Renal cell carcinoma (RCC) is a common and life-threatening cancer. Among RCCS, clear-cell renal cell carcinoma (ccRCC) is the most prevalent type and is highly malignant. ccRCC is initiated by loss of the von Hippel-Lindau tumor suppressor gene VHL. The pVHL protein binds and stabilzes the renal suppressor protein Jade-1 and exerts important growth suppressive activities through Jade-1. Since many solid tumors, like ccRCC, exhibit chromosomal instability and hence have defects in repair of DNA double-strand breaks (DSBs), we sought to determine the roles of Jade-1 and pVHL in these processes to elucidate mechanisms of cancer development. This study focused on the impact of pVHL on Jade-1 localization and expression levels in renal cancer cells by immunofluorescence microscopy and on Jade-1 expression levels by immunoblotting and qPCR when double-strand DNA damage is introduced using doxorubicin, neocarzinostatin or gamma irradiation. Early results suggested but do not yet confirm that there are differences in Jade-1 localization and expression levels in response to DNA DSBs in renal cells and renal cancer cells with versus without wild-type pVHL. More experiments are required to draw conclusions from these early data.

The C terminal binding proteins (CtBP) 1 and 2 are a family of transcriptional co-repressors overexpressed in a variety of cancers, and are frequently associated with poor prognosis and chemoresistance. CtBP has also been characterized in cell culture models as drivers of migration/invasion and epithelial-mesenchymal transition. CtBP mediates its transcriptional corepressor activity via its dehydrogenase domain, and inhibition of this domain interferes with CtBP oncogenic functions. The role of CtBP in APC mutant neoplasia remains obscure even though APC is responsible for degradation of both β-catenin and CtBP in suppressing colorectal tumorigenesis. Our prior work demonstrated that CtBP proteins can be effectively therapeutically targeted with substrate analogues of their intrinsic dehydrogenase domains. In addition, CtBP2 has been reported to play an important role in human colon cancer stem cells via its interaction with the transcription factor TCF4 on chromatin and promotes self-renewal of human colon tumor initiating cells (TICs) in vitro. To study CtBP2’s role in TIC activity in vivo, we studied TIC’s from Apc min/+ mice, which exhibit massive intestinal polyposis, in Ctbp2 wildtype or haploinsufficient backgrounds. Indeed, LGR5+, CD44+/CD24+, and CD133+ TIC populations were substantially decreased in Apc min/+ Ctbp2 +/- vs. Apc min/+ intestinal epithelia. Validating CtBP as a therapeutic target for TIC activity, we investigated intestinal TIC populations and polyposis in Apc Min/+ mice treated with the CtBP inhibitor 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP). Like Ctbp2 haploinsufficiency, 4-Cl-HIPP significantly decreased intestinal polyposis and downregulated LGR5+, CD44+/CD24+, and CD133+ TIC populations. To understand if CtBP2’s role in TIC activity and tumor progression extended to a cancer model, we studied the impact of Ctbp2 gene dosage in a mutant KRAS mouse pancreatic ductal adenocarcinoma (PDAC) model (CKP). Ctbp2 haploinsufficiency remarkably prolonged survival, abrogated peritoneal metastasis and ascites, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. Overall, our data suggest a key role of CtBP2 in driving the TIC compartment and progression in both pre-malignant intestinal polyposis and aggressive murine PDAC models.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 150-152).

Osteosarcoma is the most common primary malignancy of bone in children and young adults, with a worldwide incidence of 3.4 cases per million people per year. For most of the 20th century — before the advent of chemotherapy — osteosarcoma was inevitably fatal. Despite effective local control achieved through highly invasive and ultimately disabling surgical procedures, the vast majority of patients developed pulmonary metastasis and most often died in a matter of months. Fortunately, treatment strategies have evolved tremendously to include multi-agent adjuvant chemotherapy and various forms of limb-sparing surgery that have largely taken the place of amputation. This transformation in therapeutic approach materialized gradually, and became firmly established in practice during the early 1990s. Not surprisingly, it was around that same time that a rather dramatic increase in five-year survival was noted in patients presenting with localized disease — jumping from less than 20% prior to the advent of chemotherapy, to 60-70% following implementation of the current standard of care. However, since this initial period of advancement, very little progress has been made. Systemic treatment strategies have barely evolved over the course of the past two decades, and the probability of long-term survival thus remains largely unchanged. While it is true that roughly two-thirds of patients with localized conventional osteosarcoma survive for at least 5 years after receiving multi-modal therapy, the following fact better reflects the highly-aggressive nature of the disease, and thus also provides a more realistic representation of the long-term prognostic implications with which its typically associated: the risk of recurrence and metastasis remains markedly elevated following complete eradication of the primary tumor. After undergoing surgical resection and multiple rounds of both neoadjuvant and postoperative chemotherapy, a significant quantity of patients thought to be cured see their malignancy recur, spread, and invade distant tissue — at which point, the probability of disease-free survival drops to well below 20%. Thus, the need for enhanced, more precisely-targeted mechanisms of treatment is indisputable. Accordingly, this work will provide an in-depth description of the molecular etiology, pathophysiology, clinical presentation, diagnosis, and treatment of osteosarcoma, while also exploring potentially promising novel therapies aimed to improve patient outcomes.

<p> Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically-activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release cytokines in an NADPH oxidase 2 (NOX2)-dependent manner that signal through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity.</p><p>

The expected growth of the older adult population in the United States over the next several decades will have an unprecedented impact on the health care system. Research has shown that age is the greatest risk factor for developing cancer and certain hematological malignances. Insights on acute myeloid leukemia have suggested that premalignant somatic mutations in stem cells are responsible for age associated medical conditions. Persistence of preleukemic clones and the risk of relapse is linked with an abnormal DNA methyltransferase 3A (DNMT3A) gene especially in the R882H region which may lead to a phenomenon known as clonal hematopoiesis. The DNMT3A gene provides instructions for making an enzyme that establishes DNA methylation patterns and is believed to form the initial mutation in acute myeloid leukemia. Because of the significance of DNMT3A mutations in the pathogenesis of leukemias and clonal hematopoiesis with respect to the geriatric population, the goal of the thesis was to generate DNMT3A proteins for future research via a bacterial expression vector. Wildtype and dominant negative DNMT3A proteins were not successfully generated, but the study is still an ongoing process. The overview of the entire long term study is to focus on the mechanism insight on DNMT3A activity and its contribution to acute myeloid leukemia development.

This literature review summarizes the biological concept behind cancer and focuses on the use of PD-1 in tumors as a way of immune evasion as well as the use of PD-1/PD-L1 blockade as an innovative target for immunotherapy. Cancer arises from mutagenic events resulting in the presence of abnormal cells and uncontrollable cell proliferation. It is able to evade immune activity through many methods of immune evasion, one of which is the PD-1/PD-L1 blockade. Normally PD-1 binds to PD-L1 to dampen the immune response after activation and cancer is able to take advantage of this immune homeostasis pathway to prevent immune attack. It has been shown that inhibition of the PD-1/PD-L1 blockade can act to block the interaction between PD-1 and PD-L1, thus allowing the T cells of the immune system to activate and attack the cancer. This has led to the invention of PD-1/PD-L1 checkpoint inhibitors, with currently 6 approved by the FDA for the treatment of a wide spectrum of cancers. The discovery of PD-1/PD-L1 blockade has made a leap of advancements in cancer immunotherapy; however, as the number of therapies is expected to rise in the future, several issues remain that require further investigation to optimize the potential of PD-1/PD-L1 inhibitors. Specifically, mechanisms of resistance, mechanisms behind non-immunogenic tumors, and immune-related adverse events are areas that warrant further examination in order to fully maximize the benefits and minimize the risks of PD-1/PD-L1 inhibitors. The bispecific combination molecule cotargeting PD-1/PD-L1 could be a possible alternative therapeutic approach with enhanced antitumor activity compared to the traditional monoclonal PD-1 or PD-L1 inhibitors.

Colorectal cancer (CRC) is one of the most diagnosed malignancies and third most leading causes of death in the world. In the pathogenesis of CRC, a benign adenomatous polyp can develop into an invasive cancer through multiple routes of gene inactivation. One of the most common mutations found in CRC is a loss of function mutation of APC. Wild-type APC forms a destruction complex with Axin2 and GSK-3β to degrade β-catenin in the cytosol. If β-catenin is not degraded, it can be translocated into the nucleus, wherewith the help of LSF it binds to the DNA and initiates Wnt signaling. The Wnt pathway is responsible for the upregulation of pro-oncogenic genes. The components of this pathway have become a prime target for CRC drug therapies. In this study, we examined the effectiveness of a newly developed drug named FQI-234. FQI-234 is designed to target LSF and hinder its ability to modulate the binding of β-catenin to DNA. An animal model was developed and 20 nude mice were subcutaneously injected with HT-29 cells. Following approximately one week, 10 mice were randomly selected to be in the experimental group and given 15 administrations of FQI-234 at 5 mg/kg over three weeks. Volumes of the tumors from each mouse were calculated throughout the experiment and at its conclusion. These calculations revealed a slower growth rate and smaller volume in those tumors treated with FQI-234. Tumors were then harvested and divided. Half of the tumors halves were used for RT-PCR and the other halves were fixed in formalin, embedded in paraffin, and then stained for histological examination. IHC staining exhibited a downregulation in levels of β-catenin, LSF, Axin2, and Sox9. Suppression of cell proliferation and upregulation of cell apoptosis was also evident. RT PCR confirmed these results with a decrease in levels of Axin2, Sox9, and Cyclin D1 shown in the xenografts treated with FQI-234. Overall this study showed for the first time in an animal model the tumor-suppressive effects of the LSF targeted compound, FQI-234. / 2023-12-14T00:00:00Z

No description available.

Prostate Cancer (PCa) is the most common cancer that affect men worldwide. As PCa depends on androgen receptor (AR) signaling, AR blockade remains the prime choice for PCa therapy. Nonetheless, treatment failure is common and warrants a better understanding of the molecular underpinnings of AR and other key signaling pathways in PCa. Non-coding RNAs, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play important roles as master regulators of protein coding and noncoding gene expression. Previous studies in our lab identified downregulation of AR-targeting miRNAs, miR-299-3p, miR-30e and miR-34c in PCa tumors, particularly in African American compared to Caucasian PCa patients. Here we show that miR-299-3p and miR-30e exert their tumor suppressor functions through modulation of a variety of signaling pathways through regulation of genes including VEGFA, PI3K/Akt, FBXO45, PARPBP and MYBL2 and other downstream effector genes in addition to AR using in vitro and in vivo xenograft models. We showed validation of miR-299-3p and miR-30e interactions with and functional regulation of the target mRNAs associated with phenotypic changes in PCa cells through overexpression and knockdown approaches. We showed improved drug sensitivity of PCa cells upon restored expression of miRNAs. We provide evidence on the role of two novel miRNA-interacting lncRNAs HELLPAR and PAINT in modulating key signaling pathways that could significantly impact PCa progression. We also demonstrate that loss of expression of miR-299-3p and miR-34c in PCa tumors, that also show racial disparity, is associated with promoter hypermethylation mediated through DNA Methyltransferase (DNMT) activation and expression. We show that miR-299-3p and miR-30e target DNMT3A and DNMT3B and loss of miRNA expression stabilizes DNMT expression suggesting a double-negative feedback loop that leads to further silencing of miRNA expression. This study show involvement of a novel miRNA/lncRNA/mRNA network in PCa progression, which can be used as prognostic marker for aggressive PCa.