEAR ,SHOPPING ,WEDDING gowns - Abstract
The article discusses how a bride can look good and feel comfortable during her wedding by having properly fitting undergarments that work with the dress. Brides-to-be are advised to bring their gown when shopping for undergarments and allow plenty of time to get the right fit. It also suggests for the brides to play it safe.
- Published
- 2013
305. Dutch Made Custom Cabinetry.
- Author
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Davis, Tammy
- Subjects
- INDIANA, DUTCH Made Custom Cabinetry (Company)
- Abstract
The article focuses on Dutch Made Custom Cabinetry, a company founded in Harlan, Indiana in 1969.
- Published
- 2013
306. FLYING HIGH.
- Author
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Davis, Tammy
- Subjects
AQUATIC sports ,SPORTING goods - Abstract
The article evaluates the Zapata Racing Flyboard from the Midwest Flyboard.
- Published
- 2013
307. Wayne kitchen & Bath Works.
- Author
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Davis, Tammy
- Subjects
KITCHENS ,BATHS ,SHOWROOMS ,EQUIPMENT & supplies - Abstract
The article provides information on Wayne Kitchen & Bath Works showroom located in Fort Wayne, Indiana.
- Published
- 2013
308. TRAIL BLAZING.
- Author
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Davis, Tammy
- Subjects
TRAILS ,FINANCE ,INVESTMENT of public funds ,ENDOWMENTS ,GOAL (Psychology) - Abstract
The article discusses the pivotal role played by Fort Wayne Trails, Indiana in building a vibrant community. Fort Wayne trail network is made up of 68 miles of paved paths where an average of 1,200 people bike, run and walk. Development of the trail depends on private funding and Fort Wayne Trails are funded through a combination of private and public funds and where public funding is not available without an accompanying private donations. The Trails has reached only 10% of its funding goal.
- Published
- 2013
309. NOT YOUR TYPICAL VILLA.
- Author
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Davis, Tammy
- Subjects
DOMESTIC architecture ,HOUSE construction ,SIDEWALKS ,ROADS ,LIFESTYLES - Abstract
The article offers information on Parker's Bay, a project by Granite Ridge Builders featuring 44 individually owned villas with each home custom-built to the owner's specifications. The community's amenities will include property care, wide sidewalks and easy highway access as the Granite Ridge team realizes that a villa is the solution to the busy lifestyle of most people. Granite Ridge is owned by Tony Reincke.
- Published
- 2013
310. A Foundation of Caring.
- Author
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Davis, Tammy
- Subjects
BRASSIERES ,SPECIALTY stores ,MASTECTOMY ,OFFICE buildings - Abstract
The article focuses on Barbara's New Beginnings, a specialty bra shop set up by Barb Gilbert for fellow patients recovering from mastectomies. It describe how Gilbert began looking at the possibility of opening a fitting shop and decided to apply for Medicare accreditation, getting all the support she needed from office space to furniture after store managers heard about her plans. It adds that Gilbert has turned her business not only as a bra business but a caring business.
- Published
- 2013
311. The Power of Giving.
- Author
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Davis, Tammy
- Subjects
NONPROFIT organizations ,FUNDRAISING ,CHARITABLE giving - Abstract
The article narrates how United Way of Allen County in Fort Wayne, Indiana can turn a 1 U.S.-dollar donation into 2 or 3 U.S. dollars through its Community Campaign. It says that the campaign is an annual fundraising effort to support services at 34 of United Way's partner agencies and its own initiatives. It adds that the campaign is designed to attract new gifts.
- Published
- 2013
312. The End of the Road.
- Author
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Davis, Tammy
- Subjects
SCRAPPING of automobiles ,BUSINESS enterprises ,INDIANA. Dept. of Environmental Management ,USED cars ,AUTOMOBILE parts - Abstract
The article features Fort Wayne, Indiana-based Legal Chop Shop, an auto salvage company that earned the Clean Yard status from the Indiana Department of Environmental Management. It explains how the company processes used vehicles in ways that protect the environment before selling parts that are still usable, or before sending other pieces for crushing and processing. It says that customers contact the shop for almost any kind of auto part they might need.
- Published
- 2013
313. Cooking with Wine.
- Author
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Davis, Tammy
- Subjects
WINES ,SALAD dressing ,COOKING - Abstract
The article offers suggestions from Linda Hankins, chef owner of Aprons Inn Catering And Event Facility in Angola, on how to use wine in cooking which include making a quick sauce, livening up salad dressings, and reheating leftovers.
- Published
- 2013
314. Best in Glass.
- Author
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Davis, Tammy
- Subjects
WINERIES ,GRAPES ,WINE industry - Abstract
The article focuses on Satek Winery in Indiana and the intent of head winemaker Shane Christ to change the belief that good wine in the U.S. not only comes from Napa Valley, California. Director of marketing Christina Koher says that the winery has introduced 40 wines in 2012. The article mentions that 85% of grapes used by Satek are grown within 350 miles of the winery. Moreover, information on the process of winemaking including fermentation is presented.
- Published
- 2013
315. INTIMATE SECRETS.
- Author
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Davis, Tammy
- Subjects
WEDDING gowns ,MARRIAGE customs & rites ,WEDDING supplies ,WOMEN'S clothing ,UNDERWEAR - Abstract
The article presents advice on choosing the right intimate apparel to be worn on the wedding day. Barb Gilbert, owner of Barbara's New Beginnings recommends that in order for the bride to look good and feel comfortable, one should start by properly fitting undergarments that work with the wedding dress, ideally be fit for the undergarments before the dress is altered. She suggests bringing the gown when shopping for undergarments to get the right fit.
- Published
- 2012
316. FOR THE LOVE OF KIDS.
- Author
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Davis, Tammy
- Subjects
PEDIATRICS ,MEDICAL practice ,WORKING mothers - Abstract
The article focuses on the pediatric practice at Parkview Physicians Group in Fort Wayne, Indiana of working mother-doctors including Shobana Pandian, Reshna Khatri and Kristin Will.
- Published
- 2012
317. INTIMATE FRIENDS.
- Author
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Davis, Tammy
- Subjects
RETAIL stores ,BRASSIERES ,LINGERIE ,RETAIL industry - Abstract
The article features Barbara's New Beginnings, the boutique stores located in Indiana at Fort Wayne and Indianapolis, Indiana that offer personalized service to help women shop for a bra. It is owned by Barb Gilbert. It describes the personalized service being offered by Gilbert to the store's customers.
- Published
- 2012
318. Reconnecting People Through the Gift of Hearing.
- Author
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Davis, Tammy
- Subjects
HEARING ,EQUIPMENT & supplies - Abstract
The article features Ted Blanford and his firm, Summit Hearing Solutions. The Fort Wayne, Indiana-based firm is a supplier of Audibel hearing instruments. According to Blanford, the company aims to reconnect families by helping them to hear. The opinion of the firm's operations manager Joy Fulk on the goals and operation of the company is also cited.
- Published
- 2012
319. A Different Shade of Green.
- Author
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Warburton, Peter and Davis, Tammy
- Subjects
- *
GREEN technology , *RENEWABLE energy sources , *SCHOOL districts , *BIOMASS energy & the environment , *ENERGY consumption - Abstract
The article focuses on renewable energy options used by school districts of Pembroke and Winnisquam in New Hampshire. It says that the implemented environmental programs through the application of green technology like the central biomass plant leads into energy savings for the next 15 years along with other benefits. It adds that these alternative technologies address energy consumption, utility cost reduction, and greenhouse gas emissions.
- Published
- 2010
320. Carlisle Full of Growth and Activity.
- Author
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Davis, Tammy
- Subjects
COMMUNITIES ,ATMOSPHERE ,COMMERCE ,ECONOMIC indicators ,SPECIAL events - Abstract
The article provides information on Carlisle Chamber of Commerce in Carlisle, Iowa. According to the author, although the community has continued to flourish and grow, they never lose their family values, friendly atmosphere and sense of pride. She adds that they will be holding an events for the month of June and July to promote their area, which include the Carlisle Sizzling Saturdays on June 16 and July 21, garden party on June 2, and a city-wide garage sale on June 16, others.
- Published
- 2007
321. ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth.
- Author
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Atanassov, Boyko S., Mohan, Ryan D., Lan, Xianjiang, Kuang, Xianghong, Lu, Yue, Lin, Kevin, McIvor, Elizabeth, Li, Wenqian, Zhang, Ying, Florens, Laurence, Byrum, Stephanie D., Mackintosh, Samuel G., Calhoun-Davis, Tammy, Koutelou, Evangelia, Wang, Li, Tang, Dean G., Tackett, Alan J., Washburn, Michael P., Workman, Jerry L., and Dent, Sharon Y.R.
- Subjects
- *
CELL proliferation , *TUMOR growth , *HISTONES , *UBIQUITINATION , *GENETIC regulation - Abstract
Summary Histone H2B monoubiquitination (H2Bub1) is centrally involved in gene regulation. The deubiquitination module (DUBm) of the SAGA complex is a major regulator of global H2Bub1 levels, and components of this DUBm are linked to both neurodegenerative diseases and cancer. Unexpectedly, we find that ablation of USP22, the enzymatic center of the DUBm, leads to a reduction, rather than an increase, in global H2bub1 levels. In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 for activity. Like USP22, USP51 and USP27X are required for normal cell proliferation, and their depletion suppresses tumor growth. Our results reveal that ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes and that imbalances in these activities likely potentiate human diseases including cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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322. Dissociated Primary Human Prostate Cancer Cells Coinjected with the Immortalized Hs5 Bone Marrow Stromal Cells Generate Undifferentiated Tumors in NOD/SCID-γ Mice.
- Author
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Chen, Xin, Liu, Bigang, Li, Qiuhui, Honorio, Sofia, Liu, Xin, Liu, Can, Multani, Asha S., Calhoun-Davis, Tammy, and Tang, Dean G.
- Subjects
- *
PROSTATE cancer , *CANCER cells , *MESENCHYMAL stem cells , *IMMUNODEFICIENCY , *TUMOR growth , *LABORATORY mice ,GENITOURINARY organ tumors - Abstract
Reconstitution of tumor development in immunodeficient mice from disaggregated primary human tumor cells is always challenging. The main goal of the present study is to establish a reliable assay system that would allow us to reproducibly reconstitute human prostate tumor regeneration in mice using patient tumor-derived single cells. Using many of the 114 untreated primary human prostate cancer (HPCa) samples we have worked on, here we show that: 1) the subcutaneum represents the most sensitive site that allows the grafting of the implanted HPCa pieces; 2) primary HPCa cells by themselves fail to regenerate tumors in immunodeficient hosts; 3) when coinjected in Matrigel with rUGM (rat urogenital sinus mesenchyme), CAF (carcinoma-associated fibroblasts), or Hs5 (immortalized bone marrow derived stromal) cells, primary HPCa cells fail to initiate serially transplantable tumors in NOD/SCID mice; and 4) however, HPCa cells coinjected with the Hs5 cells into more immunodeficient NOD/SCID-IL2Rγ−/− (NSG) mice readily regenerate serially transplantable tumors. The HPCa/Hs5 reconstituted ‘prostate’ tumors present an overall epithelial morphology, are of the human origin, and contain cells positive for AR, CK8, and racemase. Cytogenetic analysis provides further evidence for the presence of karyotypically abnormal HPCa cells in the HPCa/Hs5 tumors. Of importance, HPCa/Hs5 xenograft tumors contain EpCAM+ cells that are both clonogenic and tumorigenic. Surprisingly, all HPCa/Hs5 reconstituted tumors are undifferentiated, even for HPCa cells derived from Gleason 7 tumors. Our results indicate that primary HPCa cells coinjected with the immortalized Hs5 stromal cells generate undifferentiated tumors in NSG mice and we provide evidence that undifferentiated HPCa cells might be the cells that possessed tumorigenic potential and regenerated HPCa/Hs5 xenograft tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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323. Drug-Tolerant Cancer Cells Show Reduced Tumor- Initiating Capacity: Depletion of CD44+ Cells and Evidence for Epigenetic Mechanisms.
- Author
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Hong Yan, Xin Chen, Qiuping Zhang, Jichao Qin, Hangwen Li, Can Liu, Calhoun-Davis, Tammy, Coletta, Luis Della, Klostergaard, Jim, Fokt, Izabela, Skora, Stanislaw, Priebe, Waldemar, Yongyi Bi, and Tang, Dean G.
- Subjects
- *
DRUG tolerance , *CANCER stem cells , *CD44 antigen , *DRUG resistance in cancer cells , *EPIGENETICS , *PROSTATE cancer , *CARCINOGENESIS , *CANCER cell proliferation - Abstract
Cancer stem cells (CSCs) possess high tumor-initiating capacity and have been reported to be resistant to therapeutics. Vice versa, therapy-resistant cancer cells seem to manifest CSC phenotypes and properties. It has been generally assumed that drug-resistant cancer cells may all be CSCs although the generality of this assumption is unknown. Here, we chronically treated Du145 prostate cancer cells with etoposide, paclitaxel and some experimental drugs (i.e., staurosporine and 2 paclitaxel analogs), which led to populations of drug-tolerant cells (DTCs). Surprisingly, these DTCs, when implanted either subcutaneously or orthotopically into NOD/SCID mice, exhibited much reduced tumorigenicity or were even nontumorigenic. Drug-tolerant DLD1 colon cancer cells selected by a similar chronic selection protocol also displayed reduced tumorigenicity whereas drug-tolerant UC14 bladder cancer cells demonstrated either increased or decreased tumorregenerating capacity. Drug-tolerant Du145 cells demonstrated low proliferative and clonogenic potential and were virtually devoid of CD44+ cells. Prospective knockdown of CD44 in Du145 cells inhibited cell proliferation and tumor regeneration, whereas restoration of CD44 expression in drug-tolerant Du145 cells increased cell proliferation and partially increased tumorigenicity. Interestingly, drug-tolerant Du145 cells showed both increases and decreases in many "stemness" genes. Finally, evidence was provided that chronic drug exposure generated DTCs via epigenetic mechanisms involving molecules such as CD44 and KDM5A. Our results thus reveal that 1) not all DTCs are necessarily CSCs; 2) conventional chemotherapeutic drugs such as taxol and etoposide may directly target CD44+ tumor-initiating cells; and 3) DTCs generated via chronic drug selection involve epigenetic mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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324. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.
- Author
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Can Liu, Kelnar, Kevin, Bigang Liu, Xin Chen, Calhoun-Davis, Tammy, Hangwen Li, Patrawala, Lubna, Hong Yan, Jeter, Collene, Honorio, Sofia, Wiggins, Jason F., Bader, Andreas G., Fagin, Randy, Brown, David, and Tang, Dean G.
- Subjects
- *
RNA , *CANCER , *METASTASIS , *CARCINOGENESIS , *XENOGRAFTS , *SPONTANEOUS cancer regression , *CANCER cells - Abstract
Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors-including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary-have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44+ cell population, but whether miRNAs regulate CD44+ prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44+ prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44+ prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44− prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44+ prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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325. Critical and Distinct Roles of p16 and Telomerase in Regulating the Proliferative Life Span of Normal Human Prostate Epithelial Progenitor Cells.
- Author
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Bhatia, Bobby, Ming Jiang, Suraneni, Mahipal, Patrawala, Lubna, Badeaux, Mark, Schneider-Broussard, Robin, Multani, Asha S., Jeter, Collene R., Calhoun-Davis, Tammy, Limei Hu, Jianhua Hu, Tsavachidis, Spiridon, Wei Zhang, Chang, Sandy, Hayward, Simon W., and Tang, Dean G.
- Subjects
- *
LIFE spans , *TELOMERASE , *EPITHELIAL cells , *MALE reproductive organs , *DNA polymerases , *GENE expression - Abstract
Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo, but the underlying molecular mechanisms remain obscure. Here we show that the senescence of primary NHP cells, which are immunophenotyped as intermediate basal-like cells expressing progenitor cell markers CD44, α2β1, p63, hTERT, and CK5/CK18, involves loss of telomerase expression, up-regulation of p16, and activation of p53. Using genetically defined manipulations of these three signaling pathways, we show that p16 is the primary determinant of the NHP cell proliferative capacity and that hTERT is required for unlimited proliferative life span. Hence, suppression of p16 significantly extends NHP cell life span, but both p16 inhibition and hTERT are required to immortalize NHP cells. Importantly, immortalized NHP cells retain expression of most progenitor markers, demonstrate gene expression profiles characteristic of proliferating progenitor cells, and possess multilineage differentiation potential generating functional prostatic glands. Our studies shed important light on the molecular mechanisms regulating the proliferative life span of NHP progenitor cells. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
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326. Physiology, Lactation
- Author
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Pillay J and Davis TJ
- Abstract
The normal physiology of lactation is a process that begins to take effect well before the initial latch of the newborn infant. It requires the breast to change in composition, size, and shape during each stage of female development. Development includes puberty, pregnancy, and lactation. These stages are influenced by a cascade of physiologic changes that are crucial to successful breastfeeding. This article will review the development of the mammary gland (mammogenesis), the process by which the mammary gland develops the ability to secrete milk (lactogenesis), and the process of milk production (lactation)., (Copyright © 2022, StatPearls Publishing LLC.)
- Published
- 2022
327. Author Correction: LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer.
- Author
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Li Q, Liu B, Chao HP, Ji Y, Lu Y, Mehmood R, Jeter C, Chen T, Moore JR, Li W, Liu C, Rycaj K, Tracz A, Kirk J, Calhoun-Davis T, Xiong J, Deng Q, Huang J, Foster BA, Gokhale A, Chen X, and Tang DG
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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328. LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer.
- Author
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Li Q, Liu B, Chao HP, Ji Y, Lu Y, Mehmood R, Jeter C, Chen T, Moore JR, Li W, Liu C, Rycaj K, Tracz A, Kirk J, Calhoun-Davis T, Xiong J, Deng Q, Huang J, Foster BA, Gokhale A, Chen X, and Tang DG
- Subjects
- Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Male, Membrane Glycoproteins genetics, Mice, Inbred NOD, Mice, SCID, Oncogene Protein p55(v-myc) genetics, Oncogene Protein p55(v-myc) metabolism, Prostatic Neoplasms genetics, Protein Binding, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptors, Androgen genetics, Signal Transduction, Tumor Suppressor Proteins genetics, Membrane Glycoproteins metabolism, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism, Tumor Suppressor Proteins metabolism
- Abstract
LRIG1 has been reported to be a tumor suppressor in gastrointestinal tract and epidermis. However, little is known about the expression, regulation and biological functions of LRIG1 in prostate cancer (PCa). We find that LRIG1 is overexpressed in PCa, but its expression correlates with better patient survival. Functional studies reveal strong tumor-suppressive functions of LRIG1 in both AR
+ and AR- xenograft models, and transgenic expression of LRIG1 inhibits tumor development in Hi-Myc and TRAMP models. LRIG1 also inhibits castration-resistant PCa and exhibits therapeutic efficacy in pre-established tumors. We further show that 1) AR directly transactivates LRIG1 through binding to several AR-binding sites in LRIG1 locus, and 2) LRIG1 dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth. Collectively, our study indicates that LRIG1 represents a pleiotropic AR-regulated feedback tumor suppressor that functions to restrict oncogenic signaling from AR, Myc, ERBBs, and, likely, other oncogenic drivers.- Published
- 2019
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329. Descriptive Epidemiology of Childhood Disability Prevalence by Sex in the Mississippi Delta and Appalachian Regions.
- Author
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McDaniel JT, Davis T, Yahaya M, and Nuhu K
- Subjects
- Adolescent, Appalachian Region epidemiology, Child, Child, Preschool, Databases, Factual, Epidemiologic Studies, Female, Health Status Disparities, Health Surveys, Humans, Male, Mississippi, Prevalence, Sex Distribution, United States, Disabled Children statistics & numerical data
- Abstract
Background: Evidence suggests a rise in childhood disability rates across the United States with males and those with lower socioeconomic status bearing greater burden. We investigated childhood disability rates in the Mississippi Delta (MDR) and Appalachian regions (AR) in comparison to other parts of the country., Methods: Using data from the US Census Bureau, we calculated childhood disability rates by type and sex at national, regional, and subregional levels. We used risk ratios (RR) to compare childhood disability rates by sex, type, and region. We generated choropleth maps to represent the geographic distribution of disability., Results: Childhood disability was more prevalent, at the national level, among boys (6.64%) than girls (4.08%). Children in the MDR (boys = 8.60%; girls = 5.08%) and AR (boys = 7.81%; girls = 4.83%) had greater risk of disability than those elsewhere in the country (boys = 6.47%; girls = 3.98%), with rates generally higher in rural compared to urban areas in said regions., Conclusions: Childhood disability affects rural areas of the country more extensively, with the MDR and AR affected to an even greater extent. School-based health centers, in particular, which are disproportionately located in urban areas, could benefit disabled children living in the MDR and AR., (© 2019, American School Health Association.)
- Published
- 2019
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330. Love with No Exceptions: A Statewide Faith-Based, University-Community Partnership for Faith-Based HIV Training and Assessment of Needs in the Deep South.
- Author
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Lanzi RG, Footman AP, Jackson E, Araya BY, Ott C, Sterling RD, Davis TR, and Kaiser KA
- Subjects
- Adult, Aged, Alabama, Capacity Building, Community-Based Participatory Research, Discrimination, Psychological, Female, HIV Infections ethnology, Health Promotion methods, Humans, Leadership, Love, Male, Middle Aged, United States, Universities, Black or African American psychology, Clergy, HIV Infections prevention & control, HIV Infections psychology, Health Education methods, Health Knowledge, Attitudes, Practice, Religion, Social Stigma
- Abstract
This project established a faith-based, university-community partnership with the African Methodist Episcopal (AME) church in Alabama to develop a statewide training model to address HIV knowledge and stigma, promote discussion and generate action plans to address HIV in the Deep South. A community-engaged research team consisting of church leadership and university researchers developed and implemented the model, "Love with No Exceptions." Mixed methods were used to evaluate the model delivered in 3-h sessions in five state regions (N = 146 clergy and laity). The majority of participants reported feeling better prepared to serve those living with or affected by HIV and would implement education and awareness activities in their churches. Participants' HIV knowledge increased from pre- to post-training. Stigma-related attitudes showed minor changes from baseline. These results reflect that partnerships between academic institutions and churches can deliver promising steps towards impactful HIV education in the Deep South.
- Published
- 2019
- Full Text
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331. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.
- Author
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Li Q, Deng Q, Chao HP, Liu X, Lu Y, Lin K, Liu B, Tang GW, Zhang D, Tracz A, Jeter C, Rycaj K, Calhoun-Davis T, Huang J, Rubin MA, Beltran H, Shen J, Chatta G, Puzanov I, Mohler JL, Wang J, Zhao R, Kirk J, Chen X, and Tang DG
- Subjects
- Animals, Antineoplastic Agents pharmacology, Benzamides, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Inbred NOD, Mice, Knockout, Molecular Targeted Therapy, Nitriles, Phenylthiohydantoin pharmacology, Prostatic Neoplasms, Castration-Resistant pathology, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Receptors, Androgen metabolism, Signal Transduction, Xenograft Model Antitumor Assays, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Receptors, Androgen genetics
- Abstract
Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR
-/lo ). Xenograft modeling demonstrates that AR+ CRPC is enzalutamide-sensitive but AR-/lo CRPC is resistant. Genome editing-derived AR+ and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR+/hi and AR-/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR-/lo PCa cells/clones.- Published
- 2018
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332. Developing a Novel Two-Dimensional Culture System to Enrich Human Prostate Luminal Progenitors that Can Function as a Cell of Origin for Prostate Cancer.
- Author
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Zhang D, Lin K, Lu Y, Rycaj K, Zhong Y, Chao HP, Calhoun-Davis T, Shen J, and Tang DG
- Subjects
- Castration, Cell Lineage, Cell Transformation, Neoplastic pathology, Cells, Cultured, Culture Media, Epithelial Cells metabolism, Epithelial Cells pathology, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Invasiveness, Neoplasm Metastasis, Organoids pathology, Prostate metabolism, Prostatic Neoplasms genetics, Regeneration, Stem Cells metabolism, Survival Analysis, Transcriptome genetics, Cell Culture Techniques methods, Prostate pathology, Prostatic Neoplasms pathology, Stem Cells pathology
- Abstract
Elucidating the cell of origin of cancer has great significance in stratifying patients into appropriate treatment groups and for developing novel targeted therapies. Early studies demonstrate that only stem-like basal cells in the normal human prostate (NHP) can function as the cell of origin for prostate cancer (PCa). Here, we show that the organoids derived from bulk NHP luminal cells can also be tumorigenically transformed. We further show that the WIT medium, which is used to culture human mammary epithelial progenitor cells, when combined with the ROCK inhibitor, can readily propagate a population of progenitor-like cells from the primary NHP luminal cell isolates. Such functionally defined luminal progenitors can be transformed by distinct sets of genetic perturbations (i.e., AR+AKT/ERG or c-MYC+PTEN knockout) to form tumor glands. Genome-wide RNA-Seq analysis of freshly purified unperturbed human benign prostatic basal and luminal cells and culture-expanded lineage-specific stem/progenitor populations reveals that the luminal progenitors possess a distinct gene expression profile that is greatly enriched in advanced, castration-resistant, and metastatic PCa, and it associates with poor patient survival. The ability of the simple two-dimensional culture system reported herein to greatly enrich NHP progenitor-like cells should facilitate biological and biochemical studies as well as high-throughput screening in these cells and in progenitor-like PCa cells. Stem Cells Translational Medicine 2017;6:748-760., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Published
- 2017
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333. NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis.
- Author
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Jeter CR, Liu B, Lu Y, Chao HP, Zhang D, Liu X, Chen X, Li Q, Rycaj K, Calhoun-Davis T, Yan L, Hu Q, Wang J, Shen J, Liu S, and Tang DG
- Abstract
The pluripotency transcription factor NANOG has been implicated in tumor development, and NANOG-expressing cancer cells manifest stem cell properties that sustain tumor homeostasis, mediate therapy resistance and fuel tumor progression. However, how NANOG converges on somatic circuitry to trigger oncogenic reprogramming remains obscure. We previously reported that inducible NANOG expression propels the emergence of aggressive castration-resistant prostate cancer phenotypes. Here we first show that endogenous NANOG is required for the growth of castration-resistant prostate cancer xenografts. Genome-wide chromatin immunoprecipitation sequencing coupled with biochemical assays unexpectedly reveals that NANOG co-occupies a distinctive proportion of androgen receptor/Forkhead box A1 genomic loci and physically interacts with androgen receptor and Forkhead box A1. Integrative analysis of chromatin immunoprecipitation sequencing and time-resolved RNA sequencing demonstrates that NANOG dynamically alters androgen receptor/Forkhead box A1 signaling leading to both repression of androgen receptor-regulated pro-differentiation genes and induction of genes associated with cell cycle, stem cells, cell motility and castration resistance. Our studies reveal global molecular mechanisms whereby NANOG reprograms prostate cancer cells to a clinically relevant castration-resistant stem cell-like state driven by distinct NANOG-regulated gene clusters that correlate with patient survival. Thus, reprogramming factors such as NANOG may converge on and alter lineage-specific master transcription factors broadly in somatic cancers, thereby facilitating malignant disease progression and providing a novel route for therapeutic resistance.
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- 2016
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334. Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer.
- Author
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Chen X, Li Q, Liu X, Liu C, Liu R, Rycaj K, Zhang D, Liu B, Jeter C, Calhoun-Davis T, Lin K, Lu Y, Chao HP, Shen J, and Tang DG
- Subjects
- Androgens metabolism, Animals, Biomarkers, Tumor, Castration, Cell Line, Tumor, Disease Models, Animal, Gene Expression Profiling, Heterografts, Humans, Immunophenotyping, Male, Mice, Mice, Knockout, MicroRNAs genetics, Neoplastic Stem Cells pathology, Phenotype, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology, SOX9 Transcription Factor genetics, SOX9 Transcription Factor metabolism, Tumor Cells, Cultured, Neoplastic Stem Cells metabolism, Prostatic Neoplasms, Castration-Resistant metabolism
- Abstract
Purpose: We have shown that the phenotypically undifferentiated (PSA(-/lo)) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA(-/lo) population bearing the ALDH(hi)CD44(+)α2β1(+) phenotype (Triple Marker(+)/TM(+)) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM(+) prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC)., Experimental Design: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies., Results: By focusing on the LAPC9 model, we show that the TM(+) cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM(+) cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM(+) cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and (iii) the TM(+) cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir., Conclusions: Our results define the TM(+) prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM(+) cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505-16. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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335. miR-199a-3p targets stemness-related and mitogenic signaling pathways to suppress the expansion and tumorigenic capabilities of prostate cancer stem cells.
- Author
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Liu R, Liu C, Zhang D, Liu B, Chen X, Rycaj K, Jeter C, Calhoun-Davis T, Li Y, Yang T, Wang J, and Tang DG
- Subjects
- Animals, Apoptosis genetics, Carcinogenesis genetics, Cell Line, Tumor, Cell Proliferation, Cyclin D1 metabolism, ErbB Receptors metabolism, Humans, Hyaluronan Receptors metabolism, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Prostatic Neoplasms genetics, Signal Transduction, Gene Expression Regulation, Neoplastic, MicroRNAs metabolism, Neoplastic Stem Cells metabolism, Prostatic Neoplasms metabolism
- Abstract
Human cancers exhibit significant cellular heterogeneity featuring tumorigenic cancer stem cells (CSCs) in addition to more differentiated progeny with limited tumor-initiating capabilities. Recent studies suggest that microRNAs (miRNAs) regulate CSCs and tumor development. A previous library screening for differential miRNA expression in CD44+ (and other) prostate CSC vs. non-CSC populations identified miR-199a-3p to be among the most highly under-expressed miRNAs in CSCs. In this study, we characterized the biological functions of miR-199a-3p in CD44+ prostate cancer (PCa) cells and in tumor regeneration. Overexpression of miR-199a-3p in purified CD44+ or bulk PCa cells, including primary PCa, inhibited proliferation and clonal expansion without inducing apoptosis. miR-199a-3p overexpression also diminished tumor-initiating capacities of CD44+ PCa cells as well as tumor regeneration from bulk PCa cells. Importantly, inducible miR-199a-3p expression in pre-established prostate tumors in NOD/SCID mice inhibited tumor growth. Using target prediction program and luciferase assays, we show mechanistically that CD44 is a direct functional target of miR-199a-3p in PCa cells. Moreover, miR-199a-3p also directly or indirectly targeted several additional mitogenic molecules, including c-MYC, cyclin D1 (CCND1) and EGFR. Taken together, our results demonstrate how the aberrant loss of a miRNA-mediated mechanism can lead to the expansion and tumorigenic activity of prostate CSCs, further supporting the development and implementation of miRNA mimics for cancer treatment., Competing Interests: The authors claim no potential conflicts of interest.
- Published
- 2016
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336. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer.
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Zhang D, Park D, Zhong Y, Lu Y, Rycaj K, Gong S, Chen X, Liu X, Chao HP, Whitney P, Calhoun-Davis T, Takata Y, Shen J, Iyer VR, and Tang DG
- Subjects
- Adenocarcinoma metabolism, Biomarkers, Cell Lineage, Gene Knockdown Techniques, Humans, Male, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, RNA, Ribosomal genetics, RNA, Ribosomal metabolism, Ribosomes metabolism, Gene Expression Regulation physiology, Prostate cytology, Prostatic Neoplasms metabolism, Stem Cells physiology, Transcriptome
- Abstract
The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.
- Published
- 2016
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337. Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells.
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Liu X, Chen X, Rycaj K, Chao HP, Deng Q, Jeter C, Liu C, Honorio S, Li H, Davis T, Suraneni M, Laffin B, Qin J, Li Q, Yang T, Whitney P, Shen J, Huang J, and Tang DG
- Subjects
- Animals, Antineoplastic Agents chemistry, Apoptosis, Cell Line, Tumor, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Neoplasm Transplantation, Neoplastic Stem Cells cytology, Phenotype, Promoter Regions, Genetic, Prostate-Specific Antigen blood, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, RNA, Messenger metabolism, Receptors, Androgen metabolism, Signal Transduction, Prostatic Neoplasms metabolism
- Abstract
Human cancers are heterogeneous containing stem-like cancer cells operationally defined as cancer stem cells (CSCs) that possess great tumor-initiating and long-term tumor-propagating properties. In this study, we systematically dissect the phenotypic, functional and tumorigenic heterogeneity in human prostate cancer (PCa) using xenograft models and >70 patient tumor samples. In the first part, we further investigate the PSA-/lo PCa cell population, which we have recently shown to harbor self-renewing long-term tumor-propagating cells and present several novel findings. We show that discordant AR and PSA expression in both untreated and castration-resistant PCa (CRPC) results in AR+PSA+, AR+PSA-, AR-PSA-, and AR-PSA+ subtypes of PCa cells that manifest differential sensitivities to therapeutics. We further demonstrate that castration leads to a great enrichment of PSA-/lo PCa cells in both xenograft tumors and CRPC samples and systemic androgen levels dynamically regulate the relative abundance of PSA+ versus PSA-/lo PCa cells that impacts the kinetics of tumor growth. We also present evidence that the PSA-/lo PCa cells possess distinct epigenetic profiles. As the PSA-/lo PCa cell population is heterogeneous, in the second part, we employ two PSA- (Du145 and PC3) and two PSA+ (LAPC9 and LAPC4) PCa models as well as patient tumor cells to further dissect the clonogenic and tumorigenic subsets. We report that different PCa models possess distinct tumorigenic subpopulations that both commonly and uniquely express important signaling pathways that could represent therapeutic targets. Our results have important implications in understanding PCa cell heterogeneity, response to clinical therapeutics, and cellular mechanisms underlying CRPC.
- Published
- 2015
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338. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration.
- Author
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Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR, Calhoun-Davis T, Li H, Palapattu GS, Pang S, Lin K, Huang J, Ivanov I, Li W, Suraneni MV, and Tang DG
- Subjects
- Adenocarcinoma diagnosis, Adenocarcinoma surgery, Animals, Asymmetric Cell Division, Castration, Cell Differentiation, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Humans, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Transplantation, Neoplastic Stem Cells classification, Neoplastic Stem Cells pathology, Prostatic Neoplasms diagnosis, Prostatic Neoplasms surgery, Adenocarcinoma pathology, Antigens, Differentiation metabolism, Neoplastic Stem Cells metabolism, Prostate-Specific Antigen metabolism, Prostatic Neoplasms pathology
- Abstract
Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA(+)) and low (PSA(-/lo)) levels of the differentiation marker PSA. PSA(-/lo) PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division to generate PSA(+) cells. Importantly, PSA(-/lo) PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and they harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH(+)CD44(+)α2β1(+) phenotype. In contrast, PSA(+) PCa cells possess more limited tumor-propagating capacity, undergo symmetric division, and are sensitive to castration. Altogether, our study suggests that PSA(-/lo) cells may represent a critical source of castration-resistant PCa cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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339. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.
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Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, Wiggins JF, Bader AG, Fagin R, Brown D, and Tang DG
- Subjects
- Animals, Gene Expression Regulation, Neoplastic drug effects, Male, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Reverse Transcriptase Polymerase Chain Reaction, Hyaluronan Receptors drug effects, MicroRNAs therapeutic use, Neoplastic Stem Cells drug effects, Prostatic Neoplasms drug therapy
- Abstract
Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.
- Published
- 2011
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340. Drug-tolerant cancer cells show reduced tumor-initiating capacity: depletion of CD44 cells and evidence for epigenetic mechanisms.
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Yan H, Chen X, Zhang Q, Qin J, Li H, Liu C, Calhoun-Davis T, Coletta LD, Klostergaard J, Fokt I, Skora S, Priebe W, Bi Y, and Tang DG
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Etoposide pharmacology, Etoposide therapeutic use, Fluorescent Antibody Technique, Humans, Hyaluronan Receptors genetics, Immunoblotting, Male, Mice, Mice, SCID, Paclitaxel pharmacology, Paclitaxel therapeutic use, Retinoblastoma-Binding Protein 2 genetics, Retinoblastoma-Binding Protein 2 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Staurosporine pharmacology, Staurosporine therapeutic use, Antineoplastic Agents therapeutic use, Epigenesis, Genetic genetics, Hyaluronan Receptors metabolism, Neoplastic Stem Cells cytology, Neoplastic Stem Cells metabolism
- Abstract
Cancer stem cells (CSCs) possess high tumor-initiating capacity and have been reported to be resistant to therapeutics. Vice versa, therapy-resistant cancer cells seem to manifest CSC phenotypes and properties. It has been generally assumed that drug-resistant cancer cells may all be CSCs although the generality of this assumption is unknown. Here, we chronically treated Du145 prostate cancer cells with etoposide, paclitaxel and some experimental drugs (i.e., staurosporine and 2 paclitaxel analogs), which led to populations of drug-tolerant cells (DTCs). Surprisingly, these DTCs, when implanted either subcutaneously or orthotopically into NOD/SCID mice, exhibited much reduced tumorigenicity or were even non-tumorigenic. Drug-tolerant DLD1 colon cancer cells selected by a similar chronic selection protocol also displayed reduced tumorigenicity whereas drug-tolerant UC14 bladder cancer cells demonstrated either increased or decreased tumor-regenerating capacity. Drug-tolerant Du145 cells demonstrated low proliferative and clonogenic potential and were virtually devoid of CD44(+) cells. Prospective knockdown of CD44 in Du145 cells inhibited cell proliferation and tumor regeneration, whereas restoration of CD44 expression in drug-tolerant Du145 cells increased cell proliferation and partially increased tumorigenicity. Interestingly, drug-tolerant Du145 cells showed both increases and decreases in many "stemness" genes. Finally, evidence was provided that chronic drug exposure generated DTCs via epigenetic mechanisms involving molecules such as CD44 and KDM5A. Our results thus reveal that 1) not all DTCs are necessarily CSCs; 2) conventional chemotherapeutic drugs such as taxol and etoposide may directly target CD44(+) tumor-initiating cells; and 3) DTCs generated via chronic drug selection involve epigenetic mechanisms.
- Published
- 2011
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341. Functional evidence that the self-renewal gene NANOG regulates human tumor development.
- Author
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Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, Calhoun-Davis T, Zaehres H, Daley GQ, and Tang DG
- Subjects
- Animals, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Clone Cells, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Homeodomain Proteins metabolism, Humans, Hyaluronan Receptors metabolism, Male, Nanog Homeobox Protein, Pseudogenes, RNA Interference, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering metabolism, Rats, Transcription, Genetic, Transduction, Genetic, Homeodomain Proteins genetics, Neoplasms genetics, Neoplasms pathology
- Abstract
Tumor development has long been known to resemble abnormal embryogenesis. The embryonic stem cell (ESC) self-renewal gene NANOG is purportedly expressed by some epithelial cancer cells but a causal role in tumor development has remained unclear. Here, we provide compelling evidence that cultured cancer cells, as well as xenograft- and human primary prostate cancer cells express a functional variant of NANOG. NANOG mRNA in cancer cells is derived predominantly from a retrogene locus termed NANOGP8. NANOG protein is detectable in the nucleus of cancer cells and is expressed higher in patient prostate tumors than matched benign tissues. NANOGP8 mRNA and/or NANOG protein levels are enriched in putative cancer stem/progenitor cell populations. Importantly, extensive loss-of-function analysis reveals that RNA interference-mediated NANOG knockdown inhibits tumor development, establishing a functional significance for NANOG expression in cancer cells. Nanog short hairpin RNA transduced cancer cells exhibit decreased long-term clonal and clonogenic growth, reduced proliferation and, in some cases, altered differentiation. Thus, our results demonstrate that NANOG, a cell-fate regulatory molecule known to be important for ESC self-renewal, also plays a novel role in tumor development.
- Published
- 2009
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342. Methodologies in assaying prostate cancer stem cells.
- Author
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Li H, Jiang M, Honorio S, Patrawala L, Jeter CR, Calhoun-Davis T, Hayward SW, and Tang DG
- Subjects
- Animals, Biological Assay, Biomarkers, Tumor metabolism, Cell Separation, Humans, Male, Mice, Mice, SCID, Neoplasm Metastasis pathology, Neoplasm Transplantation, Cell Culture Techniques methods, Neoplastic Stem Cells pathology, Prostatic Neoplasms pathology
- Abstract
The cancer stem cell (CSC) theory posits that only a small population of tumor cells within the tumor has the ability to reinitiate tumor development and is responsible for tumor homeostasis and progression. Tumor initiation is a defining property of putative CSCs, which have been reported in both blood malignancies and solid tumors. In order to test whether any given human tumor cell population has CSC properties, the relatively enriched single cells have to be put into a foreign microenvironment in a recipient animal to test their tumorigenic potential. Furthermore, various in vitro assays need be performed to demonstrate that the presumed CSCs have certain biological properties normally associated with the stem cells (SCs). Herein, we present a comprehensive review of the experimental methodologies that our lab has been using in assaying putative prostate cancer (PCa) SCs in culture, xenograft tumors, and primary tumor samples.
- Published
- 2009
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343. Evidence that senescent human prostate epithelial cells enhance tumorigenicity: cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT.
- Author
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Bhatia B, Multani AS, Patrawala L, Chen X, Calhoun-Davis T, Zhou J, Schroeder L, Schneider-Broussard R, Shen J, Pathak S, Chang S, and Tang DG
- Subjects
- Cell Transformation, Neoplastic, Epithelial Cells metabolism, Humans, Karyotyping, Male, Mutation, Polymorphism, Single-Stranded Conformational, Prostatic Neoplasms etiology, Prostatic Neoplasms metabolism, Tumor Suppressor Protein p53 genetics, Cell Fusion, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Epithelial Cells pathology, Prostate metabolism, Prostate pathology, Prostatic Neoplasms pathology, Telomerase metabolism
- Abstract
Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo but the potential role of senescent NHP cells in prostate tumorigenesis remain unclear. Here we show that senescent NHP cells enhance the in vivo tumorigenicity of low-tumorigenic LNCaP prostate cancer and low/non-tumorigenic subset of cells (called L cells) isolated from multiple bulk-cultured prostate (and other) cancer cell lines. Subsequent studies suggest cell-cell fusion as a potential mechanism for senescent NHP cell-enhanced tumor development. Using fluorescently tagged tumor cells and/or NHP cells, we find that NHP cells, like fibroblasts, can undergo fusion with unfractionated tumor cells or the L cells. Using 293T-L cells as the model cell system, we verify NHP and 293T-L cell fusion by using differential RT-PCR, karyotyping, and gene expression analyses. Further experiments demonstrate that senescent NHP cells that have lost progenitor markers, accumulated p16INK4a (p16) protein expression, and acquired the AR mRNA expression, appear to be the preferential fusion targets. Strikingly, the tumorigenicity of the NHP/293T-L hybrid cells was inhibited by exogenous p16 as well as hTERT. Chromosomal analyses revealed that hTERT probably inhibited the in vivo tumorigenicity by maintaining genomic stability. These results suggest that senescent NHP cells, like senescent fibroblasts, may promote tumor development and that one of the mechanisms underlying the senescent NHP cell-enhanced tumorigenicity could be through cell fusion., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2008
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344. PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells.
- Author
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Li H, Chen X, Calhoun-Davis T, Claypool K, and Tang DG
- Subjects
- Animals, Cell Growth Processes physiology, Cell Line, Tumor, Clone Cells, Humans, Hyaluronan Receptors biosynthesis, Integrin alpha2beta1 biosynthesis, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism, Transplantation, Heterologous, beta Catenin biosynthesis, Prostatic Neoplasms pathology
- Abstract
Primary keratinocytes exhibit three typical clonal morphologies represented by holoclones, meroclones, and paraclones, with holoclones containing self-renewing stem cells, and meroclones and paraclones containing more mature and differentiated cells. Interestingly, long-term-cultured human epithelial cancer cells in clonal cultures also form holoclones, meroclones, and paraclones, and tumor cell holoclones have been hypothesized to harbor stem-like cells or cancer stem cells. However, the key question of whether tumor cell holoclones genuinely contain tumor-initiating cells has not been directly addressed. Here, using PC3 human prostate carcinoma cells as a model, we provide direct experimental evidence that tumor cell holoclones contain stem-like cells that can initiate serially transplantable tumors. Importantly, holoclones derived from either cultured PC3 cells or holoclone-initiated tumors can be serially passaged and regenerate all three types of clones. In contrast, meroclones and paraclones cannot be continuously propagated and fail to initiate tumor development. Phenotypic characterizations reveal high levels of CD44, alpha(2)beta(1) integrin, and beta-catenin expression in holoclones, whereas meroclones and paraclones show markedly reduced expression of these stem cell markers. The present results have important implications in understanding morphologic heterogeneities and tumorigenic hierarchies in human epithelial cancer cells.
- Published
- 2008
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345. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells.
- Author
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Patrawala L, Calhoun-Davis T, Schneider-Broussard R, and Tang DG
- Subjects
- Animals, Cell Line, Tumor, Humans, Hyaluronan Receptors biosynthesis, Integrin alpha2beta1 biosynthesis, Male, Mice, Mice, Inbred NOD, Mice, SCID, Models, Biological, Neoplasm Transplantation, Gene Expression Regulation, Neoplastic, Neoplasms metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology
- Abstract
Prostate cancer cells are heterogeneous in their tumorigenicity. For example, the side population cells isolated from LAPC9 xenografts are 100 to 1,000 times more tumorigenic than the corresponding non-side population cells. Highly purified CD44(+) prostate cancer cells from several xenografts are also enriched in prostate cancer stem/progenitor cells. Because the CD44(+) prostate cancer cell population is still heterogeneous, we wonder whether we could further enrich for tumorigenic prostate cancer cells in this population using other markers. Integrin alpha2beta1 has been proposed to mark a population of normal human prostate stem cells. Therefore, we first asked whether the alpha2beta1(+/hi) cells in prostate tumors might also represent prostate cancer stem cells. Highly purified (> or =98%) alpha2beta1(+/hi) cells from three human xenograft tumors, Du145, LAPC4, and LAPC9, show higher clonal and clonogenic potential than the alpha2beta1(-/lo) cells in vitro. However, when injected into the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse prostate or s.c., the alpha2beta1(+/hi) prostate cancer cells are no more tumorigenic than the alpha2beta1(-/lo) cells. Immunofluorescence studies reveal that CD44 and alpha2beta1 identify an overlapping and inclusive population of prostate cancer cells in that approximately 70% of alpha2beta1(+/hi) cells are CD44(+) and 20% to 30% of CD44(+) cells are distributed in the alpha2beta1(-/lo) cell population. Subsequently, we sorted out CD44(+)alpha2beta1(+/hi), CD44(+)alpha2beta1(-/lo), CD44(-)alpha2beta1(+/hi), and CD44(-)alpha2beta1(-/lo) cells from LAPC9 tumors and carried out tumorigenicity experiments. The results revealed a hierarchy in tumorigenic potential in the order of CD44(+)alpha2beta1(+/hi) approximately CD44(+)alpha2beta1(-/lo) > CD44(-)alpha2beta1(+/hi) >> CD44(-)alpha2beta1(-/lo). These observations together suggest that prostate cancer cells are organized as a hierarchy.
- Published
- 2007
- Full Text
- View/download PDF
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