Browsing by Subject "Endometrial Neoplasms"
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Item Genetic and Molecular Studies of Endometrial Cancer(2010-11-02) Akbay, Esra; Castrillon, Diego H.Endometrial cancer, which develops from the inner lining of the uterus, is the most common cancer of the female reproductive tract. Endometrial cancer is comprised of two epidemiologic, molecularly and genetically different subtypes known as type I and type II. Because of its clinical significance and aggressive behavior, my research focused on type II endometrial cancer. Type II endometrial cancer is associated with advanced age and TP53 mutations, which suggests a link between telomeres and the development of type II tumors. Telomeres and other markers of telomere status in type I and type II tumors were analyzed, short telomeres are observed in both tumor types. However, only type II tumors are associated with critical telomere shortening in the adjacent, morphologically normal epithelium. This suggests that telomere shortening contributes to the initiation of type II, but not of type I tumors. To further explore this hypothesis, 5th generation telomerase knockout mice with critically short telomeres were analyzed and a distinctive endometrial lesion that resembles the in situ precursor of type II carcinomas, endometrial intraepithelial carcinomas were observed. Subsequently, the role of dysfunctional telomeres in endometrial cancer development was investigated in the mouse by conditionally inactivating Pot1a, a key component of the shelterin complex that stabilizes telomeres in endometrial epithelium. Inactivation of Pot1a by itself does not stimulate endometrial carcinogenesis. However, simultaneous inactivation of Pot1a and p53 results in endometrial intraepithelial carcinoma-like lesions by 9 months and metastatic tumors in 100% of the animals by 15 months. These tumors are poorly differentiated endometrial carcinomas with prominent nuclear atypia, DNA damage, and aneuploidy, resembling human type II tumors. These studies thus lend support to the hypothesis that dysfunctional telomeres play a critical role in type II endometrial carcinogenesis.Item LKB1, CCL2, and Macrophages: A New Axis of Endometrial Cancer Progression(2015-04-07) Peña, Christopher George; Brekken, Rolf A.; Lum, Lawrence; Amatruda, James F.; Castrillon, Diego H.Cancer of the uterus is a common malignancy in women with no adequate treatments for tumors that have progressed beyond the uterus. The serine-threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer. Combined genetic, proteomic, and in vivo studies in genetically engineered mouse models show that loss of LKB1 protein is associated with high grade, high stage tumors with unfavorable clinical outcomes. However, the mechanism(s) by which LKB1 drives malignant transformation of uterine cancers remains unclear. Here I show that LKB1 unexpectedly suppresses tumor progression via pAMPK dependent secretion of the inflammatory cytokine CCL2. Lkb1 inactivation in vivo resulted in abnormal production of CCL2, which led to recruitment of pro-tumorigenic macrophages (aka immunosuppressive macrophages) responsible for tumor invasion. Conditional inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression, increased survival, and significantly reduced infiltration of macrophages in the tumor microenvironment. In human primary endometrial cancers (EMCAs), loss of LKB1 protein was strongly associated with increased CCL2 and macrophage density. Additionally, high stage and high grade EMCAs were characterized by loss of LKB1 protein, elevated production of CCL2, and increased macrophage density. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating new therapeutic opportunities for targeting CCL2 and the tumor microenvironment.Item Pathologic Staging of Gynecological Cancers: An Interactive Visual Resource for Surgeons(2008-05-12) Chaphalkar, Maya D.; Krumwiede, Kimberly HoggattThe goal of this thesis was to create a useful teaching and review tool for staging procedures, specifically made for medical students, residents, fellows and practitioners in the field of general gynecology and gynecological oncology. The thesis question to be answered was "Can an interactive, visual guide for surgical staging procedures of gynecological cancers be created to aid in the teaching of this process?" I created one interactive program for endometrial cancer as a model in response to this question. The program contains text, animations, and surgical video. It was created to supplement textbooks already in use. Evaluation questions showed an increase in learning as well as a positive reaction to the program. The interactive guide could be useful for studying or reviewing surgical staging of endometrial cancer.Item The Role of LKBI Tumor Suppressor in Endometrial Cancer(2009-09-04) Contreras, Cristina Maria; Castrillon, Diego H.The LKB1 gene contributes to endometrial carcinogenesis in both the mouse and human. Although this role was not anticipated based on the tumor spectrum observed in Peutz Jegher women, many tumor suppressors have been found to have a much broader role in cancer than would have been predicted on the tumor spectrum associated with the hereditary syndrome. The studies that comprise this dissertation work first demonstrate that in addition to gastrointestinal polyposis, mice heterozygous for LKB1 develop endometrial cancers. To develop a better model of LKB1-driven endometrial carcinogenesis not prone to death from GI obstruction, two model systems were developed based on conditional ablation of the LKB1. In the first, intrauterine delivery of a CRE-expressing adenovirus was employed. A striking 65% of mice in this system, developed highly invasive endometrial tumors by 9 months. Although this system allowed the demonstration and exploration of the role of LKB1 as an endometrial tumor suppressor, the model suffered from technical limitations stemming from its recombination inefficiency. Then, in collaboration, a much more efficient transgenic model was developed using the promoter region of SPRR2F to drive CRE expression specifically in the endometrial epithelium. With this model, female mice with homozygous endometrial LKB1 inactivation developed diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, by 7 months, suggesting that LKB1 inactivation was sufficient to promote the development of invasive endometrial cancer. This much improved model also permitted the exploration of theory that LKB1-deficient tumors should be hypersensitive to rapamycin. Collectively these studies demonstrate that LKB1 is a uniquely potent endometrial tumor suppressor but also suggest that clinical responses to mTOR inhibitors may be linked to LKB1 inactivation.Item [UT Southwestern Medical Center News](2010-02-10) McKenzie, Aline