Medicine and Health Sciences Commons^™

Does Sex Of The Patient Play A Role In Survival For Msi Colorectal Cancer?, Adrian Tulin, Iulian Slavu, Raluca Tulin, Lucian Alecu, Radu C. Jecan, Cristina Orlov, Cristian I. Iaciu, Dana L. Stanculeanu, Razvan Hainarosie, Silviu Pituru, Anca Pantea Stoian, Cornelia Nitipir

Journal of Mind and Medical Sciences

Microsatellite instability (MSI) is a feature of colorectal tumors that develops as a result of inactivation of the DNA mismatch repair system. It is found in about 15% of all colorectal cancers and is an important prognostic molecular marker when assessing patients with colorectal cancer. It can influence prognosis and treatment decisions in both the advanced and early stages. Although in early stages this marker suggests a favorable prognosis and presents an important argument against adjuvant treatment in stage II disease, in metastatic stages it no longer associated with such an optimistic outcome. The present trial is a prospective, single-center …

Impact Of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer, Jonathan M. Loree

Dissertations & Theses (Open Access)

Introduction: Mutations in KRAS/NRAS (RAS) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define RAS mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.

Methods: Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF RAS mutations (RAS MAF by the MAF of the mutated gene with …

The Heat-Stable Enterotoxin Receptor, Guanylyl Cyclase C, As A Pharmacological Target In Colorectal Cancer Immunotherapy: A Bench-To-Bedside Current Report., Trevor R. Baybutt, Allison A. Aka, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Cancer immunotherapy is becoming a routine treatment modality in the oncology clinic, in spite of the fact that it is a relatively nascent field. The challenge in developing effective immunotherapeutics is the identification of target molecules that promote anti-tumor efficacy across the patient population while sparing healthy tissue from damaging autoimmunity. The intestinally restricted receptor guanylyl cyclase C (GUCY2C) is a target that has been investigated for the treatment of colorectal cancer and numerous animal, and clinical studies have demonstrated both efficacy and safety. Here, we describe the current state of GUCY2C-directed cancer immunotherapy and the future directions of this …

Guanylate Cyclase C As A Target For Prevention, Detection, And Therapy In Colorectal Cancer., Allison A. Aka, Jeff A. Rappaport, Amanda M. Pattison, Takami Sato, Adam E. Snook, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

INTRODUCTION: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the …

Evaluation Of Risk Factors For The Recurrence Of Colorectal Polyps And Colorectal Cancer, Öztürk Ateş, Bülent Si̇vri̇, Saadetti̇n Kiliçkap

Turkish Journal of Medical Sciences

Background/aim: Colorectal adenomatous polyps are precursors of colorectal cancer (CRC), which can be prevented with surveillance colonoscopy. This study aimed to assess risk factors for the recurrence of colorectal polyps and CRC following polypectomy. Materials and methods: In this single-center trial, a total of 510 patients who applied to the endoscopy unit of Hacettepe University Hospital for various reasons and who were diagnosed with at least one colorectal adenomatous polyp between 2000 and 2010 were retrospectively analyzed. Patients with colorectal adenomatous polyps or CRC recurrences were examined in terms of clinical and histological risk factors. Results: A total of 190 …

Polymorphisms Of Cancer-Related Genes And Risk Of Multipleprimary Malignancies Involving Colorectal Cancer, Peiguo Cao, Li Yu, Anshan Wu, Jingjing Li, Ling Liu, Chunlan Liu, Jianda Zhou, Ke Cao, Chengxian Guo

Turkish Journal of Medical Sciences

Background/aim: This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of cancer-related genes and the risk of multiple primary malignancies involving colorectal cancer.Materials and methods: We collected tissue samples from 22 multiple primary cancer patients with primary colorectal cancer and performed genotyping assay for 116 SNP loci from 62 genes encoding peptides functioning in various signaling pathways using the DNA MassARRAY system. The chi-square test was used to compare the differences in base frequencies between patients and a control Chinese population from HapMap through the NCBI database.Results: No significant differences in frequencies were detected for 81 SNPs …

The Influence Of Mir-99a On Mtor Signaling Regulation In Colorectal Cancer Cell Lines., Jonathan Rice

Electronic Theses and Dissertations

Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of death. These are staggering statistics for a disease that can essentially be cured if caught early and the pathology is favorable to therapeutic intervention. There is currently a drastic decrease in five year survival as the cancer stage increases from locally confined disease to metastatic disease. These statistics suggest that although some strides have been made with colon cancer screening and early intervention, there is still much room for improvement in both screening and treatment of CRC. One of the pathways that have …

Novel Cellular Targets Of Aspirin In Chemoprevention Studies On P53, G6pd And C-Myc, Guoqiang Ai

Electronic Theses and Dissertations

Background

Aspirin has generated a significant interest in recent years as a potential chemopreventive agent supported by strong evidence from epidemiological data; however, the mechanisms are not well understood. The objective of this dissertation is to identify novel cyclooxygenase (COX)-independent pathways by which aspirin exerts its anticancer effects in epithelial cancer cell lines. We investigated the effect of aspirin on p53, glucose 6-phosphate dehydrogenase (G6PD), and c-Myc, all of which are known to play a major role in cancer development. p53 is a tumor suppressor protein, often mutated in cancers causing its inactivation. Expression of G6PD is elevated in many …

The Chemopreventive Effect Of Polymethoxyflavones: Targeting The Colorectal Cancer Stem Cells, Fei Xu

Doctoral Dissertations

Among all the cancers, the death rate of colorectal cancer is one of the highest. Evidence from both murine xenograft model and human trials have shown cancer stem cells (CSCs) are responsible for the initiation, metastasis and recurrence of multiple cancers therefore targeting colorectal CSCs would be a promising chemo-preventive/ therapeutic strategy. Polymethoxyflavones including nobiletin (NBT) and 5-demethylatednobiletin (5DN) are exclusively found in citrus peels and have been shown to have anti-cancer effects. Our previous studies in the biotransformation and tissue distribution of NBT and 5DN have shown that in order to fuller evaluate the biological impact of those two …

Methylation Of Egfr By Arginine Methyltransferase Prmt1 Enhances Egfr Signaling And Cetuximab Resistance, Hsin-Wei Liao

Dissertations & Theses (Open Access)

Protein modifications of epidermal growth factor receptor (EGFR) intracellular domain are well known regulators of EGFR functions whereas those of its extracellular domain remain relatively unexplored. Here, we report that methylation at R198 and R200 of EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) upregulates its binding to EGF and subsequent receptor dimerization and signaling activation. Methylation-defective EGFR mutant reduced tumor growth in mouse orthotopic xenograft model. Importantly, increased EGFR methylation sustains its signaling activation and cell proliferation in the presence of therapeutic EGFR monoclonal antibody, cetuximab. EGFR methylation level also correlates with higher recurrence rate after cetuximab treatment …

Co-Targeting Of Cyclooxygenase-2 And Foxm1 Is A Viable Strategy In Inducing Anticancer Effects In Colorectal Cancer Cells, Maqbool Ahmed, Azhar Hussain, Abdul K. Siraj, Shahab Uddin, Nasser Al-Sanea, Fouad Al-Dayel, Mohammed Al-Assiri, Shaham Beg, Khawla S. Al-Kuraya

Centre for Regenerative Medicine & Stem Cell Research

Background: Cross-talk between deregulated signaling pathways in cancer cells causes uncontrolled growth and proliferation. These cancers cells become more aggressive and quickly develop resistance to therapy. Therefore targeting of these deregulated pathways simultaneously can result in efficient cell death of cancer cells. In this study we investigated co-expression of Cox-2 and FoxM1 in a cohort of colorectal carcinoma (CRC) samples and also examined whether inhibition of Cox-2 and FoxM1 simultaneously can lead to inhibition of cell viability and induction of apoptosis in colorectal cancer cell lines and in vivo xenograf
Methods: Protein expression of Cox-2 and FoxM1 was determined …

Mcp-1 In Colorectal Cancer: Benefits Of Exercise, Jamie Lee Mcclellan

Theses and Dissertations

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. Tumors associated macrophages drive the pro-inflammatory response in the tumor micro-environment and are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. In chapter 1, we examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in …

The Frequency Of Human Papillomaviruses In Colorectal Cancer Samples In Mashhad, Northeastern Iran, Mojtaba Meshkat, Naser Tayyebi Meibodi, Samaneh Sepahi, Narges Fadaee, Masoumeh Salehpour, Zahra Meshkat

Turkish Journal of Medical Sciences

Infection with the human papillomaviruses (HPVs) is associated with the development of several cancers, including oral, esophageal, skin, lung, and cervical. However, the association of HPVs and colorectal cancers remains controversial. The aim of this study was to evaluate the association between HPV infection and paraffin-embedded colorectal tissue samples in Mashhad in the northeast of Iran. Materials and methods: Paraffin-embedded tissue specimens from 111 patients with colorectal cancer were subjected to DNA extraction. The quality of extracted DNA was confirmed by amplification of a b-globin fragment using polymerase chain reaction (PCR) and GH20/PCO4 primers. PCR with GP5+/GP6+ primers was then …

Plasma Soluble Thrombomodulin And Soluble Endothelial Protein C Receptor Levels In Colorectal Cancer Patients, Serap Ünal Ti̇lki̇, Hüseyi̇n Engi̇n, Ayla Gökmen, Cemi̇l Bi̇li̇r, Yücel Üstündağ

Turkish Journal of Medical Sciences

Thrombomodulin (TM) and endothelial protein C receptor (EPCR) are 2 transmembrane proteins that are thought to play an important role in cancer. We aimed to discover whether these 2 proteins are prognostic indicators in colorectal cancer. Materials and methods: Plasma TM and EPCR levels were measured using the ELISA method in 50 patients in different tumor stages that had been recently diagnosed with colorectal cancer and in a healthy control group of 50 people. Results: In colorectal cancer patients, higher plasma TM (21.3 ± 22.8 ng/mL, 13.2 ± 16.2 ng/mL, P = 0.010) and plasma EPCR levels (149.9 ± 79.6, …

The Expression Of Cell Adhesion Molecules In Colorectal Cancer Tissue And Its Clinical Values, Dong Chen, Huiying Zhao, Feng Ye

Turkish Journal of Medical Sciences

To investigate the role of cell adhesion molecules CD44v6 and CEA in the occurrence, development, and metastasis of colorectal cancer (CRC). Materials and methods: The expression of CD44v6 and CEA in 76 CRC tissues and 43 normal colon tissues was detected using an immunohistological technique. The relationship between the 2 molecules’ expression and their pathologic characteristics, especially for metastasis, was investigated. Furthermore, the relevance between the expression of CD44v6 and of CEA was also assessed. Results: Expression of CD44v6 and CEA protein in CRC tissues was higher than in paracarcinoma tissue and normal colorectal mucosa (both P < 0.001). Positive expression of CD44v6 in CRC was associated with lymph node metastasis, Dukes’ stage, and histological differentiation. Higher expression intensity of CEA in CRC was related to lymph node involvement, distant metastasis, and invasion depth. Combining analysis of CD44v6 and CEA can improve the sensitivity and specificity in evaluating the metastatic potential of CRC (P < 0.05). There was no relevance between the expression of CD44v6 and CEA in CRC (P > 0.05). Conclusion: CD44v6 …

Clinical Consequences Of Micrornas In Colorectal Cancer, Liselle C. Bovell

All ETDs from UAB

Colorectal cancer (CRC) is a heterogeneous disease, and factors such as tumor location, the environment, genetics, and ethnic differences, can influence its development and progression. Over the last few decades, overall CRC mortality rates have declined; however, racial disparities in mortality rates have increased. The discovery of biomarkers that focus on identifying individual differences based on confounders such as tumor stage and patient race/ethnicity is needed, for such biomarkers can lead to development of personalized therapeutic approaches to target these molecules. MicroRNAs (miRNAs) are a class of small molecules that regulate genes at the post-transcriptional level. Altered miRNA expression levels …

Cyclic Gmp Phosphodiesterase As A Novel Target For Colorectal Cancer Chemoprevention, Nan Li

All ETDs from UAB

Nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. However, many investigators have concluded that COX-independent mechanisms are responsible for their antineoplastic activity. We previously reported that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) is a non-COX target of sulindac sulfide (SS). However, the specific isozyme families involved have not been well studied. Here we demonstrate that SS inhibits the growth of colon tumor cells through a novel mechanism involving inhibition of two cGMP degrading isozymes, PDE5 and PDE10, to activate cGMP-dependent protein kinase (PKG). …

Molecular Staging Of Node Negative Patients With Colorectal Cancer., Terry Hyslop, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Metastatic disease is the principle cause of death from colorectal cancer. In that context, the most significant indicator of overall survival and therapeutic response to adjuvant chemotherapy is the presence of metastatic tumor cells in regional lymph nodes. Although histopathologic analysis of lymph nodes is central to all colorectal cancer staging paradigms, its prognostic and predictive value is limited. Indeed, about 30% of patients with histopathology-negative lymph nodes (pN0) die from metastatic disease, reflected by microscopic lymph node metastases that are overlooked by standard techniques. These unrecognized tumor cells are especially important when considering racial disparities in outcomes in colorectal …

A Pooled Analysis Of Smoking And Colorectal Cancer: Timing Of Exposure And Interactions With Environmental Factors

Shuo Jiao

Background:Considerable evidence suggests that cigarette smoking is associated with a higher risk of colorectal cancer. What is unclear, however, is the impact of quitting smoking on risk attenuation and whether other risk factors for colorectal cancer modify this association. Methods:We performed a pooled analysis of 8 studies, including 6,796 colorectal cancer cases and 7,770 controls to evaluate the association between cigarette smoking history and colorectal cancer risk, and to investigate potential effect modification by other risk factors. Results:Current smokers (OR=1.26, 95% CI=1.11-1.43) and former smokers (OR=1.18, 95% CI=1.09-1.27), relative to never smokers, showed higher risks of colorectal cancer. Former smokers …

Phosphorylation Of Vasodilator-Stimulated Phosphoprotein Ser239 Suppresses Filopodia And Invadopodia In Colon Cancer., David S Zuzga, Joshua Pelta-Heller, Peng Li, Alessandro Bombonati, Scott A Waldman, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) …

Molecular Staging Individualizing Cancer Management, Alex Mejia, Stephanie Schulz, Terry Hyslop, David S. Weinberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, ∼30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy. J. Surg. Oncol. 2012; 105:468-474. © 2012 Wiley Periodicals, Inc.

Copyright © 2012 Wiley Periodicals, Inc.

Biochemical And Cellular Mechanisms For The Antineoplastic Properties Of Sulindac, Jason Derek Whitt

All ETDs from UAB

ABSTRACT The nonsteroidal anti-inflammatory drug (NSAID) sulindac has displayed the ability to inhibit the proliferation of colorectal cancer (CRC) cells and to increase the sensitivity of multidrug resistant (MDR) cancer cells to a wide variety of chemotherapeutic agents. The antineoplastic activity of sulindac has been attributed to inhibition of the prostaglandin producing enzyme COX-2, but the exact mechanism remains elusive and the inhibition of prostaglandin synthesis can result in gastrointestinal, hepatic, and cardiovascular toxicities. Enzymatic, cellular, and imaging assays were used to identify mechanisms that could contribute to the antiproliferative and apoptotic activity of sulindac. Screening of more than 500 …

A Conserved Tissue-Specific Homeodomain-Less Isoform Of Meis1 Is Downregulated In Colorectal Cancer., Richard C Crist, Jacquelyn J Roth, Scott A Waldman, Arthur M Buchberg

Department of Microbiology and Immunology Faculty Papers

Colorectal cancer is one of the most common cancers in developed nations and is the result of both environmental and genetic factors. Many of the genetic lesions observed in colorectal cancer alter expression of homeobox genes, which encode homeodomain transcription factors. The MEIS1 homeobox gene is known to be involved in several hematological malignancies and solid tumors and recent evidence suggests that expression of the MEIS1 transcript is altered in colorectal cancer. Despite this potential connection, little is known about the role of the gene in the intestines. We probed murine gastrointestinal tissue samples with an N-terminal Meis1 antibody, revealing …

Chronic Diseases: The Emerging Pandemic., Andre Terzic, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

According to the 2011 World Health Organization Global Status Report, of the 57 million annual global deaths – a staggering 36 million or over 63% are due to chronic diseases.¹ Four noncommunicable diseases - namely cardiovascular, cancer, diabetes, and chronic respiratory diseases - emerge as the leading cause of mortality in the world, accounting respectively for 17, 7.6, 4.2, and 1.3 million deaths based on the latest available global epidemiology data. By 2020, global deaths due to chronic diseases are projected to worsen by at least 15 to 20%. It is estimated that the four major noncommunicable diseases will …

Molecular Staging Estimates Occult Tumor Burden In Colorectal Cancer, Alex Mejia, Stephanie Schulz, Terry Hyslop, David S. Weinberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumor cells in regional lymph nodes are a key prognostic marker of survival and predictive marker of response to adjuvant chemotherapy in colorectal cancer. However, clinicopathologic techniques to detect lymph node metastases remain imperfect, and ~30% of patients with lymph nodes negative by histology (pN0) develop recurrent disease, reflecting occult metastases that escape detection. These observations underscore an unmet clinical need for accurate approaches to identify occult nodal metastases in colorectal cancer patients. GUCY2C is a receptor whose expression normally is restricted to intestinal epithelial cells, but is universally over-expressed by colorectal cancer cells. A prospective, multicenter, blinded clinical trial …

Enterotoxin Preconditioning Restores Calcium-Sensing Receptor-Mediated Cytostasis In Colon Cancer Cells, Giovanni Mario Pitari, Jieru E. Lin, Fawad J. Shah, Wilhelm J. Lubbe, David Zuzga, Peng Li, Stephanie Schulz, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs), inhibits colorectal cancer cell proliferation by co-opting Ca(2+) as the intracellular messenger. Similarly, extracellular Ca(2+) (Ca(2+)(o)) opposes proliferation and induces terminal differentiation in intestinal epithelial cells. In that context, human colon cancer cells develop a phenotype characterized by insensitivity to cytostasis imposed by Ca(2+)(o). Here, preconditioning with ST, mediated by GCC signaling through cyclic nucleotide-gated channels, restored Ca(2+)(o)-dependent cytostasis, reflecting posttranscriptional regulation of calcium-sensing receptors (CaRs). ST-induced GCC signaling deployed CaRs to the surface of human colon cancer cells, whereas elimination of GCC signaling in mice nearly abolished …

Does Early Enteral Feeding Affect Clinical Outcome Or Cytokine Profiles After Elective Surgery For Colorectal Cancer?, Elizabeth Anne Baker, Lynne Williams, Sanaa El-Gaddal, Fintan Bergin, David John Leaper

Turkish Journal of Medical Sciences

Patients who have intestinal cancer are prone to malnutrition, which can result in deterioration of physiological function, poor wound healing, increased risk of infection and prolonged hospital stay. These complications are particularly relevant after colorectal surgery. Early enteral feeding, to enhance nutritional status, has been reported to reduce post-operative complications, length of hospital stay and morbidity and mortality after upper gastro-intestinal cancer surgery. Inflammatory cytokines (IL-6, TNF-a (\alpha)), clinical outcomes and postoperative complications were measured in 147 patients undergoing elective surgery for colorectal cancer (84 standard care; 64 patients had early enteral feeding in addition). There were no significant differences …

Immune Response To The Carcinoembryonic Antigen In Patients Treated With An Anti-Idiotype Antibody Vaccine, Kenneth A. Foon, Mala Chakraborty, William J. John, Amanda Sherratt, Heinz Köhler, Malaya Bhattacharya-Chatterjee

Markey Cancer Center Faculty Publications

We have generated an IgG1 murine monoclonal anti-idiotype antibody (Ab2) designated 3H1, which mimics a specific epitope on the carcinoembryonic antigen (CEA). Patients with CEA positive tumors are immunologically "tolerant" to CEA. We used 3H1 as a surrogate for CEA for vaccine therapy of 12 patients with advanced colorectal cancer. Each of the patients received a minimum of four intracutaneous injections of aluminum hydroxide precipitated 3H1 at either 1, 2, or 4 mg dosage per injection. 9 of 12 patients demonstrated anti-anti-idiotypic (Ab3) response to 3H1. All nine patients generated specific anti-CEA antibody demonstrated by reactivity with radiolabeled purified CEA; …