Cancer Biology Commons^™

Molecular Mechanisms Of Squamous Cell Carcinoma Tumor Stem Cell Creation Via High Nitric Oxide (Hno) Adaptation, Niresh T. Kuganeswaran '16, Krishi Korrapati '17, Thomas Wan '16, Timothy Tamas, James A. Radosevich

Student Publications & Research

Cancer relapse or recurrence is defined as the return of cancer or its signs/symptoms after a period of improvement. Surgery may not remove all cancer cells and leave behind a few which cannot be detected by scans or other tests. It is also possible that some tumor cells are resistant to chemotherapy or radiation. Although many cancer cells are killed by these treatments, there may exist a few which contain a different genetic makeup which allows them to survive. These hypermalignant cancer cells, or cancer stem cells (CSCs), have been associated with causing cancer relapse. It has also been predicted …

Role Of Pseudogenes In Cancer Stem Creation Via High Nitric Oxide (Hno) Adaptation, Krishi Korrapati '17, Niresh T. Kuganeswaran '16, Thomas Wan '16, Timothy Tamas, James A. Radosevich

Student Publications & Research

Gene chip analysis of ten HNO adapted cell lines (Squamous cells: SCC-016, SCC-040, SCC-056, SCC-114, SCC-116; Adenocarcinomas: A549, BT20, Hs578, MCF7, and T47D) was carried out. Known pseudogenes were identified in each line, as well as their coding counterparts.

The adenocarcinoma cell lines had no up regulated pseudogenes, while they had the following down regulated pseudogenes: RP6-159A1.2, RP11-255N24.3, AC004490.1, LDHBP, RP11-572H4.2. The squamous cell carcinomas (SCCs) had the following up regulated pseudogenes: RPL37AP1, AC138972.1, RP11-641D5.1, AC005534.6, AC022431.1, RPL26P12, and they had these down regulated pseudogenes: RP6-159A1.2, RP11-255N24.3, RBMXP1, RP11-20O23.1, RP11-551G24.2. All cell lines adhered to the hypothesis that an increase …

Stromal Fibroblasts Facilitate Cancer Cell Invasion By A Novel Invadopodia-Independent Matrix Degradation Process, Hong Cao, Robbin Eppinga, Gina L. Razidio, Eugene W. Krueger, Jing Chen, Li Qiang, Mark A. Mcniven

Faculty Work Comprehensive List

Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process utilizes complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of …

Toward Repurposing Metformin As A Precision Anti-Cancer Therapy Using Structural Systems Pharmacology, Thomas Hart, Shihab Dider, Weiwei Han, Hua Xu, Zhongming Zhao, Lei Xie

Publications and Research

Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally …

Non-Thermal Atmospheric Plasma Induces Ros-Independent Cell Death In U373mg Glioma Cells And Augments The Cytotoxicity Of Temozolomide, Gillian Conway, Alan Casey, Vladimir Milosavljevic, Yupeng Liu, Orla L. Howe, Patrick J. Cullen, James Curtin

Articles

Non-thermal atmospheric plasma (NTAP) is an ionised gas produced under high voltage that can generate short-lived chemically active species and induce a cytotoxic insult in cancer cells. Cell-specific resistance to NTAP-mediated cytotoxicity has been reported in the literature. The aim of this study was to determine whether resistance against NTAP could be overcome using the human glioma cell line U373MG.

Methods:

Non-thermal atmospheric plasma was generated using a Dielectric Barrier Device (DBD) system with a maximum voltage output of 120 kV at 50 Hz. The viability of U373MG GBM cells and HeLa cervical carcinoma cells was determined using morphology, flow …

Decorin As A Multivalent Therapeutic Agent Against Cancer., Thomas Neill, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell …

Lim Protein Ajuba Participates In The Repression Of Atr-Mediated Dna Damage Response In Human Cells, Sampada Kalan

Dissertations, Theses, and Capstone Projects

LIM proteins constitute a superfamily characterized by the presence of specialized domains called LIM. LIM domain is a unique double-zinc finger motif found in a variety of proteins and is mainly involved in protein-protein interactions. Previous work has implicated that members of the Zyxin subfamily of LIM proteins, namely TRIP6 and LPP are involved in the repression of the DNA damage response (DDR) at telomeres. We further explore if another member from this family has an influence on DDR prevention in the cells. Here, we describe a novel role for Ajuba, a Zyxin family LIM protein, in repressing inappropriate activation …

Automated Assessment Of Disease Progression In Acute Myeloid Leukemia By Probabilistic Analysis Of Flow Cytometry Data, Bartek Rajwa, Paul K. Wallace, Elizabeth A. Griffiths, Murat Dundar

Bindley Publications

Objective: Flow cytometry (FC) is a widely acknowledged technology in diagnosis of acute myeloid leukemia (AML) and has been indispensable in determining progression of the disease. Although FC plays a key role as a post-therapy prognosticator and evaluator of therapeutic efficacy, the manual analysis of cytometry data is a barrier to optimization of reproducibility and objectivity. This study investigates the utility of our recently introduced non-parametric Bayesian framework in accurately predicting the direction of change in disease progression in AML patients using FC data. Methods: The highly flexible non-parametric Bayesian model based on the infinite mixture of infinite Gaussian …

Targeting Wnt/Β-Catenin Pathway In Hepatocellular Carcinoma Treatment, Valery Vilchez, Lilia M. Turcios, Francesc Marti, Roberto Gedaly

Surgery Faculty Publications

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug …

Mir-671-5p Inhibits Epithelial-To-Mesenchymal Transition By Downregulating Foxm1 Expression In Breast Cancer., Xiaohui Tan, Yebo Fu, Liang Chen, Woojin Lee, Yinglei Lai, M. Katayoon Rezaei, Sana Tabbara, Patricia Latham, Christine B Teal, Yan-Gao Man, Robert S. Siegel, Rachel F. Brem, Sidney W. Fu

Medicine Faculty Publications

MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 …

Uncovering New Roles For The Aryl Hydrocarbon Receptor (Ahr) In Breast Cancer, Justin Kirk Tomblin

Theses, Dissertations and Capstones

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is responsive to many exogenous and endogenous ligands. AHR is of particular interest in cancer, and has been shown to play roles in tumor progression. As such, it has received growing attention as a possible chemotherapeutic target. Obesity increases the risk of breast cancer, complicates treatment of breast cancer, and stimulates the growth of larger, more aggressive mammary tumors. Many breast tumors in obese women are estrogen receptor (ER)-positive and, while targeting hormone receptors like ER is beneficial, many obese women see a recurrence of their cancer after standard …

Hexokinase Ii Localization Is Independent Of Ampk Activation In Hela Cells, Alyssa Brown

Graduate School of Biomedical Sciences Theses and Dissertations

In order for a cancer cell to thrive, it must alter its metabolism to produce the energy needed for rapid growth. Cells accomplish this by the Warburg Effect, or switching metabolism to aerobic glycolysis, where a cell can rapidly break down sugar into ATP, lactic acid and additional byproducts. Hexokinase 2, the enzyme that catalyzes the first committed step of glycolysis, may also be upregulated in cancer cells to increase glucose breakdown. Similar proteins for metabolism are found in both S. cerevisiae and mammalian cells. S. cerevisiae regulates metabolism through glucose repression, by Snf1 (mammalian homolog: AMPK) activation, which aids …

A Point Mutation In Dna Polymerase Β (Polb) Gene Is Associated With Increased Progesterone Receptor (Pr) Expression And Intraperitoneal Metastasis In Gastric Cancer, Xiaohui Tan, Xiaoling Wu, Shuyang Ren, Hongyi Wang, Weaam Alshenawy, Wenmei Li, Jiantao Cui, Guangbin Luo, Robert S. Siegel, Sidney W. Fu, Youyong Lu

Medicine Faculty Publications

Increased expression of progesterone receptor (PR) has been reported in gastric cancer (GC). We have previously identified a functional T889C point mutation in DNA polymerase beta (POLB), a DNA repair gene in GC. To provide a detailed analysis of molecular changes associated with the mutation, human cDNA microarrays focusing on 18 signal transduction pathways were used to analyze differential gene expression profiles between GC tissues with T889C mutant in POLB gene and those with wild type. Among the differentially expressed genes, notably, PR was one of the significantly up-regulated genes in T889C mutant POLB tissues, which were subsequently confirmed in …

Management Of Hypercalcemia Of Malignancy, Sonia Thomas, Soo-Hwan Chung

PCOM Scholarly Works

Malignancy is one of the most common causes of hypercalcemia, particularly in cancer associated with bone metastases. Hypercalcemia occurs in up to 20% to 30% of cancer patients at some time during the course of their disease. Clinical manifestations of hypercalcemia vary in calcium level in blood. Signs and symptoms of hypercalcemia occur when the serum calcium level rises above those ranges. Fluids are first-line treatment with hypercalcemia followed by bisphosphanates if the calcium is high and the patient is experiencing symptoms. Various other medications are used as second-line agents in hypercalcemia of malignancy.

The Cytotoxic Synergy Of Nanosecond Electric Pulses And Low Temperature Leads To Apoptosis, Claudia Muratori, Andrei G. Pakhomov, Elena C. Gianulis, Sarah D. Jensen, Olga N. Pakhomova

Bioelectrics Publications

Electroporation by nanosecond electric pulses (nsEP) is an emerging modality for tumor ablation. Here we show the efficient induction of apoptosis even by a non-toxic nsEP exposure when it is followed by a 30-min chilling on ice. This chilling itself had no impact on the survival of U-937 or HPAF-II cells, but caused more than 75% lethality in nsEP-treated cells (300 ns, 1.8-7 kV/cm, 50-700 pulses). The cell death was largely delayed by 5-23 hr and was accompanied by a 5-fold activation of caspase 3/7 (compared to nsEP without chilling) and more than 60% cleavage of poly-ADP ribose polymerase (compared …

An In Vitro Study On The Effect Of Synthesized Tin (Iv) Complexes On Glioblastoma, Colorectal, And Skin Cancer Cell Lines, Jennie L. Williams, Lesley C. Lewis-Alleyne, Melinda Solomon, Long Nguyen, Robert Johnson, Jennifer Vital, Ping Ji, John Durant, Camille Cooper, Patrice Cagle, Patrick Martin, Don Vanderveer, William L. Jarrett, Alvin A. Holder

Chemistry & Biochemistry Faculty Publications

((E)-2-(2-hydroxybenzylideneamino)phenolato-2,2-diphenyl-6-aza-1,3-dioxa-2-stanna-[d,h]dibenzocyclononene, [Sn(Ph₂SB)] (compound 1, where Ph₂SB=(E)-2-(2-hydroxybenzylideneamino)phenolato Schiff base) and two novel compounds, [[SnPh2(F-azoSB)] (compound 2, where F-azoSB=4-((E)-(4-fluorophenyl)diazenyl)-2-((E)-(2-hydroxyphenylimino)methyl)phenolato Schiff base), [[SnPh2(sulf-azoSB)]0.125CHCl₃ (compound 3, where sulfamerazineazosalSB=4-((E)-(4-hydroxy-3-((E)-(2-hydroxyphenylimino)methyl)phenyl)diazenyl)-N-(4-methylpyrimidin-2-yl) benzenesulfonamide Schiff base), and the control compound, cisplatin (compound 4) were analysed to comparatively determine their effect on cancer cell growth. Anti-cancer properties of compounds 1-4 were examined using glioblastoma (U-1242 MG), colorectal (HT-29 and HCT-116), and skin (A431) human cancer cell lines. With regards to human glioblastoma cells, compounds 1 and 3 demonstrated anti-proliferative capacity in the cell line tested. Specifically, compounds 1 and 3 inhibited cell proliferation by 50% at …

Characterizing The Oncogenic Properties Of C-Terminal Binding Protein, Evan T. Sumner

Theses and Dissertations

The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as …

Metformin Represses Bladder Cancer Progression By Inhibiting Stem Cell Repopulation Via Cox2/Pge2/Stat3 Axis, Q. Liu, W. Yuan, D. Tong, G. Liu, W. Lan, Diangzheng Zhang, H. Xiao, Y. Zhang, J. Yang, J. Zhang

PCOM Scholarly Works

Cancer stem cells (CSCs) are a sub-population of tumor cells playing essential roles in initiation, differentiation, recurrence, metastasis and development of drug resistance of various cancers, including bladder cancer. Although multiple lines of evidence suggest that metformin is capable of repressing CSC repopulation in different cancers, the effect of metformin on bladder cancer CSCs remains largely unknown. Using the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model, we demonstrated that metformin is capable of repressing bladder cancer progression from both mild to moderate/severe dysplasia lesions and from carcinoma in situ (CIS) to invasive lesions. Metformin also can arrest bladder cancer cells …

Fibronectin Deposition Participates In Extracellular Matrix Assembly And Vascular Morphogenesis, Abigail Hielscher, Kim Ellis, Connie Qiu, Josh Porterfield, Sharon Gerecht

PCOM Scholarly Works

The extracellular matrix (ECM) has been demonstrated to facilitate angiogenesis. In particular, fibronectin has been documented to activate endothelial cells, resulting in their transition from a quiescent state to an active state in which the cells exhibit enhanced migration and proliferation. The goal of this study is to examine the role of polymerized fibronectin during vascular tubulogenesis using a 3 dimensional (3D) cell-derived de-cellularized matrix. A fibronectin-rich 3D de-cellularized ECM was used as a scaffold to study vascular morphogenesis of endothelial cells (ECs). Confocal analyses of several matrix proteins reveal high intra- and extra-cellular deposition of fibronectin in formed vascular …

Screening For Anticancer Agents To Inhibit Mitotic Kinases And Proliferation Of Metastatic Prostate Cancer Cells, Khoa Nguyen

Honors Undergraduate Theses

Current treatments for prostate cancer (PCa) are marred with high relapse frequency and development of progressively aggressive cancers; developing new treatment options for PCa remains crucial. In this project, a series of synthetic compounds based on natural products will be screened to identify inhibitors for Aurora-A kinase (Aur-A). Aur-A facilitates centrosome separation and bipolar spindle formation during mitosis. Aur-A is overexpressed in metastatic PCa cells, and is a good candidate for targeted therapies. Compound libraries are designed using natural compounds that contain simple structural elements as starting points for developing drug like libraries. High-throughput screening of these libraries will be …