A Method of Limited Replication for the Efficient In Vivo Delivery of Adenovirus to Cancer Cells

Overview summary Replication-defective viral vectors are limited in their ability to diffuse through tissue. This poses a problem for treating tumors in vivo using gene transfer. This article demonstrates that limited replication of adenovirus leads to greater gene transfer efficiency in vitro and in vivo without introducing additional safety concerns beyond traditional adenovirus administration. This has implications for the improvement of current gene transfer methods for treating cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63280/1/hum.1998.9.8-1209.pd

Biological and clinical significance of cancer stem cell plasticity

In the past decade, the traditional view of cancers as a homogeneous collection of malignant cells is being replaced by a model of ever increasing complexity suggesting that cancers are complex tissues composed of multiple cell types. This complex model of tumorigenesis has been well supported by a growing body of evidence indicating that most cancers including those derived from blood and solid tissues display a hierarchical organization of tumor cells with phenotypic and functional heterogeneity and at the apex of this hierarchy are cells capable of self‐renewal. These “tumor imitating cells” or “cancer stem cells” drive tumorigenesis and contribute to metastasis, treatment resistance and tumor relapse. Although tumor stem cells themselves may display both genetic and phenotypic heterogeneity, recent studies have demonstrated that cancer stem cells maintain plasticity to transition between mesenchymal‐like (EMT) and epithelial‐like (MET) states, which may be regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in tumor progression and treatment resistance. In this review, we discuss the emerging knowledge regarding the plasticity of cancer stem cells with an emphasis on the signaling pathways and noncoding RNAs including microRNAs (miRNA) and long non‐coding RNAs (lncRNAs) in regulation of this plasticity during tumor growth and metastasis. Lastly, we point out the importance of targeting both the EMT and MET states of CSCs in order to eliminate these lethal seeds of cancers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155480/1/ctm2s4016901400323.pd

Mammary stem cell number as a determinate of breast cancer risk

The 'cancer stem cell hypothesis' posits that cancers, including breast cancer, arise in tissue stem or progenitor cells. If this is the case, then it follows that the risk for developing breast cancer may be determined in part by the number of breast stem/progenitor cells that can serve as targets for transformation. Stem cell number may be set during critical windows of development, including in utero, adolescence, and pregnancy. The growth hormone/insulin-like growth factor-1 axis may play an important role in regulating breast stem cell number during these developmental windows, suggesting an important link between this signaling pathway and breast cancer risk

Diet and risk for breast cancer recurrence and survival

Dietary factors may influence the risk for breast cancer and also the prognosis following diagnosis and treatment. The aim of this study was to assess whether self-reported prediagnosis diet or other patient factors associated with breast cancer incidence were predictive of recurrence and survival. Patients (n=149) diagnosed with primary breast cancer between 1989 and 1991 were followed for five or more years. Total energy (hazard ratio (HR)=1.58, 95%, confidence interval (CI)= 1.05, 2.38) as well as total (HR = 1.46, 95% CI = 1.05, 2.01), saturated (HR = 1.79,95% CI = 1.05, 3.04), and monounsaturated (HR = 1.65, 95% CI = 1.09,2.49) fat intakes were associated with increased risk, and energy-adjusted bread and cereal consumption (HR = 0.55, 95% CI = 0.33, 0.93) with decreased risk of recurrence. Both total energy (HR = 1.58, 95% CI = 1.03, 2.43) and polyunsaturated fat (HR = 1.84, 95% CI = 1.09, 3.13) intakes were associated with an increased risk of death. All associations between dietary fat and recurrence and survival attenuated following energy adjustment. Oral contraceptive use (HR = 1.28, 95% CI = 1.03, 1.60), lymph node positive status (HR = 2.36, 95% CI = 1.01, 5.49), and tumor stage (HR = 2.22, 95% CI = 1.02, 4.81) were associated with increased risk of recurrence. Tumor stage (HR = 4.96, 95% CI = 1.86, 13.23), lymph node positive status (HR = 3.31, 95% CI = 1.38, 7.95, and estrogen receptor negative status (HR = 2.46, 95% CI = 1.02, 5.94) were associated with increased risk, and arm muscle circumference (HR = 0.27, 95% CI = 0.09, 0.86) and mammographic utilization (HR = 0.77, 95% CI = 0.61, 0.98) with decreased risk of death. Higher levels of energy, fat intakes, and selected patient characteristics (particularly disease stage and anthropometric indicators of adiposity) appear to increase risk of recurrence and/or shortened survival following the diagnosis of breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44203/1/10549_2004_Article_194284.pd

Concise Review: Targeting Cancer Stem Cells Using Immunologic Approaches

Cancer stem cells (CSCs) represent a small subset of tumor cells which have the ability to self‐renew and generate the diverse cells that comprise the tumor bulk. They are responsible for local tumor recurrence and distant metastasis. However, they are resistant to conventional radiotherapy and chemotherapy. Novel immunotherapeutic strategies that specifically target CSCs may improve the efficacy of cancer therapy. To immunologically target CSC phenotypes, innate immune responses to CSCs have been reported using Natural killer cells and γδ T cells. To target CSC specifically, in vitro CSC‐primed T cells have been successfully generated and shown targeting of CSCs in vivo after adoptive transfer. Recently, CSC‐based dendritic cell vaccine has demonstrated significant induction of anti‐CSC immunity both in vivo in immunocompetent hosts and in vitro as evident by CSC reactivity of CSC vaccine‐primed antibodies and T cells. In addition, identification of specific antigens or genetic alterations in CSCs may provide more specific targets for immunotherapy. ALDH, CD44, CD133, and HER2 have served as markers to isolate CSCs from a number of tumor types in animal models and human tumors. They might serve as useful targets for CSC immunotherapy. Finally, since CSCs are regulated by interactions with the CSC niche, these interactions may serve as additional targets for CSC immunotherapy. Targeting the tumor microenvironment, such as interrupting the immune cell, for example, myeloid‐derived suppressor cells, and cytokines, for example, IL‐6 and IL‐8, as well as the immune checkpoint (PD1/PDL1, etc.) may provide additional novel strategies to enhance the immunological targeting of CSCs. Stem Cells 2015;33:2085–2092Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112006/1/stem2039.pd

Regulatory Roles of miRNA in the Human Neural Stem Cell Transformation to Glioma Stem Cells

To investigate the expressional alternation of microRNAs (miRNA) during the malignant transformation and development of human glioma, we measured miRNA expression profile as well as mRNA expression profile in normal human neural stem cells (hNSCs) and human glioma stem cells (hGSCs). We found 116 miRNA up‐regulated and 62 miRNA down‐regulated in GSCs. On the other hand, we identified 1,372 mRNA down‐regulated, and 1,501 mRNA up‐regulated in GSCs compared to those in NSCs. We then analyzed the pathways and the predicted target genes of the miRNAs which differ significantly in expression between GSCs and NSCs using the statistical enrichment methods. These target mRNAs are involved in many cancer‐related signaling pathways, such as cell cycle, axon guidance, glioma development, adhesion junction, MAPK and Wnt signaling. Furthermore, we obtained the differently expressed miRNA‐target relationships according to the θ value which is used to calculate the regulation extent of miRNA‐target and using the databases of miRanda, Targetscans and Pictar. Among the top 10 miRNA‐target relationships, hsa‐miR‐198 and its potential targeted gene DCX and NNAT were selected for validation, and NNAT was found to be the direct target of miR‐198. Finally, the functional roles of miR‐155–5p and miR‐124–3p whose expressions altered significantly between GSCs and NSCs were addressed. Our results provide new clues for the potential mechanisms involved in the origin and development of glioma. Clinically, the altered miRNAs may serve as potential targets and diagnostic tools for novel therapeutic strategies of glioblastoma. J. Cell. Biochem. 115: 1368–1380, 2014. © 2014 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107550/1/jcb24786.pd

Identification of murine mammary stem cells: implications for studies of mammary development and carcinogenesis

The epithelial components of the mammary gland are thought to arise from a stem cell capable of both self-renewal and multi-lineage differentiation. Furthermore, there is increasing evidence that mammary carcinomas originate in these cells or their immediate progeny. The recent identification of murine mammary stem cells should facilitate their molecular characterization and help to elucidate their role in mammary carcinogenesis. In addition, an understanding of the biology of these cells including the pathways that regulate their self-renewal and differentiation may suggest new approaches for the prevention and treatment of breast cancer

A Radial Flow Microfluidic Device for Ultra‐High‐Throughput Affinity‐Based Isolation of Circulating Tumor Cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110045/1/smll201400719.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110045/2/smll201400719-sup-0001-S1.pd

Pilot study of duloxetine for treatment of aromatase inhibitor‐associated musculoskeletal symptoms

BACKGROUND: Approximately 50% of postmenopausal women with hormone receptor‐positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI‐associated musculoskeletal symptoms. METHODS: The authors performed a single‐arm, open‐label phase 2 study of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical analysis was done with t tests for paired data. RESULTS: Twenty‐one of 29 evaluable patients (72.4%) achieved at least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol‐directed treatment continued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9% (95% confidence interval [CI], 48.6%‐73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0‐72.7%). The most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache. CONCLUSIONS: Duloxetine appears to be effective and well tolerated for treatment of AI‐associated musculoskeletal symptoms. Future randomized, placebo‐controlled studies are warranted. Cancer 2011;. © 2011 American Cancer Society. Bothersome musculoskeletal symptoms affect about half of women with early stage breast cancer treated with aromatase inhibitors. In this pilot clinical trial, treatment with duloxetine appeared to significantly improve pain and functioning, and was relatively well tolerated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89530/1/26230_ftp.pd

Cancer stem cell heterogeneity in hereditary breast cancer

The cancer stem cell hypothesis proposes that tumors arise in stem or progenitor cells generating in tumors driven by a subcomponent that retains cancer stem cell properties. Recent evidence supports the hypothesis that the BRCA1 gene involved in hereditary breast cancer plays a role in breast stem cell function. Furthermore, studies using mouse BRCA1 knockout models provide evidence for the existence of heterogeneous cancer stem cell populations in tumors generated in these mice. Although these populations may arise from different stem/progenitor cells, they share the expression of a common set of stem cell regulatory genes and show similar characteristics in in vitro mammosphere assays and xenograft models. Furthermore, these 'cancer stem cells' display resistance to chemotherapeutic agents. These studies suggest that breast tumors may display intertumor stem cell heterogeneity. Despite this heterogeneity, cancer stem cells may share common characteristics that can be used for their identification and for therapeutic targeting