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  • American Association for Cancer Research (AACR)  (11)
  • 1
    Online Resource
    Online Resource
    Abstract A21: Chemokine directed migration of activated stellate cells in pancreatic ductal adenocarcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 24_Supplement ( 2016-12-15), p. A21-A21
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 24_Supplement ( 2016-12-15), p. A21-A21
    Abstract: Multiple studies have shown that the extreme desmoplasia observed in pancreatic tumors modulates the effectiveness of chemotherapeutic agents. Despite this, the specific mechanisms by which stroma develops in pancreatic tumors are unknown and the role that it plays in pathogenesis of the disease is unsettled. Chemokines are a family of nearly 50 different secreted proteins playing a key role in the recruitment of a wide variety of cell types in health and disease. While we and others have extensively explored the role of the chemokine CXCL12 in pancreatic cancer, the expression and potential role of other chemokines, or their cognate receptors, in pancreatic cancer remains an area of active exploration. To this end, we profiled the expression of the chemokine family in pancreatic cancer. RT-PCR of a battery of established human pancreatic cancer cell lines revealed elevated transcript levels of the chemokine ligands CCL28 and CXCL16, as well as their cognate receptors CCR10 and CXCR6, respectively. These results were mirrored in cell lines derived from transgenic murine models of pancreatic cancer. Immunohistochemical analysis of both diseased and normal human pancreatic tissue showed that the expression of CCL28, CXCL16, CCR10, and CXCR6 proteins were upregulated in pancreatic adenocarcinoma compared with normal exocrine ductal epithelium. Interestingly, CCR10 and CXCR6 were also expressed in pancreatic tumor fibroblasts, while their cognate ligands, CCL28 and CXCL16 were absent in the stromal compartment. Based on those data we hypothesized that expression of chemokines in cancer cells with the concomitant expression of their cognate receptors by activated fibroblasts facilitates recruitment of those cancer-associated fibroblasts into the tumor microenvironment. Analysis of tissue from patients with pancreatitis revealed that CCL28/CCR10, but not CXCL16/CXCR6, proteins were upregulated. Consistent with its known regulation by inflammatory mediators, we found that interferon-gamma stimulated significant increases in CCL28 secretion by human pancreatic cancer cell lines. In contrast, interferon-gamma had little if any effect on CCL28 secretion by an immortalized activated human pancreatic stellate cell (HPSC) line. Stimulation with exogenous CCL28 elicited the prototypical dose dependent calcium signaling expected of a ligand activated chemokine receptor. CCL28 stimulated the dose dependent directional migration of HPSC without altering cell viability. These data are consistent with HPSC being a functional target for the chemokine. Finally, in a 2-D co-culture model, CCL28 secreted from human pancreatic cancer cells induced HPSC chemotactic migration. Pretreatment with neutralizing antibody to the chemokine blocked HPSC chemotaxis toward the cancer cells. Together, these data suggest that the CCL28-CCR10 chemokine axis plays a role in the inflammation-mediated recruitment of cancer-associated fibroblasts into the stromal compartment of pancreatic tumors. More broadly, we have demonstrated a new role for chemokines in the pancreatic tumor microenvironment, suggestive of their potential role in stromal remodeling in pancreatic cancer. This is the first study to establish the differential expression and functional role for the CCL28 chemokine in pancreatic disease. Citation Format: Ishan Roy, Kathleen A. Boyle, A Craig Mackinnon, Rosa F. Hwang, Susan Tsai, Douglas B. Evans, Michael B. Dwinell.{Authors}. Chemokine directed migration of activated stellate cells in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2 016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A21.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA16-A21
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
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    Heritable Susceptibility to Breast Cancer among African-American Women in the Detroit Research on Cancer Survivors Study
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 11 ( 2020-11-01), p. 2369-2375
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 11 ( 2020-11-01), p. 2369-2375
    Abstract: African-American women have high rates of breast cancer associated with hereditary features. However, no studies have reported the prevalence of inherited variation across all genes known to be breast cancer risk factors among African-American patients with breast cancer not selected for high-risk characteristics. Methods: We evaluated 182 African-American women diagnosed with invasive breast cancer in metropolitan Detroit via targeted capture and multiplex sequencing of 13 well-established breast cancer risk genes and five suggested breast cancer risk genes. Results: We identified 24 pathogenic variants in 23 women [12.6%; 95% confidence interval (CI), 8.2%–18.4%] and five genes (BRCA2, BRCA1, ATM, RAD50, CDH1). BRCA1 and BRCA2 accounted for 58.3% of all pathogenic variants. An additional six pathogenic variants were found in suggested breast cancer risk genes (MSH6, MUTYH, NF1, BRIP1). Conclusions: The prevalence of germline pathogenic variants is relatively high among African-American patients with breast cancer unselected for high-risk characteristics across a broad spectrum of genes. Impact: This study helps to define the genomic landscape of breast cancer susceptibility in African-American women who could benefit from enhanced surveillance and screening.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-20-0564
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Proteasome-Mediated Degradation and Functions of Hematopoietic Progenitor Kinase 1 in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 3 ( 2009-02-01), p. 1063-1070
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 3 ( 2009-02-01), p. 1063-1070
    Abstract: Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. In this study, we examined the expression, regulation, and functions of HPK1 in pancreatic ductal adenocarcinomas (PDA). We found that loss of HPK1 protein expression correlated significantly with the progression of pancreatic intraepithelial neoplasias (P = 0.001) and development of invasive PDA. Similarly, HPK1 protein was not expressed in any of eight PDA cell lines examined but was expressed in immortalized human pancreatic duct epithelial (HPDE) cells. There was no difference in HPK1 mRNA levels in PDA cell lines or primary PDA compared with those in HPDE cells or ductal epithelium in chronic pancreatitis and normal pancreas, respectively. Treatment of Panc-1 cells with a proteasome inhibitor, MG132, increased the HPK1 protein levels in a dose-dependent manner, suggesting that alteration in proteasome activity contributes to the loss of HPK1 protein expression in pancreatic cancer. Like the endogenous HPK1, both wild-type HPK1 and its kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by proteasome-mediated degradation. After MG132 withdrawal, wild-type HPK1 protein expression was markedly decreased within 24 hours, but kinase-dead HPK1 mutant protein expression was sustained for up to 96 hours. Therefore, HPK1 kinase activities were required for the loss of HPK1 protein in PDAs. Furthermore, restoring wild-type HPK1 protein in PDA cells led to the increase in p21 and p27 protein expression and cell cycle arrest. Thus, HPK1 may function as a novel tumor suppressor and its loss plays a critical role in pancreatic cancer. [Cancer Res 2009;69(3):1063–70]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-1751
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 4
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    Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 3 ( 2008-02-01), p. 918-926
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 3 ( 2008-02-01), p. 918-926
    Abstract: Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC-CM) on in vitro proliferation, migration, invasion, soft-agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co-injecting them with cancer cells and analyzing growth and metastasis. HPSC-CM dose-dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC-CM. HPSC-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. Co-injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC-derived factors may lead to novel stroma-targeted therapies for pancreatic cancer. [Cancer Res 2008;68(3):918–26]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-5714
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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  • 5
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    Abstract 3389: Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3389-3389
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3389-3389
    Abstract: Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis, and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM. Citation Format: Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria Zismann, Valerie De Luca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3389. doi:10.1158/1538-7445.AM2017-3389
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3389
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 6
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    Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Discovery Vol. 6, No. 9 ( 2016-09-01), p. 1052-1067
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 9 ( 2016-09-01), p. 1052-1067
    Abstract: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P & lt; 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P & lt; 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-1227
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Integrative Molecular Characterization of Malignant Pleural Mesothelioma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. Significance: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM. See related commentary by Aggarwal and Albelda, p. 1508. This article is highlighted in the In This Issue feature, p. 1494
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-18-0804
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 26, No. 1 ( 2017-01-01), p. 126-135
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 26, No. 1 ( 2017-01-01), p. 126-135
    Abstract: Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-16-0106
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 9
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    A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 23 ( 2014-12-01), p. 5946-5955
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 23 ( 2014-12-01), p. 5946-5955
    Abstract: Purpose: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies. Experimental Design: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1. Results: There were no dose-limiting toxicities, patients reached the 3 × 1010 TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months. Conclusions: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. Clin Cancer Res; 20(23); 5946–55. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-1404
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 10
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    Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 1 ( 2008-01-01), p. 190-197
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 1 ( 2008-01-01), p. 190-197
    Abstract: Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138+ multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138neg B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138+ multiple myeloma plasma cells but had little effect on CD138neg precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138neg cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury. [Cancer Res 2008;68(1):190–7]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-3096
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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