Cancer Biology Commons^™

Peptoid Based Slide Coatings For Disease Detection Via Elisa Microarray Analysis, Melissa Lea Hebert

Graduate Theses and Dissertations

Poly-N-substituted glycines (peptoids) are a very versatile family of synthetic molecules that can be customized for any number of applications. In this study, we chose to use peptoids as a foundation for sandwich ELISA microarray analysis with a long term goal of creating an early detection device for complex diseases such as cancer. The peptoids were designed to self-assemble into microspheres to be used in coatings on the surface of the microarray substrates to increase the surface area available for antibody attachment. This increased antibody density would lead to an increase in the microarray analysis sensitivity and dynamic range. Studies …

Optimizing Protocols For The Derivation Of Primary Cultures From Mammalian Tissue, Eduardo Ramirez, Natzidielly Lerma, Paloma Valenzuela, Karla Parra, Courteny L. Becerril, Irving Miramontes, Howard West, Cynthia Rodriguez, Giulio Francia

COURI Symposium Abstracts, Summer 2012

The isolation of primary cell cultures from fresh mammalian tissue is a major interest of our laboratory. Thus, the ability to generate cancer cell lines from cancer tissue, or to generate non-malignant cultures form the host stroma surrounding a tumor, allows us to develop new laboratory models to study the behavior of cancer cells and its microenvironment. We report our proof of principle study on optimizing the derivation of primary culture, using rat tissues as a model. Thus, rat kidney and rat skin samples were isolated, minced with surgical blades, and then incubated with an enzyme digestion cocktail (Collagenase III- …

Messenger Mrna Analysis As A Means To Identify Mechanisms Of Cancer Drug Resistance, Courtney L. Becerril, Irving Miramontes, Jiselle Del Cid, Natzidielly Lerma, Karla Parra, Eduardo D. Ramirez, Howard West, Paloma Valenzuela, Cynthia Rodriguez, Giulio Francia

COURI Symposium Abstracts, Summer 2012

On principal approach to identify the mechanisms by which cancers escape from anti-cancer therapies is the analysis of messenger RNAs (mRNAs) in those tumor cells that survive treatment. Thus, by studying Her-2 positive human breast tumor cells that survived anti-Her-2 based therapies (i.e., using anti-Her-2 antibody) we observed the 3-fold or greater overexpression of Vascular Endothelial Growth Factor (VEGF) mRNA. Similarly, by studying the mRNAs of tumor cell cultures resistant to chemotherapy (such as cisplatin), we found that low levels of mRNAs for DNA mismatch repair genes correlates with drug resistance. These results suggest that two possible strategies of sensitizing …

Protein Expression Analysis Of Cell Lines Derived From Drug Resistant Tumors, Paloma Valenzuela, Karla Parra, Natzidielly Lerma, Courtney Becerril, Eduardo Ramirez, Irving Miramontes, Howard West, Cynthia Rodriguez, Yang Li, Jianying Zhang, Giulio Francia

COURI Symposium Abstracts, Summer 2012

There are a number of effective treatments for breast cancer, including chemotherapy and targeted strategies such as the use of the Her-2 targeting drugs lapatinib and trastuzumab. However, in a number of cases, tumors that initially respond to therapy eventually develop drug resistance, leading to the relapse of the disease. By studying protein levels in different drug resistant variants, we have observed two mechanisms by which drug resistance may develop. Thus, some Her-2 human breast cancer cells (e.g., MDA-MB-231H2N) treated with the clinically used trastuzumab agent, can escape therapy by shedding, or losing, the target Her-2 protein. Similarly, EMT-6 mouse …

Evaluating Ceramide Analogs, 5-Lipoxygenase Expression, And Lipid Raft Biology In Breast Cancer, Jiselle Del Cid, Debarshi Roy, Atasi De Chatterjee, Karla Parra, Howard West, Guido Bocci, Cynthia Rodriguez, Siddhartha Das, Giulio Francia

COURI Symposium Abstracts, Summer 2012

To investigate the role of lipid rafts in the biology of breast cancer cells, we designed a human breast cancer cell line panel (using MCF-7, MDA-MB-231, and HCC1419 cells) to test the anti-tumor impact of new ceramide analogs. Our aim is to use such a screening to ultimately develop a project to investigate the role of 5-lipoxygenase enzyme on the behavior of breast cancer cells, including MDA-MB231 that express 5-lipoxygenase and MCF-7 which do not, and to ask whether ceramide analogs can have an impact on this behavior.

To date, we have evaluated three ceramide analogs, termed C2, C6 and …

Development Of New Models To Study Human Her-2 Positive Breast Cancer, Howard J. West, Karla Parra, Natzidielly Lerma, Paloma Valenzuela, Eduardo Ramirez, Courtney L. Becerril, Irving Miramontes, Elizabeth Gamez, Cynthia Rodriguez, Guido Bocci, Giulio Francia

COURI Symposium Abstracts, Summer 2012

To study the evolution of human Her-2 positive breast cancer, we evaluated a model of three dimensional spheroid co-culture using H2N human breast cancer cells that express high amounts of Her-2 protein, with the Her-2 negative MDA-231 cells. Human HCC1419, which can form compact spheroids, were used as controls. In tissue culture plates, H2N cells were found to have a doubling rate of about 48 hours, compared to around 144 hours for MDA231. Since H2N cells were engineered to express a fluorescent protein, we could note that these cells did not immediately overgrow the non-fluorescent MDA231 cells in a mixed …

Cytotoxic Effects Of Creosote (Larrea Tridentata) Plant Extracts On Human Lymphoma Cells Lines, Emanuel Cordero, Yahaira Santiago, Carolina Lema, Armando Varela-Ramirez, Renato J Aguilera

COURI Symposium Abstracts, Summer 2012

Larrea tridentata also known as Creosote is a North American shrub, whose leave extracts are proposed to contain anti-cancer properties. The main metabolite in this plant is the nordihydroguaiaretic acid (NDGA) has been shown to have anti-neoplastic, anti-viral and anti-inflammatory properties. NDGA is a strong anti-oxidant that can scavenge or inhibit reactive oxygen spices production, stimulate nitric oxide production, increase immune function, enhance central nervous system function, and prevent cardiovascular or other diseases. Although extracts from this plant are currently used in Mexico as an herbal medicine, the Food and Drug Administration and Health Canada have issued health hazard warming …

In Vitro Evaluation Of Human Her2-Positive Breast Cancer Cells, Karla Parra, Howard West, Paloma Valenzuela, Eduardo D. Ramirez, Natzidielly Lerma, Courtney Becerril, Irving Miramontes, Cynthia M. Rodriguez, Guido Bocci, Giulio Francia

COURI Symposium Abstracts, Summer 2012

One in four cases of breast cancer shows over expression of the Her-2 protein, and there is an urgent need to improve therapies for this disease. We have evaluated two Her-2 positive human breast cancer cell lines, MDA-231H2N and HCC1419. MDA-231 human breast cancer cell, which are Her-2 negative, were used as a control. The cell lines were evaluated in vitro for their relative growth rate, their growth under reduced (i.e. 3% serum) conditions, or as spheroid cultures, and for their sensitivity to drugs such as ceramide analogs and tyrosine kinase inhibitors (i.e. CLM3, CLM29, and CLM94) that are being …

The Human Phosphotyrosine Signaling Network: Evolution And Hotspots Of Hijacking In Cancer., Lei Li, Chabane Tibiche, Cong Fu, Tomonori Kaneko, Michael F. Moran, Martin Schiller, Shawn Shun-Cheng Li, Edwin Wang

Life Sciences Faculty Research

Phosphotyrosine (pTyr) signaling, which plays a central role in cell-cell and cell-environment interactions, has been considered to be an evolutionary innovation in multicellular metazoans. However, neither the emergence nor the evolution of the human pTyr signaling system is currently understood. Tyrosine kinase (TK) circuits, each of which consists of a TK writer, a kinase substrate, and a related reader, such as Src homology (SH) 2 domains and pTyr-binding (PTB) domains, comprise the core machinery of the pTyr signaling network. In this study, we analyzed the evolutionary trajectories of 583 literature-derived and 50,000 computationally predicted human TK circuits in 19 representative …

Melanoma Induction By Ultraviolet A But Not Ultraviolet B Radiation Requires Melanin Pigment, Frances P. Noonan, M. Raza Zaidi, Agnieszka Wolnicka-Glubisz, Miriam R. Anver, Jesse Bahn, Anastas Popratiloff, +9 Additional Authors

Anatomy and Regenerative Biology Faculty Publications

Malignant melanoma of the skin (CMM) is associated with ultraviolet radiation exposure, but the mechanisms and even the wavelengths responsible are unclear. Here we use a mammalian model to investigate melanoma formed in response to precise spectrally defined ultraviolet wavelengths and biologically relevant doses. We show that melanoma induction by ultraviolet A (320–400 nm) requires the presence of melanin pigment and is associated with oxidative DNA damage within melanocytes. In contrast, ultraviolet B radiation (280–320 nm) initiates melanoma in a pigment-independent manner associated with direct ultraviolet B DNA damage. Thus, we identified two ultraviolet wavelength-dependent pathways for the induction of …

Interleukin-1Β Mediates Metalloproteinase-Dependent Renal Cell Carcinoma Tumor Cell Invasion Through The Activation Of Ccaat Enhancer Binding Protein Β, Brenda L. Petrella, Matthew P. P. Vincenti

Dartmouth Scholarship

Effective treatment of metastatic renal cell carcinoma (RCC) remains a major medical concern, as these tumors are refractory to standard therapies and prognosis is poor. Although molecularly targeted therapies have shown some promise in the treatment of this disease, advanced RCC tumors often develop resistance to these drugs. Dissecting the molecular mechanisms underlying the progression to advanced disease is necessary to design alternative and improved treatment strategies. Tumor-associated macrophages (TAMs) found in aggressive RCC tumors produce a variety of inflammatory cytokines, including interleukin-1 b (IL-1b). Moreover, the presence of TAMs and high serum levels of IL-1b in RCC patients correlate …

Pv1 Down-Regulation Via Shrna Inhibits The Growth Of Pancreatic Adenocarcinoma Xenografts, Sophie J. Deharvengt, Dan Tse, Olga Sideleva, Caitlin Mcgarry, Jason R. Gunn, Daniel S. Longnecker, Catherine Carriere, Radu V. Stan

Dartmouth Scholarship

PV1 is an endothelial-specific protein with structural roles in the formation of diaphragms in endothelial cells of normal vessels. PV1 is also highly expressed on endothelial cells of many solid tumours. On the basis of in vitro data, PV1 is thought to actively participate in angiogenesis. To test whether or not PV1 has a function in tumour angiogenesis and in tumour growth in vivo, we have treated pancreatic tumour-bearing mice by single-dose intratumoural delivery of lentiviruses encoding for two different shRNAs targeting murine PV1. We find that PV1 down-regulation by shRNAs inhibits the growth of established tumours derived from two …

Oxaliplatin And Oxaliplatin Derivatives: Synthesis, Characterization, And Reactivity With Biologically Relevant Ligands, Amy Poynter

Mahurin Honors College Capstone Experience/Thesis Projects

Oxaliplatin is a third generation anticancer drug that has proven to be successful in fighting ovarian and testicular cancer. We are interested in determining how oxaliplatin and oxaliplatin derivatives interact with proteins, as well as how that interaction is affected by the size and shape of these platinum compounds. We have synthesized oxaliplatin as it is used in cancer treatment, as well as similar platinum compounds with the same diaminocyclohexane ligand as oxaliplatin but with additional bulk added to the nitrogen atoms. We are reacting oxaliplatin with key amino acids, including methionine, and will be comparing the kinetics of this …

Effect Of Combining Bcl-2 Inhibition And Radiation On Apoptotic Cell Death In Human Breast Cancer Cell Lines As Determined By Clonogenic Assay And Western Blots, Amari Sasha Howard

Renée Crown University Honors Thesis Projects - All

Cancer is a group of diseases characterized by abnormal control of cell growth and cell survival. Current treatment for cancer employs a combination of modalities including surgery, radiation, chemotherapeutic drugs, and immunotherapy. Our lab focuses on personalized medicine and treatments that can specifically target molecular features of a tumor as presented by the particular patient being treated. Cancers often exhibit an over-expression or under-expression of certain proteins that play a large role in regulating the process of apoptosis, which is programmed cell death. This study focuses on proposing drug treatment for cancer that is personalized in that it targets a …

Elucidating The Igfbp2 Signaling Pathway In Glioma Development And Progression, Kristen M. Holmes

Dissertations and Theses (Open Access)

Diffuse gliomas are highly lethal central nervous system malignancies which, unfortunately, are the most common primary brain tumor and also the least responsive to the very few therapeutic modalities currently available to treat them. IGFBP2 is a newly recognized oncogene that is operative in multiple cancer types, including glioma, and shows promise for a targeted therapeutic approach. Elevated IGFBP2 expression is present in high-grade glioma and correlates with poor survival. We have previously demonstrated that IGFBP2 induces glioma development and progression in a spontaneous glioma mouse model, which highlighted its significance and potential for future therapy. However, we did not …

Microrna Regulation Of Prostate Cancer Stem/Progenitor Cells And Prostate Cancer Development, Can Liu

Dissertations and Theses (Open Access)

Most human tumors contain a population of cells with stem cell properties, called cancer stem cells (CSCs), which are believed to be responsible for tumor establishment, metastasis, and resistance to clinical therapy. It’s crucial to understand the regulatory mechanisms unique to CSCs, so that we may design CSC-specific therapeutics. Recent discoveries of microRNA (miRNA) have provided a new avenue in understanding the regulatory mechanisms of cancer. However, how miRNAs may regulate CSCs is still poorly understood. Here, we present miRNA expression profiling in six populations of prostate cancer (PCa) stem/progenitor cells that possess distinct tumorigenic properties. Six miRNAs were identified …

14-3-3 Zeta Overexpression Serves As A Novel Molecular Switch Turning Tgf-Beta From Tumor Suppressor To Tumor Promoter, Jia Xu

Dissertations and Theses (Open Access)

TGF-β plays an important role in differentiation and tissue morphogenesis as well as cancer progression. However, the role of TGF-β in cancer is complicate. TGF-β has primarily been recognized as tumor suppressor, because it can directly inhibit cell proliferation of normal and premalignant epithelial cell. However, in the last stage of tumor progression, TGF-β functions as tumor promoter to enhance tumor cells metastatic dissemination and expands metastatic colonies. Currently, the mechanism of how TGF-β switches its role from tumor suppressor to promoter still remains elusive. Here we identify that overexpression of 14-3-3ζ inhibits TGF-β’s cell cytostatic program through destabilizing p53 …

Syntaxin 6- And Microtubule- Mediated Intracellular Trafficking Contributes To Golgi And Nuclear Translocation Of Egfr, Yi Du

Dissertations and Theses (Open Access)

Receptor-mediated endocytosis is well known for its degradation and recycling trafficking. Recent evidence shows that these cell surface receptors translocate from cell surface to different cellular compartments, including the Golgi, mitochondria, endoplasmic reticulum (ER), and the nucleus to regulate physiological and pathological functions. Although some trafficking mechanisms have been resolved, the mechanism of intracellular trafficking from cell surface to the Golgi is not yet completed understood. Here we report a mechanism of Golgi translocation of EGFR in which EGF-induced EGFR travels to the Golgi via microtubule (MT)-dependent movement by interacting with dynein and fuses with the Golgi through syntaxin 6 …

Chronic Stress Promotes Tumor Growth Through Increased Bdnf Production And Neo-Innervation, Julie K. Allen

Dissertations and Theses (Open Access)

Background: Activation of the sympathetic nervous system (SNS) in response to chronic biobehavioral stress results in high levels of catecholamines and persistent activation of adrenergic signaling, which promotes tumor growth and progression. However it is unknown how catecholamine levels within the tumor exceed systemic levels in circulation. I hypothesized that neo-innervation of tumors is required for stress-mediated effects on tumor growth.

Results: First, I examined whether sympathetic nerves are present in human ovarian cancer samples as well as orthotopic ovarian cancer models. Immunohistochemical (IHC) staining for neurofilament revealed that catecholaminergic neurons are present within tumor tissue. In order to determine …

Lmw-E Mediates Mammary Tumorigenesis By Deregulating Acinar Morphogenesis & Generating Cancer Stem Cells, Mylinh T. Duong

Dissertations and Theses (Open Access)

Cyclin E is the regulatory subunit of the cyclin E/CDK2 complex that

mediates the G1-S phase transition. N-terminal cleavage of cyclin E by elastase in

breast cancer generates two low molecular weight (LMW) isoforms that exhibit both

enhanced kinase activity and resistance to p21 and p27 inhibition compared to fulllength cyclin E. Clinically, approximately 27% of breast cancer patients overexpress

LMW-E and associate with poor survival. Therefore, we hypothesize that LMW-E

disrupts normal mammary acinar morphogenesis and serves as the initial route into

breast tumor development. We first demonstrate that LMW-E overexpression in

non-tumorigenic hMECs is sufficient to induce tumor …

Increased Geranylgeranylated K-Ras Contributes To Antineoplastic Effects Of Farnesyltransferase Inhibitors., Mandy A. Hall

Dissertations and Theses (Open Access)

The Ras family of small GTPases (N-, H-, and K-Ras) is a group of important signaling mediators. Ras is frequently activated in some cancers, while others maintain low level activity to achieve optimal cell growth. In cells with endogenously low levels of active Ras, increasing Ras signaling through the ERK and p38 MAPK pathways can cause growth arrest or cell death. Ras requires prenylation – the addition of a 15-carbon (farnesyl) or 20-carbon (geranylgeranyl) group – to keep the protein anchored into membranes for effective signaling. N- and K-Ras can be alternatively geranylgeranylated (GG’d) if farnesylation is inhibited but are …

Role Of Human Cytomegalovirus In Breast Cancer, Cendy Valle Oseguera, Juliet V. Spencer

Creative Activity and Research Day - CARD

Cancer results from unregulated cell growth that invades neighboring tissues. While there are many known risk factors for cancer, one area that remains largely unexplored is the impact of infectious disease. Human cytomegalovirus (HCMV) is highly prevalent in the population and has also been found in several types of tumors. We are investigating the possibility that a viral protein released from infected cells, cmvIL-10, promotes tumor metastasis by enhancing the invasive potential of breast cancer cells. These results will clarify the role of HCMV in breast cancer progression and could have broad implications for the diagnosis and treatment of cancer.

Analysis Of Her-2 Positive Breast Cancer Cell Lines, Natzidielly Lerma^, Paloma Valenzuela, Karla Parra, Eduardo Ramirez, Courtney L. Becerril, Irving Miramontes, Cynthia M. Rodriguez, Elizabeth Gamez, Giulio Francia*

COURI Symposium Abstracts, Spring 2012

No abstract provided.

Defeating Cytoplasmic Sequestration Of P53 In Human Breast Cancer Cells; Is Mortalin Involved?, Sarah Yunes

Honors Theses and Capstones

Cytoplasmic sequestration of p53, possibly caused by p53 interacting with mortalin, can prevent p53 from functioning in DNA repair and apoptosis, causing aberrant growth. This project treated SKBR3 breast cancer cells with MKT-077, a dye that is a competitive binder to mortalin to see if it would result in the release of p53 from the cytoplasm and restoration of p53 function. Treatment resulted in partial translocation of a protein suspected to be p53 to the nucleus and apoptosis initiated at the mitochondria.

Inhibition Of Fatty Acid Synthase Attenuates Cd44-Associated Signaling And Reduces Metastasis In Colorectal Cancer, Yekaterina Y. Zaytseva, Piotr G. Rychahou, Pat Gulhati, Victoria Allison Elliott, William Conan Mustain, Kathleen O'Connor, Andrew J. Morris, Manjula Sunkara, Heidi L. Weiss, Eun Young Lee, B. Mark Evers

Markey Cancer Center Faculty Publications

Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of …

Chip Sequencing Of Cyclin D1 Reveals A Transcriptional Role In Chromosomal Instability In Mice., Mathew C Casimiro, Marco Crosariol, Emanuele Loro, Adam Ertel, Zuoren Yu, William Dampier, Elizabeth A Saria, Alex Papanikolaou, Timothy J Stanek, Zhiping Li, Chenguang Wang, Paolo Fortina, Sankar Addya, Aydin Tozeren, Erik S Knudsen, Andrew Arnold, Richard G Pestell

Kimmel Cancer Center Faculty Papers

Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1-/- mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN …

Targeting The Cancer Cell Cycle By Cold Atmospheric Plasma, Olga Volotskova, Teresa S. Hawley, Mary Ann Stepp, Michael Keidar

Anatomy and Regenerative Biology Faculty Publications

Cold atmospheric plasma (CAP), a technology based on quasi-neutral ionized gas at low temperatures, is currently being evaluated as a new highly selective alternative addition to existing cancer therapies. Here, we present a first attempt to identify the mechanism of CAP action. CAP induced a robust ~2-fold G2/M increase in two different types of cancer cells with different degrees of tumorigenicity. We hypothesize that the increased sensitivity of cancer cells to CAP treatment is caused by differences in the distribution of cancer cells and normal cells within the cell cycle. The expression of γH2A.X (pSer139), an oxidative stress reporter indicating …

Effective Non-Viral Delivery Of Sirna To Acute Myeloid Leukemia Cells With Lipid-Substituted Polyethylenimines, Breanne Landry

Pharmacy Faculty Articles and Research

Use of small interfering RNA (siRNA) is a promising approach for AML treatment as the siRNA molecule can be designed to specifically target proteins that contribute to aberrant cell proliferation in this disease. However, a clinical-relevant means of delivering siRNA molecules must be developed, as the cellular delivery of siRNA is problematic. Here, we report amphiphilic carriers combining a cationic polymer (2 kDa polyethyleneimine, PEI2) with lipophilic moieties to facilitate intracellular delivery of siRNA to AML cell lines. Complete binding of siRNA by the designed carriers was achieved at a polymer:siRNA ratio of ~0.5 and led to siRNA/polymer complexes of …

Chemotherapy: The Physiological Cost Of A Cure, Megan Ellis

A with Honors Projects

This project focuses on the common long term side effects of cancer treatments, apart from cure. In addition to physiological function changes, it focuses on the chemical composition of chemotherapy drugs.

The Effects Of Cancer, Mara Lapayne

A with Honors Projects

I chose to do a project related to cancer for my Painting 1 class. Using oil paint, I wanted to create a more symbolic representation of cancer. So I made a cloud-like, cancerous mass with streaks of chaotic color swirling around a central face. The face represents any person affected by cancer and has had to “shut down” their emotions in order to function. I wanted the skin texture to be almost metallic as if it is metal armor or robotic-like, to support the idea of “shutting down” one’s emotions. The blank expression also portrays this idea.