Browsing by Subject "metastasis"
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Item A Review of Dendritic Cell Vaccines in Cancer Treatment and a Managerial Focus on Issues Related to Subject Recruitment(2006-12-01) McFarlin, Tory; Arredondo, LaChelle; Gwirtz, Patricia A.; Oglesby, MichaelMcFarlin, Tory. A Review of Dendritic Cell Vaccines in Cancer Treatment and a Managerial Focus on Issues Related to Subject Recruitment. Master of Science (Clinical Research Management), December 2006, 97 pp., 5 tables, bibliography, 24 titles. Melanoma is form of skin cancer that can become deadly if the cancer progresses to a stage of metastasis. Five year survival rates as low as 10% may be noted in such patients. Decarbazine and Proleukin have been approved by the FDA for the treatment of metastatic melanoma; however both have response rates of approximately 20% or less. New treatment modalities including dendritic cell (DC) vaccines are currently being tested for treating metastatic melanoma with greater safety and efficacy profiles. DC vaccines are made by obtaining a subject’s DCs, priming them with melanoma antigen ex vivo and then injecting them into the patient to initiate an immune response against melanoma tumor cells in vivo. Investigational new treatments such has the DC vaccine must first be tested in clinical trials on research subjects. Subject enrollment issues regarding such a trial can cause delays in advances of the treatment. As an intern with a DC vaccine clinical trial, the author assisted in screening 45 patients and observed many hindrances involving enrollment of subjects. Such hindrances include: low rates of study personnel retention, small patient pools, and competing trials. Recommendations to improve enrollment include: more effective advertisement strategies and increased patient education.Item Akt Isoforms: A Family Affair in Breast Cancer(MDPI, 2021-07-09) Basu, Alakananda; Lambring, Christoffer B.Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBalpha), Akt2(PKBbeta) and Akt3(PKBgamma). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.Item Effect of CRISPR MIEN1 knockout in metastatic breast cancer cells(2018-12) Van Treuren, Timothy; Vishwanatha, Jamboor K.; Basu, Alakananda; Basha, RiyazMigration and Invasion Enhancer 1 (MIEN1) is an oncogene which is involved in facilitating the migration and invasion of cancer cells through actin dynamics and gene expression. Increased MIEN1 expression in many types of tumors correlates with disease progression and metastatic propensity. The precise mechanism by which MIEN1 functions is yet to be understood. The goal of these studies is to progress toward determination of the mechanisms and genetic context in which MIEN1 functions contribute to cancer progression. It was hypothesized that Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) mediated knockout of MIEN1 in metastatic breast cancer cells would result in reduced migration and invasion. CRISPR genome editing effectively produced specific genomic deletions in the MIEN1 gene which led to the elimination of its expression in these breast cancer cells. Migration in MDA-MB-231 (231) MIEN1 knockout (MIEN1-KO) cells exhibited no difference when compared to parental 231, which was in contrast with previous siRNA studies. Signaling in several MIEN1-KO pools was inconsistent. Knocking out MIEN1 in 231 derivative cell lines showed few significant alterations in the growth, migration, invasion, signaling, despite significant changes in metabolism. However, re-expression of the MIEN1 protein containing a mutant immunoreceptor tyrosine-based activation motif (ITAM) domain resulted in significantly decreased invasion. This revealed that MIEN1-KO 231 derivative cells were susceptible to interference of compensatory mechanisms and demonstrates the importance of the migration and invasion pathways in which MIEN1 participates in breast cancer metastasis. These findings also suggest MIEN1 may still be a promising therapeutic target to inhibit metastasis if inhibitors can be developed which block ITAM function without affecting localization or expression.Item Effect of CRISPR MIEN1 Knockout in Metastatic Breast Cancer Cells(2018-12-01) Van Treuren, Timothy R.; Vishwanatha, Jamboor K.; Basu, Alakananda; Basha, RiyazMigration and Invasion Enhancer 1 (MIEN1) is an oncogene which is involved in facilitating the migration and invasion of cancer cells through actin dynamics and gene expression. Increased MIEN1 expression in many types of tumors correlates with disease progression and metastatic propensity. The precise mechanism by which MIEN1 functions is yet to be understood. The goal of these studies is to progress toward determination of the mechanisms and genetic context in which MIEN1 functions contribute to cancer progression. It was hypothesized that Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) mediated knockout of MIEN1 in metastatic breast cancer cells would result in reduced migration and invasion. CRISPR genome editing effectively produced specific genomic deletions in the MIEN1 gene which led to the elimination of its expression in these breast cancer cells. Migration in MDA-MB-231 (231) MIEN1 knockout (MIEN1-KO) cells exhibited no difference when compared to parental 231, which was in contrast with previous siRNA studies. Signaling in several MIEN1-KO pools was inconsistent. Knocking out MIEN1 in 231 derivative cell lines showed few significant alterations in the growth, migration, invasion, signaling, despite significant changes in metabolism. However, re-expression of the MIEN1 protein containing a mutant immunoreceptor tyrosine-based activation motif (ITAM) domain resulted in significantly decreased invasion. This revealed that MIEN1-KO 231 derivative cells were susceptible to interference of compensatory mechanisms and demonstrates the importance of the migration and invasion pathways in which MIEN1 participates in breast cancer metastasis. These findings also suggest MIEN1 may still be a promising therapeutic target to inhibit metastasis if inhibitors can be developed which block ITAM function without affecting localization or expression.Item Role of Exosomal Annexin A2 in Angiogenesis and Breast Cancer Metastasis(2015-05-01) Maji, Sayantan; Vishwanatha, Jamboor K.; Clark, Abbot F.; Gryczynski, IgnacyEarly detection of cancer using circulating biomarkers is a realistic possibility with the discovery of exosomes. Cells under both physiological and pathological conditions secrete a wide array of membranous vesicles containing specific protein and RNA signatures. Exosomes, which are 40-100 nm in size, comprise a major portion of these vesicles. Exosomes play important roles in promoting tumor progression and metastasis, but the mechanisms by which they act are not yet understood. Annexin A2 (AnxA2) is a 36 kDa calcium dependent phospholipid-binding protein up-regulated in many cancer types that promotes tumorigenesis and angiogenesis. Although AnxA2 is highly expressed in exosomes, its function has never been characterized. In this study first we characterized exosomal AnxA2 (exo-AnxA2) expression in a breast cancer progression model. We found that exo-AnxA2 expression is significantly higher in malignant cells than normal and premetastatic cells. Next we explored the correlation and functionality of exo-AnxA2 in angiogenesis and breast cancer metastasis. In vitro and in vivo angiogenesis studies showed that exo-AnxA2 is an important mediator of angiogenesis and targeting the N-terminus of AnxA2 with a competitive hexapeptide greatly reduce the angiogenic effects induced by exo-AnxA2. To study the role of exo-AnxA2 in breast cancer metastasis we used MDA-MB-231 breast cancer cell line and its organ specific metastatic variants MDA-MB-831 (brain metastatic) and MDA-MB-4175 (lung metastatic) breast cancer cells. By using exosome priming in a mouse model, we show that priming with exosomes from metastatic breast cancer cells creates a favorable microenvironment for metastasis, and priming with exo-AnxA2 depleted exosomes leads to reduction of brain as well as lung metastasis. Detailed analysis of the signaling pathways revealed that p38MAPK/NF-κB and STAT3 pathways were up-regulated in the cancer exosomes primed animals than AnxA2 depleted exosome primed animals. These data demonstrate an important role for exo-AnxA2 in breast cancer pathogenesis. Finally, to validate whether exo-AnxA2 can be developed as s potential biomarker, we screened 50 breast cancer serum samples and 50 age matched control samples. Clinical analysis of the serum samples revealed that exo-AnxA2 is over expressed in breast cancer serum samples compared to normal samples. Detailed analysis of the exo-AnxA2 levels among breast cancer subtypes showed that more aggressive breast cancer subtype TNBC has higher exo-AnxA2 levels than HER2+ samples. In summary, our data suggest that exo-AnxA2 plays a major role in promoting angiogenesis and breast cancer metastasis. Further, breast cancer serum samples have higher exo-AnxA2 expression than control samples. Thus, exo-AnxA2 can be a potential diagnostic and prognostic marker in breast cancer patients to detect and monitor metastasis.