bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4275: BMI-1 promotes drug resistance and cellular invasion in head and neck cancer stem cells
Authors: Lew Daniel , Yi David , Wang-Rodriguez Jessica , Ahmad Zana K. , Kiang Alan , Abhold Eric L. , Haas Martin , Brumund Kevin , Weisman Robert A. , Ongkeko Weg M. 
Published: February 2011

Abstract
Recently, the growth and metastasis of tumors, including head and neck squamous cell carcinomas (HNSCC), have been attributed to a subpopulation within tumors known as cancer stem cells (CSC). Studies have shown that HNSCC cells that are CD44+ are putative CSC and have the capability to self-renew, differentiate and preferentially express BMI-1. The polycomb group protein BMI-1 is a transcriptional repressor that silences the genes responsible for the expression of the cell cycle inhibitor genes p16 and p19. The gene is essential for maintaining the self-renewal capability of both normal and CSC. Very recent studies have shown that BMI-1 may also be implicated in other critical roles in cancer cell behavior including its role in the invasiveness of cancer cells. In this study, we demonstrate that in HNSCC CSC, BMI-1 is critical for cellular invasion. Knockdown of BMI-1 in CD44+ cells results in significant inhibition of invasion while overexpression of BMI-1 in CD44- cells promotes invasion. Furthermore, we show that this enhaced invasion conferred by BMI-1 is through induction of epithelial-to-mesenchymal transition (EMT) genes and the down-regulation of E-cadherin. In addition, we present evidence that the proteinases MMP2 and MMP9 are induced upon overexpression of BMI-1.
CSC are also characterized by being chemoresistant, in part through their enhanced ability to extrude drugs because of their high expression of drug transporters. In this study, we demonstrate another mechanism for the resistance of CSC to DNA-damaging agents. We present evidence that another function of BMI-1 in CSC is its ability to regulate apoptosis. Knockdown of BMI1-1 in CSC using siRNA resulted in increased levels of cisplatin-induced apoptosis compared to cells transfected with scrambled siRNA. Our findings lend support to previous studies that have implicated BMI-1 in the regulation of pro-survival genes as well as the DNA damage response pathway.
Our findings have revealed that BMI-1 is not only essential for self-renewal and tumorigenesis, but also that it has critical functions in cancer stem cell drug resistance and invasion, and most likely, metastasis. Since BMI-1 controls many of the properties of CSC and is preferentially expressed in HNSCC CSC, this oncogene may serve not only as a tumor marker, but also as an ideal therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4275.
Abstract 4277: Prosective cloning of highly invasive differentiated breast cancer cells
Authors: Kim Jiyoung , Villadsen René , Fogh Louise , Fridriksdottir Agla J. , Rank Fritz , Timmermans-Wielenga Vera , Rønnov-Jessen Lone , Bissell Mina J. , Petersen Ole W. 
Published: February 2011

Abstract
Breast cancer consists of a variety of cell types with distinct phenotypes. Here, we examine the heterogeneity by a panel of normal human breast lineage markers from a recently described hierarchy. By use of multicolor imaging, we show that random heterogeneity is in fact patterned. Tumor cells exhibit traits of normal luminal-, and basal- progenitors, respectively. By combining fluorescence activated cell sorting and single cell cloning, we demonstrate that the patterned heterogeneity reflects a lineage hierarchy reminiscent of that seen in the normal breast. Distinct classes of tumor cells have differing functional abilities and behavior. Thus, multipotent basal-like tumor cells with stem cell properties give rise to lineage restricted tumor cells with luminal-like properties. Luminal-like tumor cells, in turn, are most aggressive as revealed by soft agar colony formation, invasiveness, and in vivo tumorigenecity. We therefore conclude that breast cancer heterogeneity, to some extend, arise as a consequence of normal-like lineage evolution. However, more importantly, the progeny of cancer stem cells remains deregulated raising serious doubts about the current concept of the cancer stem cell as the ultimate drug target.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4277.
Abstract 4285: C-Met signaling supports a stem-like transcriptional program and phenotype in glioblastoma
Authors: Li Yunqing , Lal Bachchu , Cázares Hugo Guerrero , Quinones-Hinjosa Alfredo , Eberhart Charles , Laterra John 
Published: February 2011

Abstract
Neoplastic stem-like cells that efficiently propagate tumor xenograft formation exist in solid cancers including glioblastoma. These cells are considered to be responsible for therapeutic resistance and tumor recurrence. The nature of these neoplastic stem-like cells and the molecular signaling pathways that support their phenotype are incompletely defined. The receptor tyrosine kinase c-Met and its ligand HGF promote the formation and growth of multiple cancers including the gliomas. We recently found that GBM-derived neurospheres that are enriched in tumor-initiating stem-like cells widely express activated c-Met. Using flow cytometry and quantitative reverse transcription-PCR, we found that neurosphere cell subpopulations expressing c-Met at high levels also express high levels of the neuroprogenitor/stem cell markers SoX2 and Nestin in comparison to low c-Met expressing cells. Also, CD133+ cells were found to express up to 10-fold higher levels of c-Met relative to CD133- cells. We hypothesize that c-Met might function to support GBM-derived stem-like cells. To test this hypothesis, we examined the effects of c-Met activation/inhibition on the growth and gene expression patterns of established human GBM neurosphere cell lines and low passage primary neurospheres derived from GBM xenograft lines. HGF statistically significantly enhanced cell growth rates and neurosphere forming capacity, a biological marker of the stem cell phenotype. Conversely, inhibiting c-Met kinase activity with SU11274 statistically significantly diminished neurosphere formation and depleted cultures of CD133+ cells. C-Met activation by HGF activated MAPK, AKT and Stat3 and induced expression of SoX2, KLF4 and c-Myc, transcription factors that support stem cell phenotypes. Together, these findings establish a link between c-Met expression/function and the neoplastic stem-like molecular fingerprint and phenotype in GBM-derived cells. The findings suggest that c-Met inhibitors may have a role in the development of therapeutic strategies for targeting tumor-initiating stem-like cells in malignant glioma and other solid cancers. Funded by CA129192 (NIH) and the Brain Tumor Funders Collaborative.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4285.
Abstract 4286: Modulation of T cell activation by malignant melanoma initiating cells
Authors: Schatton Tobias , Schütte Ute , Frank Natasha Y. , Zhan Qian , Hoerning Andre , Robles Susanne C. , Zhou Jun , Hodi F. Stephen , Spagnoli Giulio C. , Murphy George F. , Frank Markus H. 
Published: February 2011

Abstract
Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. This raises the possibility that only a restricted minority of tumorigenic malignant cells might possess the phenotypic and functional characteristics to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis, by demonstrating that tumorigenic ABCB5+ malignant melanoma-initiating cells (MMICs) possess the capacity to preferentially inhibit interleukin (IL)-2-dependent T cell activation and to support, in a B7.2-dependent manner, regulatory T (Treg) cell induction. Compared to melanoma bulk populations, ABCB5+ MMICs expressed lower levels of the major histocompatibility complex (MHC) class I, showed aberrant positivity for MHC class II, and exhibited lower expression levels of the melanoma-associated antigens (MAAs) MART-1, ML-IAP, NY-ESO-1, and MAGE-A. In addition, tumorigenic ABCB5+ subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1 in both established melanoma xenografts and clinical tumor specimens in vivo. In immune activation assays, ABCB5+ melanoma cells inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5− populations. Moreover, coculture with ABCB5+ MMICs increased, in a B7.2 signalling-dependent manner, CD4+CD25+FoxP3+ Treg cell abundance and IL-10 production by mitogen-activated PBMCs. Consistent with these findings, ABCB5+ melanoma subsets also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T cell-modulatory functions of ABCB5+ melanoma subpopulations and suggest specific roles for MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4286.
Abstract 4287: Survival and self-renewing capacity of breast cancer initiating cells during fractionated radiation treatment
Authors: Lagadec Chann H. , Vlashi Erina , Donna Lorenza Della , Meng YongHong , Dekmezian Carmen , Kim Kwanghee , Pajonk Frank 
Published: February 2011

Abstract
Purpose: Recent data indicate a hierarchical organization of many solid cancers, including breast cancer with a small number of cancer initiating cells (CICs) that have the ability to self-renew and exhibit multi-lineage potency. We, and others, have demonstrated that CICs in breast cancer and glioma were relatively resistant to ionizing radiation if compared to their non-tumorigenic counterparts. However, the extent of the remaining self-renewing capacity of CICs after fractions of radiation is currently unknown. We hypothesized that CICs, in contrast with their non-tumorigenic counterparts, not only survive fractions of ionizing radiation but also retain the CIC phenotype as defined by operational means.
Experimental Design: We used two marker systems to identify breast CICs (CD24-/low/CD44high, or lack of proteasome activity) and performed sphere-forming assays after multiple clinical fractions of radiation. Lineage tracking was performed by membrane staining. Cell cycle distribution and RNA content were assed by flow cytometry and senescence was assessed by ß-gal staining.
Results: We demonstrated that irradiated CICs survived and retained their self-renewal capacity for at least 4 generations. We show that fractionated radiation not only spared CICs but also mobilized CICs from a quiescent/G0 phase of the cell cycle into actively cycling cells while the surviving non-tumorigenic cells were driven into senescence.
Conclusions: We conclude that increases in the number of cancer initiating cells after sublethal doses of radiation are potentially of clinically important because the CICs retain increased self-renewal capacity over several generations. Prevention of this process may therefore lead to improved clinical outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4287.
Abstract 4291: Imetelstat, a telomerase inhibitor in phase I trials in solid tumor and hematological malignancies, has broad activity against multiple types of cancer stem cells
Authors: Joseph Immanual , Matsui William , LaPorta Caterina A M , Tabori Uri , Kornblum Harley , Herbert Brittney-Shea , Harley Calvin , Tressler Robert J. 
Published: February 2011

Abstract
Numerous studies show that multiple tumor types have rare subpopulations of cells that are initiators of tumor growth, recurrence, and are implicated in tumor metastasis formation. Because of their clonogenic potential, these cells are referred to as tumor initiating cells (TICs) or cancer stem cells. TICs express ABC transporters and can reside in the host in a quiescent state within their preferred niche, which contributes to their resistance to therapies that are effective against bulk tumor cells. Patients having significant objective responses often develop recurrent resistant disease that is thought to be due to TIC outgrowth, and this is thought to contribute to a lack of clinically durable responses. Therefore agents targeting TICs should be included in current therapeutic strategies to assure more effective disease control in patients. Telomerase activation is a common phenotype for the majority of cancers and is essential for maintaining their immortal phenotype. Most tumors having elevated telomerase activity also have shorter telomere lengths than their normal tissue counterparts, and these characteristics make telomerase a promising therapeutic target for cancer. Tumor initiating cells, while distinct from the bulk tumor cell population, share the common traits of increased telomerase activity and relatively short telomeres, suggesting that inhibiting telomerase would be an effective modality for targeting these cells across multiple tumor types. Imetelstat is a potent and specific competitive inhibitor of telomerase currently in phase I clinical trials in solid tumor and hematological malignancies. We have carried out in vitro and in vivo studies demonstrating that imetelstat inhibits telomerase and is effective in targeting TICs from myeloma, melanoma, breast, pancreatic, pediatric glioma, neuroblastoma, prostatic, lung and glioblastoma multiforme tumor types. Our data show that while treatment of TICs with imetelstat is effective, the mechanisms of TIC inhibition may vary depending on the tumor type, and can include antiproliferative effects, induction of apoptotosis or senescence, terminal differentiation, and inhibition of clonogenicity in vitro, as well as inhibition of tumor engraftment and spontaneous metastasis formation in vivo. In summary, imetelstat, a first in class telomerase inhibitor currently in clinical trials, is a promising agent for targeting TICs with broad activity against multiple cancer stem cell types, but the mechanism of inhibition of TICs may vary depending on the specific tumor type.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4291.
Abstract 4307: Characterization of a novel lymphoid progenitor population with predictive value in canine non-Hodgkin lymphoma
Authors: Ito Daisuke , Avery Anne C. , Mason Nicola J. , O'Brien Tim D. , Modiano Jaime F. 
Published: February 2011

Abstract
Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of lymphoid tumors divided into more than 25 subtypes. Histological classification and clinical stage are used to predict patient outcomes; however, disease progression is variable even within the same NHL subtype. Cancer stem cells (CSCs) are etiologically important cells that can maintain tumors, or whose frequency may reflect individual tumor biology. In terms of patient care and outcome, CSCs are considered to be resistant to conventional therapies. Thus, CSCs are not only etiologically important, but also might mediate treatment failure and relapse, suggesting they have prognostic impact for cancer. The presence and significance of CSCs or CSC-like progenitor cells in NHL has not been conclusively established. The objective of this study was to evaluate the existence and predictive value of lymphoid progenitor cells (LPCs) in dogs with naturally occurring NHL. We previously reported the use of flow cytometry to prospectively identify and enumerate cells in lymph nodes that co-expressed markers associated with hematopoietic progenitors (CD34, c-Kit, and CD133) and the common leukocyte antigen CD45. The number of these cells was inversely correlated (and predictive) for outcome following standard of care with CHOP-based chemotherapy. We now show that these cells represent an atypical lymphoid population, which harbors progenitor markers and lymphoid differentiation markers found within the B-cell phenotype (CD22+) comprising the malignant population. Furthermore, these cells appear to have clonal antigen receptor rearrangements that are related to the principal rearrangement found in the overall (progenitor antigen-negative) malignant cells. The number of progenitor marker- and CD22-positive cells was significantly greater (P=0.0017) in lymphoma samples as compared to lymph nodes from unaffected control dogs, where cells with this phenotype were present in vanishingly small numbers. Together, our results suggest that LPCs in malignant lymph nodes are not only predictive for survival of dogs with spontaneous NHL, but also may represent the CSC compartment for this disease (i.e., “lymphoma-initiating cells”). To confirm their CSC potential, we have adapted an in vitro culture system and a xenotransplantation model that will allow us to expand and serially transplant these primary canine B-cell lymphomas for more detailed studies. This project establishes a useful large animal (canine) model to test the validity of the cancer stem cell theory in non-Hodgkin lymphoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4307.
Abstract 4309: Isolation, expansion and molecular characterization of lung cancer stem cells from NSCLC cell lines
Authors: Singh Sandeep , Chellappan Srikumar 
Published: February 2011

Abstract
Lung cancer is the leading cause of death from cancer worldwide. NSCLC represents the most common subtype of lung cancer with the average five-year survival rate is only 16%. The majorities of these tumors are refractory to chemotherapeutics or acquire resistance to the therapy. In addition, most of the patients develop distant metastases even tough their primary tumors are surgically removed. Cancer stem cell hypothesis has emerged as a possible explanation for tumor growth, recurrence after treatment and metastasis in a variety of cancer. This hypothesis suggests that tumors are maintained by the subset of cancer stem cells (CSCs) that has the ability to self-renew and generate the diverse cells that comprise the tumor. While evidence supporting the existence of CSCs has been demonstrated in many solid cancers, it is largely underdeveloped in lung cancer. Here we have isolated cancer stem like cells from NSCLC cell lines either through isolating the side population (SP) cells based on their property to exclude Hoechst 33342 dye or enriched them by cultivating cancer cells in defined serum free medium containing N2-supplement, EGF and bFGF. Cells obtained from both these methods demonstrated higher clonogenic as well as sphere forming ability which is the typical characteristics associated with CSCs. We further characterized these cells for their ability to express progenitor/stem cell marker genes like Oct4, Sox2 and Nanog. Total RNA from SP cells showed higher expression of these genes as compared to main population. Similarly, the expression of Oct4, Sox2 and Nanog was found elevated after culturing H1650, H358, H322 and H292 cells in defined serum free medium for 10 days. Interestingly, CSCs enriched in this condition also showed the loss of E-cadherin expression and consequent gain of mesenchymal proteins like fibronectin and vimentin. Additionally, ABCG2, which is closely associated with the drug resistance and responsible for side population phenotype, was also upregulated in cancer stem like cells enriched from culturing in serum free defined media. In conclusion, results revealed that lung cancer stem like cells could be isolated and expanded from the established lung cancer cell lines by two different methodologies described here. These cells possess the characteristics of both stem cells and malignant tumors. Therefore, further studies towards targeting these cells may result in effective therapy against lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4309.