Cancer Biology Commons^™

Isolation And Characterization Of Active Elderberry Fractions That Inhibit Melanoma Growth In Vitro And In Vivo, Alexandra M. Okihiro

Master's Theses

The incidence rates of melanoma continue to rise annually despite recent progression in cancer treatments. Cancer is the most prevalent amongst elderly individuals, where immunosenescence has compromised some immune function, and therefore decreased certain tumor detection abilities. Current tumor removal strategies include radiation, chemotherapy and surgical excision: treatments that aim to lower cancer cells, but may also affect normal cells in the process. In the case of chemotherapy, which targets and kills rapidly dividing cells, many immune cells are lowered as a side effect, leaving many patients immune-suppressed and more susceptible to infection. There is a need for naturopathic treatments ...

Characterization Of Differentiation And Prognostic Biomarkers On Cd8+ Tumor-Infiltrating Lymphocytes In Metastatic Melanoma, Richard C. Wu

UT GSBS Dissertations and Theses (Open Access)

CD8⁺ cytotoxic T lymphocytes (CTL) frequently infiltrate tumors, yet most melanoma patients fail to undergo tumor regression. We studied the differentiation of the CD8⁺ tumor-infiltrating lymphocytes (TIL) from 44 metastatic melanoma patients using known T-cell differentiation markers. We also compared CD8⁺ TIL against the T cells from matched melanoma patients’ peripheral blood. We discovered a novel subset of CD8⁺ TIL co-expressing early-differentiation markers, CD27, CD28, and a late/senescent CTL differentiation marker, CD57. This CD8⁺CD57⁺ TIL expressed a cytolytic enzyme, granzyme B (GB), yet did not express another cytolytic pore-forming molecule, perforin (Perf). In contrast, the CD8⁺CD57⁺ T ...

Drosophila Prl-1 Is A Growth Inhibitor That Counteracts The Function Of The Src Oncogene, Krystle T. Pagarigan, Bryce Bunn, Jake Goodchild, Travis K. Rahe, Julie F. Weiss, Leslie J. Saucedo

All Faculty Scholarship

Abstract

Phosphatase of Regenerating Liver (PRL) family members have emerged as molecular markers that significantly correlate to the ability of many cancers to metastasize. However, contradictory cellular responses to PRL expression have been reported, including the inhibition of cell cycle progression. An obvious culprit for the discrepancy is the use of dozens of different cell lines, including many isolated from tumors or cultured cells selected for immortalization which may have missing or mutated modulators of PRL function. We created transgenic Drosophila to study the effects of PRL overexpression in a genetically controlled, organismal model. Our data support the paradigm that ...

Salinomycin: A Notch Signaling Antagonist - A Novel Way Of Targeting Cancer Stem Cells, Carlos U. Muzlera

The Meducator

Dr. Hassell’s research team aims to investigate the roles of therapeutically-relevant genes or gene signatures in the development of “tumour-initiating cells” or breast cancer stem cells. His research team also explores the effects of antagonistic compounds on certain regulatory receptor pathways using in vitro breast cancer cultures and transgenic mouse models. The following research focuses on validating the inhibitory effects of an anti-breast cancer stem cell agent, salinomycin, on downstream Notch signaling. It suggests the possibility of targeting cancer stem cells, the primary culprit in tumour initiation, chemoresistance, and metastasis, by inhibiting key regulatory pathways - such as Notch signaling ...

Carbonic Anhydrase 9 And Radiation Resistance In Rcc, Daniel R. Gallino

Open Access Dissertations and Theses

Renal cell carcinoma (RCC) is the most frequently lethal of urological cancers. It arises in the lining of the proximal convoluted tubule of the kidney and is most common in men ages 50–70. Often, partial or radical nephrectomy is needed to effectively treat the disease, leaving patients with reduced kidney function. RCC frequently displays significant radiation resistance, limiting the usefulness of traditional radiation therapy which might spare patients’ normal tissue. The enzyme carbonic anhydrase 9 (CA9), a product of the hypoxia pathway, is found upregulated in the majority of RCC, particularly the clear cell type. It catalyses the dissolution ...

Galectin-3 Enhances The Malignant Melanoma Phenotype By Regulating Autotaxin, Russell R. Braeuer

UT GSBS Dissertations and Theses (Open Access)

In melanoma patient specimens and cell lines, the over expression of galectin-3 is associated with disease progression and metastatic potential. Herein, we have sought out to determine whether galectin-3 affects the malignant melanoma phenotype by regulating downstream target genes. To that end, galectin-3 was stably silenced by utilizing the lentivirus-incorporated small hairpin RNA in two metastatic melanoma cell lines, WM2664 and A375SM, and subjected to gene expression microarray analysis. We identified and validated the lysophospholipase D enzyme, autotaxin, a promoter of migration, invasion, and tumorigenesis, to be down regulated after silencing galectin-3. Silencing galectin-3 significantly reduced the promoter activity of ...

Flash4 Dark Reference Images, George Mcnamara

George McNamara

Hamamatsu FLASH4.0 dark reference images, acquired with 10 second exposure times, no light to camera. Camera offset (set by Hamamatsu( is ~100 (the average intensity of the first image is always ~1 intensity level higher - an odd feature, but trivial in practice for a 16-bit camera).

George McNamara, Ph.D.

Single Cells Analyst at L.J.N. Cooper Lab

University of Texas M.D. Anderson Cancer Center

Mechanisms Underlying The Heterogeneous Sensitivities Of Cancer Cells To Proteasome Inhibitors, Matthew C. White

UT GSBS Dissertations and Theses (Open Access)

The mechanisms underlying cellular response to proteasome inhibitors have not been clearly elucidated in solid tumor models. Evidence suggests that the ability of a cell to manage the amount of proteotoxic stress following proteasome inhibition dictates survival. In this study using the FDA-approved proteasome inhibitor bortezomib (Velcade®) in solid tumor cells, we demonstrated that perhaps the most critical response to proteasome inhibition is repression of global protein synthesis by phosphorylation of the eukaryotic initiation factor 2-α subunit (eIF2α). In a panel of 10 distinct human pancreatic cancer cells, we showed marked heterogeneity in the ability of cancer cells to induce ...

The P63 Isoform ∆Np63Α Inhibits Epithelial – Mesenchymal Transition By Promoting The Expression Of Mir-205 In Human Bladder Cancer Cells, Mai Tran

UT GSBS Dissertations and Theses (Open Access)

p63, a p53 family member, is a transcription factor that has complex roles in cancer. This study focuses on the role of the ∆Np63α isoform in bladder cancer (BC). Epithelial – mesenchymal transition (EMT) is a physiological process that plays an important part in metastasis and drug resistance. At the molecular level, EMT is characterized by the loss of the epithelial marker E-cadherin, and the acquisition of the transcriptional repressors of E-cadherin (ZEB1, ZEB2, TWIST, SNAI1 and SNAI2). Recent publications highlight the role of microRNAs belonging to the miR-200 family and miR-205 in preventing EMT through suppression of ZEB1 and ZEB2 ...

Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle

UT GSBS Dissertations and Theses (Open Access)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the ...

Apoptosis Is Signalled Early By Low Doses Of Ionizing Radiation In A Radiation-Induced Bystander Effect, Hayley Furlong, Carmel Mothersill, Fiona Lyng, Orla Howe

Articles

It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05 Gy and 0.5 Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3 ...

Understanding Genetic Mechanisms Of Renewal In Regular Tissue And Cancer Cells: A Data Management Case From A Ph.D. Candidate Data Producer, Jan C. Day

University of Massachusetts and New England Area Librarian e-Science Symposium

OBJECTIVE: To document the challenges that a Ph.D. candidate faces as being a key producer of research in the field of cancer biology research including intellectual property rights and day-to-day practices in implementing a PI's research objective.

METHODS: The librarian conducted a semi-structured data interview of a Ph.D. candidate from the biology department at a research institution. At the time of writing, the reference interview has not been conducted. The archivist will transcribe the interview using a RDM planning instrument to categorize the RDM challenges. The archivist will author a case narrative to highlight the challenges a ...

Slow-Cycling Therapy-Resistant Cancer Cells, Nathan F. Moore, Jeanmarie Houghton, Stephen Lyle

GSBS Student Publications

Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be secondary to small subsets of cancer cells that are better able to survive traditional forms of chemotherapy and thus drive tumor regrowth. The ability to isolate and better characterize these therapy-resistant cells is critical for the future development of targeted therapies aimed at achieving more robust and long-lasting responses. Using a novel application for the proliferation marker carboxyfluorescein diacetate, succinimidyl ester (CFSE), we have identified a population of slow-cycling, label-retaining tumor cells in both in vitro sphere cultures and in vivo xenograft ...

Metabolic Rescue Of “Glucose Addicted” Cancer Cells In Vitro, Paolo Vignali

Pursuit - The Journal of Undergraduate Research at the University of Tennessee

Transformations in the glycolytic metabolism of neoplasms modulate their robust cellular division. This characteristic leads to an “addiction” to glucose for continued proliferation and viability. This study investigated whether glucose metabolites could rescue cellular viability in glucose-starvation conditions, a model of the inter-tumoral nutrient-deficient environment. Findings illustrated potential cellular viability rescue with pyruvate addition in glucose-deprived conditions, yet the same potential was not observed with lactic acid, a metabolite that exists at characteristically high concentrations within the intertumoral microenvironment. These results could implicate a predominance of certain metabolic pathways in nutrient-starved cells. Molecular transport capacities across plasma membranes are tied ...

Video Codec Performance (Excel Spreadsheet), George Mcnamara

George McNamara

Video codec performance (Excel spreadsheet). Movie was made in 2005-2006 when I worked at City of Hope National Medical Center. VTLF refers to Video Timelapse Light Facility. Videos were outputted from MetaMorph as AVI files. Personally, I always recommend uncompressed video files fro scientific uses. I also encourage posting the original scientific data format (ex. .lsm, .zvi, .lif, .stk).

Cooperativity Of Rb, Brca1, And P53 In Malignant Breast Cancer Evolution, Prashant Kumar, Malini Mukherjee, Jacob P. S. Johnson, Milan Patel, Bing Huey, Donna G. Albertson, Karl Simin

Open Access Articles

Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous ...

A Synthetic Interaction Screen Identifies Factors Selectively Required For Proliferation And Tert Transcription In P53-Deficient Human Cancer Cells, Li Xie, Claude Gazin, Sung Mi Park, Lihua Julie Zhu, Marie-Anne Debily, Ellen L. W. Kittler, Maria L. Zapp, David S. Lapointe, Stephane Gobeil, Ching-Man A. Virbasius, Michael R. Green

Open Access Articles

Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi)-based synthetic interaction screen to identify genes preferentially required for proliferation of p53-deficient (p53-) human cancer cells. We find that compared to p53-competent (p53+) human cancer cell lines, diverse p53- human cancer cell lines are preferentially sensitive to loss of the transcription factor ETV1 and the DNA damage kinase ATR. In p53- cells, RNAi-mediated knockdown of ETV1 or ATR results in decreased expression of the telomerase catalytic subunit ...

Pubspectra Tattletales, George Mcnamara

George McNamara

Tattletales for Multiplex Fluorescent Reporters in Single Cells for Metabolomics

George McNamara

Analytical Imaging Core Facility, University of Miami, Miller School of Medicine, Miami, FL

As of April 2013: L.J.N. Cooper & D.A. Lee Cellular Immunotherapy Lab, University of Texas M.D. Anderson Cancer Center, Houston, TX

Email: gmcnamara@med.miami.edu, geomcnamara@earthlink.net

Tattletales is my concept for spatial multiplexing many fluorescent protein (FP) biosensors in the same live cell. For example, there are excellent FP biosensors to Ca++ ions, pH, glucose, ribose, glutamine, glutamate, ATP, redox, ROS, pyruvate, cAMP, cGMP, IP3, PI(3,4,5)P3, cell cycle indicators (Fucci2), PKA, PKC, photsphatases, caspase(s) [1, 2]. However, these are typically used one biosensor per experiment, due in part to flooding the cell with soluble biosensor. That is, conventionally, either a metabolite (glucose) reporter or a signal transduction (Ca++) reporter can be imaged. By flooding the cell with the reporter, signal to noise ratio is compromized by autofluorescence.

Tattletales takes advantage of spatial multiplexing to both increase the number of different reporters, and improve signal to noise ratio by localizing each biosensor to a small volume. I started with the observation by Robinett et al [3] who localized 512 GFP-nls-LacI to a 256 LacO array as a 200 nm diameter diffraction limited spot (nuclear background due to overexpression). Many thousands of DNA binding proteins, of known sequence specifities, exist (LacI, TetR, GalR, etc for cell line studies; ZF-FPs, TALE-FPs to STRs, telomere repeat binding factors-FPs, etc for primary cells) and can be fused (as cDNAs) to different fluorescent proteins and FP biosensors.

Many biosensors are available as affinity series [1, 4], now enabling extended dynamic range. I realized that spatial multiplexing of many DNA binding protein-reporters by localizing to different spots in the cell nucleus and distinguished by combinatorial addressing, where N address colors ...

Cell Death Mechanisms At The Endoplasmic Reticulum, Fei Geng

Open Access Dissertations and Theses

In the recent years considerable progress has been made to understand how the protein Bcl-2 regulates apoptosis at the mitochondria. By comparison, the cell death mechanisms at the endoplasmic reticulum remain unclear. In response to the agents that cause endoplasmic reticulum stress in breast cancer cells, the cell-cell adhesion molecule E-cadherin is modified by two independent modifications comprising pro-region retention and O-glycosylation. Both the modifications on E-cadherin inhibit its cell surface transport and the resultant loss of E-cadherin on the plasma membrane sensitizes cells to apoptosis. During this process binding of E-cadherin to type I gamma phosphatidylinositol phosphate kinase (PIPKIγ ...

Slow-Cycling Cancer Cells: A Dissertation, Nathan F. Moore

GSBS Dissertations and Theses

Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be due to small subsets of stem-like cancer cells that are able to survive chemotherapy and drive tumor re-growth. A more complete understanding of stem-like cancer cell regulation is required to develop therapies to better target and eliminate these cells.

Slow-cycling stem cells are integral components of adult epithelial tissues and may give rise to cancer stem cell populations that share similar characteristics. These slow-cycling adult stem cells are inherently resistant to traditional forms of chemotherapy and transference of this characteristic may help ...