Browsing by Subject "Metastasis"
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Item ANTI-TUMOR IMMUNE RESPONSES AGAINST MTLn3 MAMMARY ADENOCARCINOMA(2014-03) Carter, KiahRae J.; Orlowski, Ashley; Hodge, LisaBreast cancer is the leading cause of cancer-related deaths. More research needs to be done to examine the role of the lymphatic system during metastasis and therapies directed at the lymphatic system. Our rat model was used because it closely mimics human breast cancer. These results will allow for the future studies of therapies targeting the lymphatic system and if they will prevent metastasis. Purpose (a): Breast cancer is the leading cause of cancer-related morbidity and mortality. New research suggests the lymphatic vessels play a key role during the metastasis of breast cancer and therapies directed at the lymph system may aid in the treatment of breast cancer. MTLn3 is a mammary adenocarcinoma that is commonly used to study the effects of tumor metastasis in Fischer 344 rats. MTLn3 closely mimics human breast cancer pathogenesis, making it ideal for the study of breast cancer disease; however, little is known about the role of the lymphatic and immune systems in this disease model. The purpose of this study was to identify the type of immune response generated during MTLn3 disease. Specifically, we proposed that natural killer cells (NK), T cells, B cells and macrophages (MO) would increase in response to disease. Methods (b): To test our hypothesis, rats were randomized into control group or were sub-cutaneously injected in the right mammary fat pad with 1x106 MTLn3 tumor cells/mL on day 0. At days 0, 7, 14, 21 and 25 post-injection, lungs, tumor-adjacent lymph nodes (ALN), tumor–opposite lymph nodes (OLN) and spleens were removed and the concentration of leukocytes was determined. Primary tumors were excised and measured to calculate tumor volume. Blood was analyzed for the complete blood count and serum was measured for cancer-specific biomarkers. Results (c): All animals gained weight until day 14 post-injection. However, rats injected with MTLn3 suffered weight loss between days 14-25 post-injection. Furthermore, primary tumor size significantly (p < 0.05) increased during this time, suggesting weight loss may be related to disease. CD4+ T cells, B cells and MO in the spleen at day 21 decreased by day 25. Tumor adjacent lymph nodes experienced an increase in all cell populations, T cells, B Cells, MO, dendritic cells and NK. There were no differences in cell populations between ALN and OLN, except MO were significantly (p < 0.05) increased in ALN at Day 25. There was no change in pulmonary leukocytes by day 25. Neutrophils, monocytes and lymphocytes in the blood were significantly (p < 0.05) increased between control and 25 days post-injection rats, suggesting there is an immune response against MTLn3 tumor cells. Conclusions (d): Collectively, our results suggest MTLn3 initiates an immune response mediated by T cells, B cells, macrophages and NK cells between days 14-25 of disease. Of interest, these cells increase in the ALN at day 25 post-injection, suggesting they migrate into the lymph nodes in response to disease. In future studies, we will determine if MTLn3 metastasizes to the sentinel lymph nodes and the lung and determine if therapies targeting the lymphatic system inhibit this process.Item CASE STUDY: A RARE PRESENTATION OF HEPATOCELLULAR CARCINOMA(2013-04-12) Persad, LeahPurpose: The purpose of this case study is to describe a rare presentation of metastatic hepatocellular carcinoma. This patient presented for evaluation of a large mass in the posterior neck with associated pain. This unique case will provide information to the scientific and medical community about the clinical features and diagnosis of hepatocellular carcinoma in order to increase awareness of the various manifestations of this disease. Methods: The case presentation was a retrospective chart review. The materials included progress notes from physicians, laboratory data, pathology reports, and radiology reports. Results: We discuss the clinical features and diagnosis of hepatocellular carcinoma. This patient did not present with the typical clinical features of chronic liver disease but rather with a metastatic lesion in a rare location. Obtaining a final diagnosis in this case was difficult due to the unusual metastatic spread pattern that was not easily detected by standard diagnostic procedures. Conclusions: Extrahepatic metastatic hepatocellular carcinoma should be considered in the differential diagnosis of a lytic mass affecting the cervical spine in a non-cirrhotic patient.Item Novel Gene C17ORF37 in Prostate Cancer Progression and Metastasis(2010-05-01) Dasgupta, Subhamoy; Vishwanatha, Jamboor K.C17orf37 also known as MGC14832, C35, Rdx12, a novel gene located on human chromosome 17q12 in the ERBB2 amplicon, is abundantly expressed in different forms of human cancer. C17orf37 expression has been reported to positively correlate with grade and stage of cancer progression; however the functional significance of C17orf37 overexpression in cancer biology is not known. Here, we show that C17orf37 is highly expressed in prostate cancer cell lines and tumors, compared to minimal expression in normal prostate cells and tissues. RNA interference mediated downregulation of C17orf37 resulted in decreased migration and invasion of DU-145 prostate cancer cells, and suppressed the DNA binding activity of NF-κB transcription factor resulting in reduced expression of downstream target genes MMP-9, uPA and VEGF. Phosphorylation of PKB/Akt was also reduced upon C17orf37 downregulation, suggesting C17orf37 acts as a signaling molecule that increases invasive potential of prostate cancer cells by NF-κB mediated downstream target genes. Cellular localization studies by confocal and total internal reflection (TIRF) microscopy revealed expression of C17orf37 protein in the cytosol predominantly surrounding the membrane of prostate cancer cells. We identified that C17orf37 has a functional prenylation motif and is posttranslationally modified by geranylgeranyl transferase-I (GGTase-I) enzyme. Prenylated proteins (often referred to as CAAX family of proteins) contain a CAAX motif (C denotes cysteine, A represents aliphatic amino acids, and X any amino acid) at the carboxyl terminal which serves as a substrate for a series of post-translational modifications converting otherwise hydrophilic to lipidated proteins with hydrophobic domain, facilitating membrane localization. Geranylgeranylation of C17orf37 at the ‘CVIL’ motif translocates the protein to the inner leaflet of plasma membrane, enhances migratory phenotype of cells by inducing increased filopodia formation and potentiates directional migration. The prenylation-deficient C17orf37 mutant is functionally inactive and fails to disseminate injected cells in the mouse model of metastasis. This implies that prenylation activates the C17orf37 protein in cancer cells and functionally regulates metastatic progression of the disease. Our data strongly suggest C17orf37 overexpression in prostate cancer functionally enhances migration and invasion facilitating metastatic dissemination of tumor cells, and is an important target for cancer therapy.