Cancer Biology Commons^™

Ibrutinib In Combination With Sorafenib Synergistically Inhibits Proliferation And Survival Of Hepatocellular Carcinoma Cells By Targeting Egfr Signaling Pathway, Cho-Hao Lin, Nissar Wani, Khadija Elkholy, Kalpana Ghoshal

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

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. …

Biomuta And Bioxpress: Mutation And Expression Knowledgebases For Cancer Biomarker Discovery, Hayley Dingerdissen, John Torcivia-Rodriguez, Yu Hu, Ting-Chia Chang, Raja Mazumder, Robel Kashay

Biochemistry and Molecular Medicine Faculty Publications

Single-nucleotide variation and gene expression of disease samples represent important resources for biomarker discovery. Many databases have been built to host and make available such data to the community, but these databases are frequently limited in scope and/or content. BioMuta, a database of cancer-associated single-nucleotide variations, and BioXpress, a database of cancer-associated differentially expressed genes and microRNAs, differ from other disease-associated variation and expression databases primarily through the aggregation of data across many studies into a single source with a unified representation and annotation of functional attributes. Early versions of these resources were initiated by pilot funding for specific research …

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) …

Therapeutic Potential Of Targeting Reactive Oxygen Species (Ros) Stress In Myelodysplastic Syndrome (Mds), Karine Z. Oben

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Myelodysplastic syndromes (MDS) are a diverse group of clonal hematologic disorders characterized by ineffective blood cell production (hematopoiesis), dysplastic (abnormal) cell morphology in one or more hematopoietic lineages, and progression to acute myeloid leukemia (AML). The response rate to current FDA approved therapies is low and not durable. Just about 50% of MDS patients respond to these drug therapies and a majority of responders relapse within 2-3 years. Hence there is a compelling need to investigate new therapy options.

We investigated the anticancer potential and possible underlying molecular mechanisms of action of a plant-derived compound, Withaferin A (WFA) in MDS. …

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 …

Dynamics Of Gene Networks In Cancer Research, Paul Scott

College of Graduate Studies: Theses & Dissertations

Cancer prevention treatments are being researched to see if an optimized treatment schedule would decrease the likelihood of a person being diagnosed with cancer. To do this we are looking at genes involved in the cell cycle and how they interact with one another. Through each gene expression during the life of a normal cell we get an understanding of the gene interactions and test these against those of a cancerous cell. First we construct a simplified network model of the normal gene network. Once we have this model we translate it into a transition matrix and force changes on …

Pioglitazone, Neet Family Proteins, And Galactose Modulation Of Liver Cell Bioenergetics, David F. Grimm

Undergraduate Honors Theses

MitoNEET was discovered through interactions with a labeled and photoactive derivative of pioglitazone (pio), a drug used to increase peripheral insulin sensitivity. Its unique coordination of a [2Fe-2S] cluster by three cysteine residues (Cys-72, Cys-74, and Cys-83) and one histidine (His-87) gives this cluster both stability and the ability to be donated to acceptor proteins. These qualities allow mitoNEET to participate in a diversity of biological functions. Functions of mitoNEET and the consequences of pioglitazone (pio) treatment in human hepatocellular carcinoma (HepG2) cells cultured in glucose or galactose-based medium were examined by respiration and proliferation studies. Pio treatment decreased complex …

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 …

Chaperonin Containing Tcp1 (Cct) As A Target For Cancer Therapy, Ana Carr

Electronic Theses and Dissertations

Treatments for aggressive cancers like triple negative breast cancer (TNBC) and small-cell lung cancer (SCLC) have not improved and remain associated with debilitating side effects. There is an unmet medical need for better, druggable targets and improved therapeutics. To this end, we investigated the role of Chaperonin-Containing TCP1 (CCT), an evolutionarily conserved protein-folding complex composed of eight subunits (CCT1-8), in oncogenesis. Our laboratory was the first to report that the CCT2 subunit is highly expressed in breast cancer and could be therapeutically targeted. To determine whether CCT is a marker of disease progression in other cancers, we analyzed CCT2 gene …

Novel Cytokine Signaling And Molecular Therapeutic Strategy In Pancreatic Cancer, Sarah Gitto

Electronic Theses and Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is highly chemo-resistant and has a five year survival rate of < 8%. Risk factors of pancreatic cancer, such as chronic pancreatitis, help to elicit a pro-tumor immune response, and highly fibrotic environment that promotes tumorigenesis. To study how chronic pancreatitis promotes cancer initiation, traditional KRasG12D mice and double mutant Akt1Myr/KrasG12D mice were used to model microenvironment changes. Akt1Myr/KrasG12D mice were more susceptible to chronic tissue damage, accelerated tumor development and metastatic disease. These mice exhibited histological changes consistent with immune cell privilege, where M2 macrophages and non-cytotoxic eosinophils were co-localized with fibrotic regions. IL-5 expression was up regulated in pancreatic cells undergoing acinar to ductal metaplasia and then diminished in advanced lesions. Tumor cells treated with IL-5 exhibit increased migration and activation through STAT5 signaling. Collectively, the results suggest that eosinophils, which are responsive to IL-5, are key mediators in the pancreatic environment subjected to chronic inflammation and injury. Current therapeutics fall short in increasing patient survival. There remains an urgent need for innovative treatments and thus we tested difluoromethylornithine (DFMO) in combination with a novel polyamine transport inhibitor, Trimer44NMe, against Gemcitabine-resistant PDAC cells. Prior clinical failures when targeting polyamine biosynthesis with DFMO monotherapy may be due to tumor escape via an undefined polyamine transport system. In pancreatic tumor cells DFMO alone and with Trimer44NMe significantly reduced PDAC cell viability by inducing apoptosis or cell cycle arrest. In vivo orthotopic PDAC growth with DFMO treatment resulted in decreased c-Myc expression, a readout of polyamine pathway dysfunction. Moreover, dual inhibition significantly prolonged survival of tumor-bearing mice, and increased M1 macrophage infiltration and reduced FoxP3 expression. Collectively, these studies demonstrate that targeting polyamine pathways in PDAC is a promising immunomodulating therapy that increases survival.

The E. Coli Protein Ybgl: A Novel Dna Repair Enzyme?, Mason H. Conen, Brooke D. Martin, Kent Sugden, Savannah Whitfield

Undergraduate Theses, Professional Papers, and Capstone Artifacts

Cr(V) is a carcinogen that oxidizes guanine aggressively to form spiroiminodihydantion (Sp) and guanidinohydantoin (Gh), both of which contain an unusual hydantoin moiety that cause G→T transversion mutations at a high rate. Endonuclease VIII (nei) can recognize and excise these oxidation products from DNA and is translated as one of five protein products of the Nei operon in Escherichia coli (E. coli). However, the functions of the other four proteins remain unknown. To address this gap in knowledge, we focused on one of the four that immediately precedes nei, the ybgL protein. Previous work by our group has suggested a …

Novel Role Of Prostate Apoptosis Response-4 Tumor Suppressor In B-Cell Chronic Lymphocytic Leukemia, Mary Kathryn Mckenna

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Chronic Lymphocytic Leukemia (CLL) is defined by the accumulation of clonally expanded CD5+ and CD19+ B lymphocytes in blood and secondary lymphoid organs with impaired apoptotic mechanisms. CLL represents one third of all leukemia cases with an average age of 72 years at diagnosis making it the most common adult leukemia. The Eµ-Tcl1 mouse serves as an excellent model to study the development of CLL as they progress to a CLL like disease by 9-14 months of age, due to overexpression of an oncogene, T cell Leukemia 1(Tcl1), specifically in B cells through the Ig VH promoter and Eµ enhancer …

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 …

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 …

Effects Of Chromium On Mouse Splenic T Lymphocytes And Effects Of Ethanol Exposure During Early Neurodevelopment On Behaviors In Mice, Lu Dai

Theses and Dissertations--Toxicology and Cancer Biology

The dissertation consists of three major projects with the focus on the immunotoxicity of chromium and the behavior disorders caused by early ETOH exposure respectively.

Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells compromises host anti-tumor immunity resulting in oncogenesis. Using mouse splenic T cells as an in vitro …

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 …

Anti-Cancer And Bioavailabilty Of Arachidin-1 And Arachidin-3 In Colon Cancer Cells, Macy R. Shirley, Cindi Brownmiller, Wing Shun Lam, Sun-Ok Lee

Discovery, The Student Journal of Dale Bumpers College of Agricultural, Food and Life Sciences

Cancer is a common cause of death in the United States and locally in the state of Arkansas. Modifiable factors such as tobacco use, physical activity, and diet lead to reduced incidence of colon cancer diagnosis. Plant-based foods may contain phytochemicals that confer health promoting properties. Specifically, peanuts contain phytochemicals known as resveratrol, arachidin-1, and arachidin-3 that have been linked to anticancer activities. However, few research studies have been done on arachidin-1 and arachidin-3 that could develop understanding of their health promoting properties or nutraceutical applications. The objectives of this study were to (1) determine the most effective concentration of …

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 …

Genetic Markers In Circulating Tumour Cells As A Measure Of The Metastatic Propensity Of Uveal Melanoma, Aaron Beasley

Theses: Doctorates and Masters

Background: Uveal melanoma (UM) is an extremely aggressive disease with approximately 50% of patients developing incurable metastatic disease. Therefore, accurate prognosis of a patient is necessary for closer follow up and the earlier implementation of systemic adjuvant therapies in those most likely to develop metastatic disease. Fortunately, UM can be classified into two distinct molecular classes based on clinically validated gene expression profiling, chromosomal aberrations and specific driver mutations, which accurately predict the metastatic propensity of the primary tumour. However, genetic testing currently requires biopsy of the eye which can lead to serious complications including permanent blindness. Therefore, an alternative …