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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Targeting Gastrin-releasing Peptide in Neuroblastoma

Paul, Pritha 04 September 2013 (has links)
The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs resulting in aggressive, refractory disease. As a neuroendocrine tumor, neuroblastomas secrete a number of peptides; one such being the gastrin-releasing peptide (GRP). GRP antagonists have been used to inhibit the proliferation of cancer cells. Here, I demonstrate that GRP silencing induced apoptosis in neuroblastoma cells and, in combination, allowed the usage of sublethal doses of chemotherapeutic drugs to elicit responses similar to lethal doses of the same drugs when used alone. GRP silencing also decreased tumorigenesis in vitro and suppressed liver metastasis in vivo. Moreover, GRP silencing increased PTEN levels with a simultaneous inhibition of AKT/mTOR/FAK activation in neuroblastoma cells. Interestingly, PTEN overexpression inhibited GRP-mediated neuroblastoma progression in vitro. This placed PTEN as a critical negative regulator of the oncogenic effects of GRP in neuroblastoma progression. This study provides a rationale for the use of GRP antagonists in patients with aggressive, refractory neuroblastomas.

Dietary and protein modifiers of colitis-associated carcinoma: selenium, selenoproteins, and myeloid translocation genes and their impacts on inflammation, stem cell properties, and oxidative stress

Barrett, Caitlyn Whitten 23 September 2013 (has links)
Inflammatory bowel disease (IBD), which affects 1 in 600 Americans, is characterized by severe and chronic inflammation, a known contributor to cancer. As such, the risk for cancer is increased in patients with IBD compared with the general population, and cancer is the most significant cause of mortality in IBD. This thesis will identify modifiers of colitis-associated cancer (CAC) utilizing a murine CAC model applied to models of dietary and genetic deficiencies. First, this thesis will focus on dietary selenium and two plasma selenoproteins as suppressors of tumorigenesis. Selenium deficiency results in increased inflammation in response to an inflammatory model utilizing dextran sodium sulfate (DSS) which, when coupled with the use of an initiator, azoxymethane (AOM/DSS inflammatory carcinogenesis model), leads to an increase in tumorigenesis concomitant with an increase in DNA damage. Knockout of the plasma selenoprotein glutathione peroxidase-3 (Gpx3) also results in increased tumor number as well as a higher degree of dysplasia. Finally, I demonstrate that selenoprotein P (Sepp1), which is considered to have both selenium transport and antioxidant properties, is a bimodal modifier of CAC. Complete loss of Sepp1 leads to decreased tumorigenesis as the result of clearance of initiated cells while haploinsufficiency leads to an increase in tumorigenesis which is mimicked by loss of either the putative selenium transport or antioxidant domains of Sepp1. A second set of CAC modifiers identified in this thesis are the myeloid translocation genes (MTGs). The MTGs are a family of transcriptional corepressors that were originally identified as targets of chromosomal translocations in acute myeloid leukemia. This thesis will first identify MTG, related-1 (MTGR1) as a modifier of inflammation which, upon its loss, leads to a decrease in inflammatory carcinogenesis. Moreover, I identify an interaction between MTG16 and the transcriptional repressor Kaiso. Knockout of MTG16 alone leads to increased tumorigenesis while knockout of Kaiso leads to unaltered tumorigenesis. Interestingly, absence of both proteins leads to rescue of the MTG16 phenotype, suggesting that Kaiso is epistatic to MTG16.


Elliott, Natalina Elizabeth 23 May 2013 (has links)
Adult T-cell leukemia/lymphoma (ATLL) is an incurable peripheral T-cell malignancy where most patients succumb within the first year of diagnosis. Development of ATLL requires human T-cell lymphotrophic virus type 1 (HTLV-I) retroviral infection followed by accumulation of somatic mutations and changes in gene expression. The discovery of genes and pathways involved in the initiation of ATLL may provide novel therapeutic targets for treatment of this fatal disease. Since the IL-2 signaling pathway plays an important role in ATLL development, mutational analysis of IL-2 signaling pathway components should yield a better understanding of disease progression and outcome. Janus kinase 3 (JAK3), a nonreceptor tyrosine kinase is a key kinase upstream in the IL-2 signaling pathway. Activating somatic mutations in JAK3 have been described in leukemias and lymphomas including acute megakaryoblastic leukemia and natural killer/T-cell lymphoma. Three mutations in the regulatory FERM domain of JAK3 were identified in four of the thirty-six ATLL patients screened and no mutations were found in the twenty-four screened ethnically matched controls. These somatic, missense mutations occurred in the amino terminal regulatory FERM domain. JAK3 FERM domain may play an autoregulatory role by inhibiting kinase activity in the absence of IL-2. In cell culture assays all three FERM domain mutations induce gain of function in JAK3 and can be inhibited with a JAK specific kinase inhibitor, tofacitinib. One of the JAK3 FERM domain mutations (E183G) was characterized in vivo and found to be oncogenic in cooperation with the loss of cell cycle regulatory proteins p16(INK4a) and p14(ARF). These findings emphasize the importance of JAK3 activation in ATLL development and offer a novel therapeutic target for this incurable disease.

A role for estrogen receptor and the estrogen-regulated protease cathepsin D in stromally-driven prostatic carcinogenesis.

Pruitt, Freddie Lee 28 June 2013 (has links)
Stromal-epithelial interactions are important in both prostate development and cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. Several molecules found to be aberrantly expressed in cancer associated fibroblasts (CAFs) (including cyclin D1 [CD1], stromal derived factor 1 [SDF-1]) contribute to tumorigenesis and malignant transformation in xenograft experiments. These molecules can be regulated by a number of different factors, but are both putative estrogen regulated genes. In this study, we show that dysregulation of ERα expression in cancer associated stroma results in the differential regulation of estrogen responsive genes that are key factors in enhancing the invasive potential of the epithelial tumor. The cell cycle regulator CD1 and the estrogen receptor are known to interact and can induce estrogenic gene transcription. Cathepsin D (CathD) is an estrogen regulated aspartic endopeptidase, known to be involved in a number of physiological processes as well as in the regulation of apoptosis. In this study, we highlight CathD as a mediator of cancer associated stromal promotion of prostate tumorigenesis. An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue in comparison to benign prostate tissue. Stromal specific overexpression of CathD in benign prostate stromal cells induced malignancy in adjacent epithelium through increased TGFβ signaling and responsive gene expression. The proteolytic function of stromally-derived CathD is dependent on the activity of hydrogen-proton pump activity on the surface of prostate epithelial cell lines. The study presented here indicates that CathD is not only an important mediator of stroma-epithelial cross talk, but also an essential component in promotion of tumorigenesis in vivo, and Inhibition of ER signaling in the cancer associated stroma inhibits malignant transformation in the adjacent epithelium.


Lu, Xinyuan 26 July 2013 (has links)
LZAP (Cdk5rap3, C53) is a putative tumor suppressor lost in 30% of human head and neck squamous cell carcinoma. LZAP depletion enhances cell invasion, xenograft tumor growth and angiogenesis. Mechanistically, LZAP inhibits activity of NF-¦ÊB and Chk1 and Chk2 through binding and decreasing phosphorylation of critical proteins. LZAP has no known enzymatic activity, implying that its biological functions are likely mediated by protein-protein interactions. The focus of this dissertation is to better understand LZAP activity through discovery of LZAP-associated proteins. Immunoprecipitation followed by liquid chromatography¨Cmass spectrometry identified members of protein phosphatase 2C family, PPM1A and PPM1B, as LZAP binding proteins Wip1/PPM1D, a known RelA phosphatase is a member of this family. Here we show that PPM1A dephosphorylates S536 and S276 of RelA and selectively inhibits NF-¦ÊB transcriptional activity resulting in decreased expression of cytokines implicated in cancer metastases. In human prostate cancer, metastatic deposits had lower PPM1A mRNA compared to primary tumors without metastases. In xenograft models, PPM1A expression inhibited bony metastases, whereasPPM1A depletion enhanced tumor growth. Interestingly, activities of LZAP and PPM1A to inhibit RelA inhibition are mutually dependent. LZAP contains motifs predicted to bind the docking domain (D domain) of mitogen activated protein kinases (MAPKs). LZAP binds and inhibit p38 phosphorylation, alters p38 cellular localization, and inhibits basal and cytokine-stimulated p38 activity. LZAP binds the p38 phosphatase, Wip1, and facilitates Wip1 binding and dephosphorylation of p38. These data suggest that LZAP inhibition of p38 phosphorylation and activity depends, at least partially, on Wip1. Regulation of LZAP activity is not well understood; however, we found that LZAP protein is modified by phosphorylation and ubiquitination, forms dimers/oligomers, and may be a target of PPM family members. These findings provide insight into LZAP activity and may lead to mechanisms to restore LZAP activity. Together, this work suggests a common mechanism of LZAP activity to regulate important cancer-related proteins, namely interaction with and regulation of PPM phosphatase family members.

Cellular and Molecular Changes Impacting Cancer Progression in Non-Alcoholic Fatty Liver Disease

Mendonsa, Alisha Maria 31 December 2014 (has links)
Non alcoholic fatty liver disease (NAFLD), is recognized as the one of the most common causes of liver disease in the United States and worldwide. NAFLD is associated with increased risk of development of hepatocellular carcinoma. Additionally, our lab has shown an increased metastatic burden in the steatotic liver using a mouse model of diet induced steatosis. NAFLD is characterized by cellular and molecular changes in the liver which include an influx of inflammatory cells, changes in gene expression and alteration in cytokine production. We hypothesize that changes in the steatotic liver contribute to a more permissive microenvironment for tumor growth and establishment of metastases. To better understand the alterations to the liver with NAFLD, we used a murine model of steatosis and corroborated our results with human samples of NAFLD. Analysis of inflammatory cell populations revealed increased infiltration of CD11b positive myeloid and CD3 positive lymphocytic cell populations in steatotic livers compared to normal livers. Significant alterations in cytokine profiles in the plasma and liver tissue lysates from normal and steatotic mice were detected including leptin, CXCL1, CXCL2, and CXCL16 that were further shown to directly increase hepatocyte proliferation in vitro. To determine molecular factors altered with NAFLD, we assessed changes in matrix metalloproteinase levels and show that MMP13, an interstitial collagenase, is significantly upregulated in the steatotic liver. To evaluate the role of host MMP13 on tumor development, we used the splenic injection model of liver metastasis in mice genetically deficient in MMP13 and show a significant decrease in metastatic tumor burden in MMP13-/- mice compared to wildtype mice. Using confocal microscopy we observed a significant decrease in the number of individual tumor cells extravasating from the hepatic vasculature in MMP13-/- mice compared to wildtype mice. Stable MMP13 knockdown cell lines were used to demonstrate that reduced tumor derived MMP13 decreased migratory and invasive properties in vitro and decreased metastatic burden in vivo. This study identifies changes in the steatotic liver that impact tumor development and establishment of metastases in the steatotic liver microenvironment.

Acquired Resistance to Targeted Therapy in EGFR-Mutant Lung Adenocarcinoma

Nebhan, Caroline Amalia 11 September 2014 (has links)
Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Lung cancers that are driven by mutations in the Epidermal Growth Factor Receptor (EGFR) are treated with targeted anti-EGFR therapy, such as first-generation tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. Unfortunately, all patients whose tumors initially respond to erlotinib or gefitinib will eventually go on to develop primary acquired resistance, most commonly through a second-site EGFR mutation, T790M. The combination of a second-generation EGFR TKI, afatinib, plus the anti-EGFR antibody, cetuximab, may overcome primary acquired resistance. Unfortunately, secondary acquired resistance is also seen with the new drug combination, and the underlying mechanisms have not yet been determined. Using tumor sample from a patient with secondary acquired resistance, we identified two unexpected NF2 mutations, neither of which was detected in the patients pre-treatment sample, suggesting that mutations in NF2 were acquired during treatment. The NF2 gene encodes merlin, a known tumor suppressor that is thought to regulate EGFR. Using cell line and animal models, we demonstrate that loss of NF2 is sufficient to induce resistance to TKI in EGFR-mutant cells. Co-treatment with the mTORC1 inhibitor, rapamycin, re-sensitizes cells to TKI. These studies suggest a novel potential mechanism of acquired resistance to targeted therapy in EGFR-mutant lung cancer. To further explore acquired resistance, we also evaluated a novel, irreversible, mutant-specific third-generation EGFR TKI, AZD9291. Pre-clinically, this drug potently inhibits signaling pathways and cellular growth in both EGFR-mutant and EGFR-mutant/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. We use cell line and mouse models to characterize AZD9291, providing the foundation for a recently-initiated clinical trial. In sum, this work evaluates mechanisms of acquired resistance to targeted therapy in EGFR-mutant lung cancer and identifies potential strategies to overcome such resistance.

TGFbeta signaling enhances wound healing inflammation in post-partum breast cancer.

Williams, Andrew John 02 December 2014 (has links)
Breast cancer is the leading cancer diagnosis in pre-menopausal women in the U.S. Of these breast cancers, 25% are diagnosed 2-5 years post-partum. Unfortunately, post-partum breast cancers (ppBCs) are highly metastatic. The reasons underlying the exaggerated lethality of ppBCs are unclear, but relate to stromal remodeling events that occur during post-partum involution, when milk-producing mammary epithelial cells (MECs) undergo widespread cell death. Upon engulfment of apoptotic cells (efferocytosis), immune suppressive wound healing cytokines are produced including Tgfβ1, IL4, and IL10, which increase macrophage polarization towards an M2 phenotype. Wound healing/TH2-like cytokines and M2 macrophages each correlate with decreased disease-free survival in breast cancer patients. Transforming growth factor (TGF)-β1 is a pleiotropic cytokine that has gained interest for its role in both tumor progression and metastasis. TGFβ1 operates to suppress cytotoxic immunity, increase fibroblast activation and collagen deposition, increases migration and invasion of tumor epithelial cells, and may enhance cancer stem cell-like properties in some tumor cells. TGFβ1 is abundantly up-regulated in response to efferocytosis during post-partum involution of the mammary gland. We recently showed that TGFβ1 is induced upon macrophage-mediated efferocytosis in the mammary tumor microenvironment (TME). Secreted TGFβ1 also acts on mammary tumor epithelial cells to increase epithelial-mesenchymal transition (EMT), cell adhesion, motility, and invasion. We utilized an immune-competent mouse model of ppBC, which recapitulates many of the clinical aspects of ppBCs in patients, including increased metastasis in response to post-partum events to show that inhibition of efferocytosis for the first 7 days of involution prevents M2 macrophage polarization, blocks induction of TGFβ1, and prevents metastasis of ppBCs through involution day 40. Our preliminary results show that ppBCs treated with the neutralizing anti-TGFβ antibody 1D11 for the first 14 d of involution produce fewer lung metastases as compared to control IgG-treated ppBCs.

Effects of alterations to the tumor microenvironment driven by transforming growth factor beta on tumor progression

Pickup, Michael William 11 October 2013 (has links)
Dissertation under the direction of Professor Harold L. Moses Transforming Growth Factor Beta (TGF-β) is acts as both a tumor suppressor and promoter in the context of epithelial tumor progression. In epithelial cells, active TGF-β signaling promotes cell cycle arrest to slow tumor growth but also promotes EMT and cell motility to enhance tumor cell metastasis. We sought to address TGF-β signaling role in tumor progression through its effects on stromal cells and microenvironmental changes. Interestingly, as with epithelial TGF- β signaling, we found active TGF-β signaling in fibroblasts to present with the same dichotomous relationship. We found that TGF-β can promote fibroblast activation which in turn drives the expression of numerous matrix remodeling genes. The phenotypic outcome of this matrix remodeling promotes tumor cell metastasis. Alternatively, abrogation of TGF-β signaling in fibroblasts also promotes tumor cell metastasis. Albeit, this occurs through a different mechanism involving altered chemokine expression to promote chemotaxis of tumor promoting myeloid cells. Gene expression analysis of stroma from reduction mammoplasty as well as breast cancer patients suggests that TGFβR2 is lost as breast cancer progresses from normal mammary tissue to invasive ductal carcinoma. Importantly, this loss of TGFβR2 in the stroma of breast cancer patients is associated with poor patient outcome and rick of recurrence. This work shows the importance of TGF-β signaling as a central player in numerous biological process which effects tumor progression through the tumor microenvironment. As this signaling axis in the tumor microenvironment is certainly important in the progression of human breast cancer, the therapeutic targeting of the TGF-β pathway will need to consider stromal effects for efficacious use.


Kaufman, Jacob Marcus 03 December 2013 (has links)
Inactivation of STK11/LKB1 is one of the most common genetic events in lung cancer, and understanding the cellular phenotypes and molecular pathways altered as a consequence will aid the development of therapeutic strategies targeting LKB1-deficient cancers. We report the comprehensive analysis of gene and protein expression patterns associated with LKB1 loss in lung adenocarcinomas, through which we identify hallmarks of altered tumor metabolism and downregulation of the PI3K/AKT pathway. Significant differences are observed between human tumors and those derived from a genetically engineered mouse model of LKB1 loss. A 16-gene signature is predictive of both mutational and non-mutational LKB1 loss in human tumors. Cell lines expressing this signature show increased sensitivity to MEK inhibition, independent of mutations in RAS and RAF family members. Restoration of LKB1 in lung cancer cell lines downregulates the gene expression pattern, attenuates FOXO3, and induces resistance to MEK inhibition. These findings identify characteristic phenotypic features of LKB1-deficient tumors and identify LKB1 loss as a novel determinant of MEK sensitivity.

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