Cancer Biology Commons^™

The Effect Of K562-Il21-2 Plasma Membrane Particles On The Proliferation Of Natural Killer Cells To Fight Cancer, Michelle Prophete

Honors Undergraduate Theses

Immunotherapy has emerged as a current and future paradigm of cancer treatment, which utilizes the body’s immune system to eradicate cancer. Natural Killer (NK) cells as part of the innate immune system have immense potential in their anti-tumor cytotoxic activities and host cell surveillance properties. NK cells comprise approximately five to fifteen percent of peripheral blood lymphocytes and can be proliferated in vitro using recently developed methods with co-cultures with feeder cells (derived from engineered tumor cells) or plasma membrane (PM) particles, produced from the fore mentioned feeder cells, in combination with soluble cytokines. For efficient growth and maintenance of …

The Role Of Kinase Fusion Dnajb1-Prkaca In Fibrolamellar Hepatocellular Carcinoma, Yi Guo

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Characterization Of Malt1 Inhibitors And Their Effect On Leukemic Cell Growth Properties, Christina Snyder

Graduate School of Biomedical Sciences Theses and Dissertations

Leukemia is the most common childhood cancer, with a combined 40,000 predicted new cases in the United States in 2016 [8]. The two most common subtypes are acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) [9-11]. The commercially available inhibitor of Bruton’s tyrosine kinase (BTK) has shown promising results in clinical trials for CLL because of the importance of BCR signaling in CLL [12-15]. Recent studies suggest that the outgrowth of BTK inhibitor resistant clonal cells in some CLL patients results in a treatment-refractory phenotype [16-18]. MALT1, a protein involved in BCR activation of the NF-κB pathway that functions …

Development Of Cellular Assays To Monitor Enzymatic And Biological Activity Of Cd73: A Key Modulator Of Anti-Tumor Immune Response, Alexandra Fanuka

Graduate School of Biomedical Sciences Theses and Dissertations

Ecto-5’-nucleotidase, known as CD73, is an extracellular enzyme that converts adenosine monophosphate (AMP) to adenosine and has recently been identified as a potential drug target for cancer immunotherapy. Its immunosuppressive effects, mediated by the activity of adenosine, are associated with higher rates of tumor invasion and metastasis, as well as poorer prognoses overall in many cancer types. CD73 is often co-expressed with ectonucleoside triphosphate diphosphohydrolase-1 (CD39), which catalyzes the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP), and ADP to AMP on the surface of tumor cells. Dual expression further propagates immunosuppressive effects of adenosine in the tumor microenvironment. …

Press-Pulse: A Novel Therapeutic Strategy For The Metabolic Management Of Cancer, Thomas Seyfried, George Yu, Joseph Maroon, Dominic D'Agostino

Urology Faculty Publications

Background

A shift from respiration to fermentation is a common metabolic hallmark of cancer cells. As a result, glucose and glutamine become the prime fuels for driving the dysregulated growth of tumors. The simultaneous occurrence of “Press-Pulse” disturbances was considered the mechanism responsible for reduction of organic populations during prior evolutionary epochs. Press disturbances produce chronic stress, while pulse disturbances produce acute stress on populations. It was only when both disturbances coincide that population reduction occurred.

Methods

This general concept can be applied to the management of cancer by creating chronic metabolic stresses on tumor cell energy metabolism (press disturbance) …

Engineered Peptides For Applications In Cancer-Targeted Drug Delivery And Tumor Detection, R. Soudy, N. Byeon, Y. Raghuwanshi, S. Ahmed, A. Lavasanifar, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Cancer-targeting peptides as ligands for targeted delivery of anticancer drugs or drug carriers have the potential to significantly enhance the selectivity and the therapeutic benefit of current chemotherapeutic agents. Identification of tumor-specific biomarkers like integrins, aminopeptidase N, and epidermal growth factor receptor as well as the popularity of phage display techniques along with synthetic combinatorial methods used for peptide design and structure optimization have fueled the advancement and application of peptide ligands for targeted drug delivery and tumor detection in cancer treatment, detection and guided therapy. Although considerable preclinical data have shown remarkable success in the use of tumor targeting …

Cellular And Molecular Mechanisms Underlying Alcohol-Induced Aggressiveness Of Breast Cancer, Yongchao Wang, Mei Xu, Zun-Ji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Breast cancer is a leading cause of morbidity and mortality in women. Both Epidemiological and experimental studies indicate a positive correlation between alcohol consumption and the risk of breast cancer. While alcohol exposure may promote the carcinogenesis or onset of breast cancer, it may as well enhance the progression and aggressiveness of existing mammary tumors. Recent progress in this line of research suggests that alcohol exposure is associated with invasive breast cancer and promotes the growth and metastasis of mammary tumors. There are multiple potential mechanisms involved in alcohol-stimulated progression and aggressiveness of breast cancer. Alcohol may increase the mobility …

Micro-Spectroscopy Of Bio-Assemblies At The Single Cell Level, Jeslin Kera

Honors Undergraduate Theses

In this thesis, we investigate biological molecules on a micron scale in the ultraviolet spectral region through the non-destructive confocal absorption microscopy. The setup involves a combination of confocal microscope with a UV light excitation beam to measure the optical absorption spectra with spatial resolution of 1.4 μm in the lateral and 3.6 μm in the axial direction. Confocal absorption microscopy has the benefits of requiring no labels and only low light intensity for excitation while providing a strong signal from the contrast generated by the attenuation of propagating light due to absorption. This enables spatially resolved measurements of single …

The Role Of Progesterone Receptor Membrane Component 1 In Receptor Trafficking And Disease, Kaia K. Hampton

Theses and Dissertations--Pharmacology and Nutritional Sciences

The progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein with a heme-binding domain that promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. PGRMC1 is upregulated in breast, colon, lung and thyroid tumors. We expanded the analysis of PGRMC1 in the clinical setting, and report the first analysis of PGRMC1 in human oral cavity and ovarian tumors and found PGRMC1 to correlate with lung and ovarian cancer patient survival. Furthermore, we discovered a specific role for PGRMC1 in cancer stem cell viability. PGRMC1 directly associates with the epidermal growth factor …

Targeting Apoptotic Pathways To Overcome Drug Resistance In Acute Myeloid Leukemia, Rongqing Pan

Dissertations and Theses (Open Access)

Evasion of apoptosis is integral to tumorigenesis and drug resistance. BCL-2 and p53 proteins represent two focal nodes in convergent apoptosis signaling. Upregulation of anti-apoptotic BCL-2 family members and inactivation of p53 functions are two canonical approaches exploited by cancer cells to escape apoptosis. In the current study, we find that BCL-2 protein is highly expressed in acute myeloid leukemia (AML) cells. BCL-2–specific inhibitor ABT-199 potently induces mitochondrial apoptosis in AML cells and effectively kills AML stem/progenitor cells. Our biomarker studies demonstrate that both BH3 profiling and the expression profiling of BCL-2 proteins may serve as predictive biomarkers for the …

Mammary Extracellular Matrix Directs Differentiation Of Testicular And Embryonic Stem Cells To Form Functional Mammary Glands In Vivo, Robert D. Bruno, Jodie M. Fleming, Andrea L. George, Corinne A. Boulanger, Pepper Schedin, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Publications

Previously, we demonstrated the ability of the normal mammary microenvironment (niche) to direct non-mammary cells including testicular and embryonic stem cells (ESCs) to adopt a mammary epithelial cell (MEC) fate. These studies relied upon the interaction of transplanted normal MECs with non-mammary cells within the mammary fat-pads of recipient mice that had their endogenous epithelium removed. Here, we tested whether acellular mammary extracellular matrix (mECM) preparations are sufficient to direct differentiation of testicular-derived cells and ESCs to form functional mammary epithelial trees in vivo. We found that mECMs isolated from adult mice and rats were sufficient to redirect testicular derived …

Comparative Genetic Screens In Human Cells Reveal New Regulatory Mechanisms In Wnt Signaling, Andres M. Lebensohn, Ramin Dubey, Leif Neitzel, Ofelia Tacchelly-Benites

Dartmouth Scholarship

The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the …

Hnrnpa2 Is A Novel Histone Acetyltransferase That Mediates Mitochondrial Stress-Induced Nuclear Gene Expression, Manti Guha, Satish Srinivasan, Kip Guja, Edison Mejia, Miguel Garcia-Diaz, F. Brad Johnson, Gordon Ruthel, Brett A. Kaufman, Eric F. Rappaport, M. Rebecca Glineburg, Ji-Kang Fang, Andres J. Klein-Szanto, Hiroshi Nakagawa, Jeelan Basha, Tapas Kundu, Narayan G. Avadhani

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced …

Analysis Of Rna Expression Of Normal And Cancer Tissues Reveals High Correlation Of Cop9 Gene Expression With Respiratory Chain Complex Components, Christina A. Wicker, Tadahide Izumi

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: The COP9 signalosome, composed of eight subunits, is implicated in cancer genetics with its deneddylase activity to modulate cellular concentration of oncogenic proteins such as IkB and TGFβ. However, its function in the normal cell physiology remains elusive. Primarily focusing on gene expression data of the normal tissues of the head and neck, the cancer genome atlas (TCGA) database was used to identify groups of genes that were expressed synergistically with the COP9 genes, particularly with the COPS5 (CSN5), which possesses the catalytic activity of COP9.

RESULTS: Expressions of seven of the COP9 genes (COPS2, COPS3, COPS4, COPS5, COPS6, …

The Role Of Streptococcus Gallolyticus Subspecies Gallolyticus In Colon Cancer Development, Jennifer L. Herold

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer in men and women and is also the third most common cause of cancer death. A large body of evidence points towards the possibility that bacteria can have a significant impact on the development of cancer. It has been suggested that Streptococcus gallolyticus subsp. gallolyticus, a group D streptococci, may play a role in the development of CRC. Sg, formerly S. bovis biotype I, has been shown to be highly associated with CRC. In observing patients with either Sg bacteremia or endocarditis it was found that 25-80% of …

Concomitant Targeting Of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets Of Non-Small Cell Lung Cancer, Dennis Ruder

Dissertations and Theses (Open Access)

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, …

Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang

Dissertations and Theses (Open Access)

Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important …

Csp And “Omics” Technology Applied On Versatile And Intelligent Portable Platform For Modeling Complex Bio-Medical Data, Florentin Smarandache, Luige Vladareanu, Mihaiela Iliescu, Hongbo Wang, Feng Yongfei, Victor Vladareanu

Branch Mathematics and Statistics Faculty and Staff Publications

This paper presents relevant aspects of the idea of using the digital medicine in cancer, so that to shape a viable strategy for creating and implementing an interactive digital platform, NEO-VIP, that should be the basic support to design the strategy for integration of basic, clinical and environmental research on neoplasia progression to cancer. The two main components of the VIPRO Platform are represented by the workstation “Engineering Station” for CPS (Cyber Physical System) and “omics” technology and by the “Graphical Station” for the development of a virtual mechatronic system environment and virtual reality for system components' motion. The NEO-VIP …

Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao

Markey Cancer Center Faculty Publications

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures …

Noncanonical Sqstm1/P62-Nrf2 Pathway Activation Mediates Proteasome Inhibitor Resistance In Multiple Myeloma Cells Via Redox, Metabolic And Translational Reprogramming., Irene Riz, Teresa S Hawley, Jeffrey W Marsal, Robert G Hawley

Anatomy and Regenerative Biology Faculty Publications

Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence …

Sulfatase 2 Facilitates Lymphangiogenesis In Breast Cancer By Regulating Vegf-D., Chenfang Zhu, Xiaoliang Qi, Xin Zhou, Xin Nie, Yan Gu

Surgery Faculty Publications

In our previous studies, sulfatase 2 (Sulf2) was found to upregulate vascular endothelial growth factor-D (VEGF-D) expression in breast cancer. As VEGF-D plays an important role in lymphangiogenesis, we hypothesized that Sulf2 facilitates lymphangiogenesis in breast cancer by regulating VEGF-D. To evaluate the functions of Sulf2 on lymphangiogenesis in breast cancer, proliferation, apoptosis, cell cycle, cell mobility and tube-formation of lymphatic endothelial cells (LECs) were measured in vitro. Lymphangiogenesis in nude mouse ears and breast cancer xenografts were examined in vivo. Furthermore, the expression levels of related signaling pathway genes were screened and verified in LECs. We found that Sulf2 …

Selective Anticancer Activity Of Hydroxyapatite/Chitosan-Poly(D,L)-Lactide-Co-Glycolide Particles Loaded With An Androstane-Based Cancer Inhibitor, Nenad Ignjatović, Katarina M. Penov-Gaši, Victoria M. Wu, Jovana J. Ajduković, Vesna V. Kojić, Dana Vasiljević-Radović, Maja Kuzmanović, Vuk Uskoković, Dragab Uskoković

Pharmacy Faculty Articles and Research

In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. ¹H NMR and ¹³C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the …

Does Persistent Hiv Replication Explain Continued Lymphoma Incidence In The Era Of Effective Antiretroviral Therapy?, Jennifer Totonchy, Ethel Cesarman

Pharmacy Faculty Articles and Research

Non-Hodgkin lymphomas are highly increased in incidence in individuals infected with HIV, and this continues to be the case in spite of highly effective combined antiretroviral therapy (cART). New evidence has demonstrated that while successful virtual recovery of CD4 counts and elimination of HIV from peripheral blood can be achieved with cART, viral replication can still occur in lymphoid tissues. In addition, recent studies have suggested that adipose tissue provides an additional reservoir for HIV-infected macrophages and T lymphocytes even in the context of successful cART therapy. In this review article, we discuss possible mechanisms leading to the development of …

Nanobubbles Provide Theranostic Relief To Cancer Hypoxia, Christopher M. Long, Pushpak N. Bhandari, Joseph Irudayaraj

The Summer Undergraduate Research Fellowship (SURF) Symposium

Hypoxia is a common motif among tumors, contributing to metastasis, angiogenesis, cellular epigenetic abnormality, and resistance to cancer therapy. Hypoxia also plays a pivotal role in oncological studies, where it can be used as a principal target for new anti-cancer therapeutic methods. Oxygen nanobubbles were designed in an effort to target the hypoxic tumor regions, thus interrupting the hypoxia-inducible factor-1α (HIF-1α) regulatory pathway and inhibiting tumor progression. At less than 100nm, oxygen nanobubbles act as a vehicle for site-specific oxygen delivery, while also serving as an ultrasound contrast agent for advanced imaging purposes. Through in vitro and in vivo studies, …

Assembly Of Nucleic Acid-Based Nanoparticles By Gas-Liquid Segmented Flow Microfluidics, Matthew L. Capek, Ross Verheul, David H. Thompson

The Summer Undergraduate Research Fellowship (SURF) Symposium

The development of novel and efficient mixing methods is important for optimizing the efficiency of many biological and chemical processes. Tuning the physical and performance properties of nucleic acid-based nanoparticles is one such example known to be strongly affected by mixing efficiency. The characteristics of DNA nanoparticles (such as size, polydispersity, ζ-potential, and gel shift) are important to ensure their therapeutic potency, and new methods to optimize these characteristics are of significant importance to achieve the highest efficacy. In the present study, a simple segmented flow microfluidics system has been developed to augment mixing of pDNA/bPEI nanoparticles. This DNA and …

Inhibition Of Nuclear Factor-Kappa B Enhances The Tumor Growth Of Ovarian Cancer Cell Line Derived From A Low-Grade Papillary Serous Carcinoma In P53-Independent Pathway, Xue Xiao, Gong Yang, Peng Bai, Shunping Gui, Tri M. Bui Nguyen, +8 Additional Authors

Biochemistry and Molecular Medicine Faculty Publications

Background: NF-kB can function as an oncogene or tumor suppressor depending on cancer types. The role of NF-kB in low-grade serous ovarian cancer, however, has never been tested. We sought to elucidate the function of NF-kB in the low-grade serous ovarian cancer.

Methods: The ovarian cancer cell line, HOC-7, derived from a low-grade papillary serous carcinoma. Introduction of a dominant negative mutant, IkBαM, which resulted in decrease of NF-kB function in ovarian cancer cell lines. The transcription ability, tumorigenesis, cell proliferation and apoptosis were observed in derivative cell lines in comparison with parental cells.

Results: Western blot analysis indicated increased …

Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang

Dissertations and Theses (Open Access)

14-3-3ζ is a ubiquitously expressed family member of proteins that have been implicated to have oncogenic potential through its interactions and involvement in cancer initiation and progression. 14-3-3ζ belongs to the highly conserved 14-3-3ζ protein family and modulates numerous pathways in cancer. Overexpression of 14-3-3ζ is an early event, occurs in more than 40% of human breast cancer cases, and is associated with disease recurrence and poor prognosis. Metabolic reprogramming is a hallmark of cancer. Cancer cells elevate aerobic glycolysis to produce metabolic intermediates and reducing equivalents, thereby facilitating cellular adaptation to the adverse environment and sustaining fast proliferation. Interestingly, …

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

Dissertations and Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found …

Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li

Dissertations and Theses (Open Access)

Molecular profiling has identified 5 distinct subtypes of breast cancer, luminal A, luminal B, HER2-enriched, basal-like, and claudin-low breast cancer. These 5 subtypes correlate with hormone response, patient prognosis, and response to therapy. Although steady state gene expression patterns have been explored using expression microarrays, very little is known about the initial, disease-driving transcriptional changes in these cancers or epigenetic changes associated with the differential gene expression signatures. Defining these changes may provide new insights into the mechanisms by which these subtypes arise, as well as new avenues for breast cancer prevention, diagnosis, and treatment. Using Chromatin Immunoprecipitation sequencing and …

Novel Mechanisms Of Β-Adrenergic Signaling In Prostate Cancer Progression, Mohit Hulsurkar

Dissertations and Theses (Open Access)

Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.

Recently, it has been found that activation of β-adrenergic signaling pathway …