Browsing by Subject "Colorectal Neoplasms"
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Item Characterization and Selective Targeting of Aneuploid Human Colonic Epithelial Cells(2012-11-28) Ly, Peter 1986-; Lum, Lawrence; Pearson, Gray W.; Pandita, Tej K.Aneuploidy, an abnormal number of chromosomes, occurs in the vast majority of sporadic colorectal cancer patients. Despite this observation, the cellular advantages conferred by recurring cytogenetic alterations are poorly understood and targeted therapies selective to aneuploid cells are currently non-existent. Here, we provide evidence that serum-free passage of originally diploid, immortalized human colonic epithelial cells give rise to the acquisition of trisomy 7 (1CT+7), an aneuploidy detected in over 40% of colorectal adenomas. Pre-existing 1CT+7 cells within the original population were undetectable through GTG-banding and fluorescent in situ hybridization analysis, suggesting a conversion of diploid cells to an aneuploid state. Compared to their isogenic diploid counterpart, 1CT+7 cells express higher levels of the epidermal growth factor receptor (EGFR, located on chromosome 7p). Treatment with the pharmacological adenosine analog 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) completely halted proliferation of 1CT+7 cells and reduced both metabolic consumption and production in vitro. Unexpectedly, treatment of 1CT+7 cells with AICAR led to a reversible 3.5-fold reduction in EGFR overexpression. AICAR-induced depletion of EGFR protein can be abrogated through inhibition of the proteasome with MG132. AICAR also heavily promoted EGFR ubiquitination in cell-based immunoprecipitation assays, suggesting enhanced degradation of EGFR protein mediated by the proteasome. Moreover, treatment with AICAR reduced EGFR protein levels in a panel of human colorectal cancer cell lines in vitro and in xenograft tumors in vivo. Our data collectively supports the compound AICAR as a novel inhibitor of EGFR protein abundance and as a potential anticancer agent for aneuploidy-driven colorectal cancer. In summary, we have isolated and characterized isogenic human colonic epithelial cells that represent recurrent chromosomal acquisitions in sporadic colorectal cancer and demonstrate how it may be possible to selectively target these cells for therapeutic intervention.Item Colon Cancer Initiation and Progression(2012-07-20) Eskiocak, Ugur; Shay, Jerry W.Landmark cancer genome resequencing efforts are leading to the identification of mutated genes in many types of cancer.The extreme diversity of mutations being detected presents significant challenges to subdivide causal from coincidental mutations in order to elucidate how disrupted regulatory networks drive cancer processes. Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints we sought to functionally interrogate candidate colorectal cancer genes (CAN-genes) to identify driver tumor-suppressors. We have developed an isogenic human colonic epithelial cell (HCEC) model to identify suppressors of anchorage-independent growth by conducting a soft agar based shRNA screen within the cohort of CAN-genes. Remarkably, depletion of 65 of the 151 CAN-genes tested collaborated with ectopic expression of K-RASV12 and/or TP53 knockdown to promote anchorage-independent proliferation of HCECs. In contrast only 5 out of 362 random shRNAs (1.4%) enhanced soft agar growth. We have identified additional members of an extensive gene network specifying matrix-dependent proliferation, by constructing an interaction map of these confirmed progression suppressors with the ~700 mutated genes that were excluded from CAN-genes, and experimentally verifying soft-agar growth enhancement in response to depletion of a subset of these genes. Collectively, this study revealed a profound diversity of nodes within a fundamental tumor suppressor network that are susceptible to perturbation leading to enhanced cell-autonomous anchorage-independent proliferative fitness. Tumor suppressor network fragility as a paradigm within this and other regulatory systems perturbed in cancer, could in large part, account for the heterogeneity of somatic mutations detected in tumors.Item Colorectal cancer syndromes: clinical implications, diagnostic obligations and chemoprevention observations(2003-07-10) Becerra, CarlosItem Colorectal cancer: prevention and early detection in persons at average, moderate or increased risk(1999-01-14) Spady, David K.Item Colorectal carcinoma pathogenesis and therapy(1990-03-22) Smith, R. GrahamItem Colorectal polyps: the scope and management of the problem(2007-09-21) Gupta, Samir.Item Current insights in the etiology, treatment and outcomes of early-onset colorectal cancer(2023-02-17) Kazmi, SyedItem Guarding your gut: understanding colon cancer screening(2023-08-18) Lo, AmyItem Identification of Small Molecule Inhibitors Targeting Truncated Adenomatous Polyposis Coli (APC) as a Novel Therapeutic Strategy in Colorectal Cancer(2014-07-18) Zhang, Lu; DeBerardinis, Ralph J.; Roth, Michael G.; White, Michael A.; Shay, Jerry W.; Wright, Woodring E.Adenomatous polyposis coli (APC) is a tumor suppressor gene that is mutated in the vast majority of colorectal tumors. Inactivation of this gene is a key and early event in colorectal tumorigenesis. APC primarily acts as a negative regulator of Wnt pathway by aiding in degradation of β-catenin. Further studies have suggested that APC plays important roles in several other cellular processes, including cell adhesion and migration, organization of actin and microtubule networks, spindle formation and chromosome segregation. Mutations in APC gene generate truncated gene products, leading to deregulation of these processes. Accumulating evidence suggest that these C terminally truncated APC may have gain of function properties beyond their loss of tumor suppressive function. Both the gain and loss of function of APC truncations contribute to CRC initiation and progression. Utilizing a series of isogenic immortalized human colonic epithelial cells (HCECs), we have screened a 200K compound library for small molecules that exhibited selective cytotoxicity towards HCECs expressing truncated APC. We identified a compound, TASIN-1(Truncated APC Selective Inhibitor-1), which showed selective cytotoxicity towards HCECs and colorectal cancer (CRC) cells with APC truncations. TASIN-1 induces apoptotic cell death in APC truncated cells and its effect is independent of canonical Wnt pathway activity. Short hairpin RNA (shRNA) mediated knockdown of truncated APC confers resistance to TASIN-1. Additionally, TASIN-1 can interact with in vitro translated APC fragments, implicating truncated APC in the mechanism of action of TASIN-1. TASIN-1 inhibits tumor growth in both xenograft and genetic CRC mouse models. TASIN-1 may represent a novel therapeutic strategy for colon cancer prevention and intervention.Item [News](1985-05-23) Rutherford, SusanItem NSAIDs and colorectal cancer: an aspirin a day keeps the (adenomatous) polyp away?(1994-06-02) Luk, Gordon D.Item Safety and Effectiveness of Cecal Retroflexion in Evaluating Proximal Colon: A Case Series(2014-04-11) Geng, Zhuo Zoe; Gupta, Samir; Singal, Amit G.; Agrawal, DeepakBACKGROUND: Cecal retroflexion is a maneuver used by colonoscopists to evaluate the proximal sides of the colonic folds in the right-sided colon. Knowledge is limited regarding cecal retroflexion-associated risk and its effectiveness for increasing neoplasia detection rates in proximal colon. Recently, we encountered a contained perforation caused by cecal retroflexion. To our knowledge, there has been no report on cecal retroflexion-associated complications in the existing literature. OBJECTIVE: We aim to 1) report the case in detail, and characterize cecal retroflexion-related complication rates, and 2) assess whether there is improved neoplasia detection with cecal retroflexion. METHODS: We performed retrospective cohort study of all patients age 18 to 85 years who received colonoscopy by one endoscopist at UT Southwestern Medical Center from 9/1/2006 to 7/31/2012.We excluded patients who received colonoscopies prior to the initiation of cecal retroflexion, had missing colonoscopy reports, or were not found in the electronic medical record system. Our primary outcome is cecal-retroflexion-associated complication rates within 30 days after the procedure; the secondary outcome is cecal-retroflexion-associated neoplasia detection rates. RESULTS: A total of 1,247 patients were included in final analysis. Mean patient age was 57 years; 58.6% of patients were women. Among these patients, 624 (50.0%) received cecal retroflexion during colonoscopy. 1(Case) out of the 624 patients had a cecal retroflexion-related complication, with a complication rate of 1.6 per 1000 cecal retroflexion (95% Cl: 0 to 4.7 per 1000 cecal retroflexion). Of 459 patients underwent screening colonoscopy, 261 (56.9%) had cecal retroflexion. No cecal retroflexion-associated complications were observed with screening colonoscopy. We observed no statistically significant improvement in neoplasia detection rates among individuals who underwent colonoscopy with vs. without documented cecal retroflexion (P>0.05 for all comparisons). CONCLUSION: Cecal retroflexion may be associated with rare but significant complications. Further, the practice does not clearly increase neoplasia detection rates. We postulate that routine implementation of this practice is unlikely to increase neoplasia detection rates substantially, and further, given the small non-significant differences observed in our study, that randomized trials of the practice are unlikely to show clinically significant superiority. We recommend future research explore alternate strategies to improve proximal neoplasia detection.Item Screening and surveillance for colorectal cancer part of the couriculum(2006-09-15) Harford, William V.Item Screening for colorectal carcinoma(1990-04-26) Zeller, Kathleen R.Item [Southwestern News](1998-09-18) Stieglitz, HeatherItem An update in the genetics of colorectal cancer(2002-05-02) Morales, Carmela P.Item [UT Southwestern Medical Center News](2011-10-10) Carlton, JeffreyItem [UT Southwestern Medical Center News](2011-09-01) Bolles, DebbieItem [UT Southwestern Medical Center News](2008-07-07) McKenzie, Aline