Medicine and Health Sciences Commons^™

Genetic And Serological Markers In Colorectal Cancer Surgery, Adrian Silaghi, Vlad Denis Constantin, Dragos Serban, Dragos Epistatu, Ioana Paunica, Daniela Gabriela Bălan, Laura Florentina Rebegea

Journal of Mind and Medical Sciences

Colon cancer is relatively asymptomatic in the early stages, the manifestations appearing and intensifying with the evolution of the disease, especially when associated with local and/or systemic complications. In such cases, surgical interventions are often emergency and involve more extensive operations (on metabolically and immune-stressed organisms), so that an early diagnosis (endoscopy, tumor markers, etc.) remains not only desirable but even a priority, especially in predisposed patients (genetic factors, lifestyle, etc.). As a consequence, the involvement of tumor markers in colon neoplasms has become more and more investigated in recent times. This review investigates the roles of serological and genetic …

Targeting Tgf-Β During Epithelial-To-Mesenchymal Progression As An Effective Therapy Against Colorectal Cancer, Joyce Fan

Undergraduate Research

Colorectal cancer is one of the most common cancers worldwide. Understanding the mechanisms of colorectal cancer progression is crucial for the development of effective therapeutics. Epithelial-to-mesenchymal transition is a hallmark feature of cancer and is defined as the loss of epithelial cell features, such as apical-basal polarity and high expression of cell adhesion molecules, and the development of mesenchymal features, such as lack of polarity and increased cell mobility. Epithelial-to-mesenchymal is essential for cell migration, proliferation, and tumor growth. Both the TGF-β and SMAD pathway are associated with colorectal cancer progression. TGF-β is crucial to the cellular mechanism of cell …

The Role Of Curcumin On Apoptosis And Nlrp3 Inflammasome-Dependent Pyroptosis On Colorectal Cancer In Vitro, Zeynep Dal, Başak Aru

Turkish Journal of Medical Sciences

Background/aim: Colorectal cancer (CRC) is one of the most common cancers worldwide. Many factors such as stress, lifestyle, and dietary habits are known to play a role in the initiation and progression of the disease. Herbal therapeutic agents including curcumin can hold a great potential against cancer treatment; however, their efficacy on CRC is still under investigation. Herein, we evaluated the anticancer mechanism of curcumin on four different CRC cell lines. Materials and methods: Cells were treated with curcumin for 24, 48 and 72 h, and IC50 doses for each cell line were calculated. Mechanistic studies were conducted with the …

Variant Characterization Of A Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition Of Risk To Lynch Syndrome, Mouadh Barbirou, Amanda A. Miller, Amel Mezlini, Balkiss Bouhaouala-Zahar, Peter J. Tonellato

Department of Medical Oncology Faculty Papers

Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, …

Dynamic Role Of Exosome Micrornas In Cancer Cell Signaling And Their Emerging Role As Noninvasive Biomarkers, Jaya Aseervatham

Department of Neurology Faculty Papers

Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40–150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial–mesenchymal transition, angiogenesis, apoptosis, …

Specific Targeting And Labeling Of Colonic Polyps In Cpc-Apc Mice With Mucin 5ac Fluorescent Antibodies: A Model For Detection Of Early Colon Cancer, Michael A. Turner, Kristin E. Cox, Shanglei Liu, Nicholas Neel, Siamak Amirfakhri, Hiroto Nishino, Mojgan Hosseini, Joshua A. Alcantara, Amer Ali Abd El-Hafeez, Thinzar M. Lwin, Kavita Mallya, Joseph R. Pisegna, Satish K. Singh, Pradipta Ghosh, Robert M. Hoffman, Surinder K. Batra, Michael Bouvet

Journal Articles: Biochemistry & Molecular Biology

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 …

The Mucin Family Of Proteins: Candidates As Potential Biomarkers For Colon Cancer, Kristin E. Cox, Shanglei Liu, Thinzar M. Lwin, Robert M. Hoffman, Surinder K. Batra, Michael Bouvet

Journal Articles: Biochemistry & Molecular Biology

Mucins (MUC1-MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal …

Applying Mci-062, A Novel Pan-Ras Inhibitor, To Treat Kras-Mutant Lung Cancer., Richard Fu

Poster Presentations

Honors thesis poster presentation.

RAS, one of the most prevalent oncogenes, is mutated in 27% of human cancers. Gainof- function RAS mutations activate multiple downstream pathways, including the RASRAF- MEK-ERK and PI3K/AKT/mTOR pathways, which are critical in tumorigenesis and cancer cell proliferation. The RAS proteins KRAS, HRAS, and NRAS along with their downstream effectors are attractive targets for cancer therapy since they act as frequent drivers in lung, colorectal, and pancreatic cancers. However, RAS proteins have relatively smooth surfaces that lack traditional binding pockets, making inhibitors specific to RAS difficult to create. Recently, a novel small molecule pan-RAS inhibitor named …

Applying Mci-062, A Novel Pan-Ras Inhibitor, To Treat Kras-Mutant Lung Cancer, Richard Fu

Honors Theses

RAS is a prevalent oncogene that is mutated in 27% of human cancers. Gain-of-function RAS mutations activate multiple downstream pathways, including the RAS-RAF-MEK-ERK and PI3K/AKT/mTOR pathways, which are critical in tumorigenesis and cancer cell proliferation. RAS proteins such as KRAS, a member of the RAS protein family, and their downstream effectors are attractive targets for cancer therapy since their mutations act as frequent drivers in lung, colorectal, and pancreatic cancers. However, RAS proteins have relatively smooth surfaces that lack traditional binding pockets, making inhibitors specific to RAS difficult to create. Recently, a novel small molecule pan-RAS inhibitor named MCI-062 was …

Targeting Gastrointestinal Cancers With Chimeric Antigen Receptor (Car)-T Cell Therapy, Ross E Staudt, Robert D Carlson, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to …

Depletion Of Transmembrane Mucin 4 (Muc4) Alters Intestinal Homeostasis In A Genetically Engineered Mouse Model Of Colorectal Cancer, Ramesh Pothuraju, Priya Pai, Sanjib Chaudhary, Jawed A. Siddiqui, Jesse L. Cox, Sukhwinder Kaur, Satyanarayana Rachagani, Hemant K. Roy, Michael Bouvet, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4^-/-) CRC mouse model by crossing with Muc4^-/- and Apc^flox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads …

The Role Of Pericytes On The Efficacy Of Bevacizumab In Colorectal Cancer, Merve Besler, Fatma Sena Dost, Fi̇li̇z Çay Şenler, Bi̇lge Ayça Kirmizi, Berna Savaş, Hakan Akbulut

Turkish Journal of Medical Sciences

Background/aim: Pericytes are mesenchymal cells surrounding capillary vessels and are known to play an essential role in tumor angiogenesis. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan and its release from pericytes and vascular smooth muscle cells is very important in tumor angiogenesis. Bevacizumab, which is a monoclonal antibody frequently used in the treatment of metastatic colorectal cancer, binds to the ligand of vascular endothelial growth factor A (VEGFA) and inhibits tumor angiogenesis. However, no reliable biomarker for predicting patients that will show a good response to this therapy has been established yet. In this study, we aimed …

The Effect Of Immunonutrition On Tumor Infiltrative T Lymphocytes And Regulatory T Cells In Rectal Tumor Patients Receiving Neoadjuvant Chemoradiotherapy: A Prospective Randomized Clinical Study, Mehmet Onur Gül, Cebrai̇l Akyüz, Selvi̇naz Özkara

Turkish Journal of Medical Sciences

Background/aim: The rationale behind using immunonutrition in cancer patients is to prevent malnutrition, manage the host's immune response, and keep cancer under control by utilizing the potential immune system available in the host against the tumor. This prospective- study aims to assess the impact of immunonutrition on tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs) in rectal cancer patients receiving neoadjuvant chemoradiotherapy. Materials and methods: This is a single-center, prospective study. Forty patients diagnosed with middle and lower rectal tumors were enrolled in the study between March 2018 and December 2019. Nutrition protocols were given to all study subjects prior …

Attenuated Bacteria Potentiate The Outcome Of Immunotherapy With Pd-L1 Blockade In A Pre-Clinical Model Of Colorectal Cancer, Besan Haytham Mohammad Al-Saafeen

Theses

After more than a century of investigation, it has become evident that cancer development and progression occur at the expense of a dysfunctional immune system. This realization has ushered cancer immunotherapy as a new modality of treatment. In the last decade, the use of immune checkpoint inhibitors to treat cancer patients resulted in unprecedented and durable clinical benefits. However, the response rate in many cancers remains rather modest, with colorectal cancer being at the lower end of the spectrum. Previous work from our laboratory demonstrated the efficacy of using attenuated bacteria as immunomodulatory anti-cancer agents. The current study investigated the …

Intestinal Dysbiosis – A New Treatment Target In The Prevention Of Colorectal Cancer, Florinela-Andrada Dumitru, Sergiu Ioan Micu, Roxana Emanuela Popoiag, Marilena Musat, Andreea Daniela Caloian, Valentin Calu, Vlad Denis Constantin, Daniela Gabriela Balan, Cornelia Nitipir, Florin Enache

Journal of Mind and Medical Sciences

The gastrointestinal microbiome contains at least 100 trillion microorganisms (bacteria, viruses, fungi), whose distribution varies from the mouth to the rectum spatially and temporally throughout one's lifetime. The microbiome benefits from advancing research due to its major role in human health. Studies indicate that its functions are immunity, metabolic processes and mucosal barrier. The disturbances of these functions, dysbiosis, influence physiology, lead to diabetes, inflammatory bowel disease, obesity and colon tumorigenesis. The third most common form of cancer, colorectal cancer, is the result of many factors and genes, and although the link between dysbiosis and this type of cancer is …

How Opportune Is Multigene Testing In Metastatic Colorectal Cancer? A Review, Cristina Orlov-Slavu, Andreea Parosanu, Mihaela Olaru, Dragos Serban, Ioana Paunica, Cornelia Nitipir

Journal of Mind and Medical Sciences

Personalized treatment in oncology is the most innovative method of care. The best method to establish personalized treatment is by genetic characterization of the malignant cell.

Theoretically, the more detailed the characterization, the more effective the choice of treatment becomes. Currently, there are fast and relatively low-cost options that allow such genetic characterization. However, test results sometimes do not detect targetable alterations and, even if they do detect, the use of the treatment-alteration combination does not always generate a satisfactory oncological response.

The present paper aims to answer two questions. First, how targetable can the most common gene alterations in …

Cyclin G2, A Novel Target Of Sulindac To Inhibit Cell Cycle Progression In Colorectal Cancer, Hongyou Zhao, Bin Yi, Zhipin Liang, Ches'nique N. Phillips, Hui Yi Lin, Adam I. Riker, Yaguang Xi

School of Medicine Faculty Publications

Sulindac has shown significant clinical benefit in preventing colorectal cancer progression, but its mechanism of action has not been fully elucidated. We have found that sulindac sulfide (SS) is able to inhibit cell cycle progression in human colorectal cancer cells, particularly through G1 arrest. To understand the underlying mechanisms of sulindac inhibitory activity, we have demonstrated that Cyclin G2 up-regulation upon SS treatment can substantially delay cell cycle progression by enhancing the transcriptional activity of FOXO3a in human colorectal tumor cells. MiR-182, an oncogenic microRNA known to inhibit FOXO3a gene expression, is also involved in the suppressive effect of SS …

Muc1 And Muc5ac Implication In Tunisian Colorectal Cancer Patients, Meriam Hazgui, Marwa Weslati, Rahma Boughriba, Donia Ounissi, Dhouha Bacha, Saadia Bouraoui

Turkish Journal of Medical Sciences

Background/aim: Mucins, such as MUC1 and MUC5AC, are known for their protective and moisturizing role in intestinal epithelium. Their expression is tightly controlled given their essential role in normal tissue homeostasis, whereas their deregulation leads to chronic inflammation, and even cancer. This study aimed to assess the expression profiles of MUC1 and MUC5AC and their implications in colorectal carcinogenesis. Materials and methods: A retrospective study of 202 patients who underwent colorectal cancer (CRC) surgery was conducted. The expression of MUC1 and MUC5AC was investigated by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR). Statistical analysis of mucin expression pattern, as well …

Potential Use Of Biotherapeutic Bacteria To Target Colorectal Cancer-Associated Taxa, Gareth Lawrence, Maire Begley, Paul D. Cotter, Caitríona M. Guinane

Department of Biological Sciences Publications

The role of the gut microbiome in human health and disease is the focus of much attention. It has been widely agreed upon that our gut bacteria play a role in host immunity, nutrient absorption, digestion, metabolism, and other key drivers of health. Furthermore, certain microbial signatures and specific taxa have also been associated with the development of diseases, such as obesity; inflammatory bowel disease; and, indeed, colorectal cancer (CRC), which is the focus of this review. By extension, such taxa represent potential therapeutic targets. In particular, the emerging human pathogen Fusobacterium nucleatum represents an important agent in CRC development …

Molecular Implications Of Muc5ac-Cd44 Axis In Colorectal Cancer Progression And Chemoresistance, Ramesh Pothuraju, Satyanarayana Rachagani, Shiv Ram Krishn, Sanjib Chaudhary, Rama Krishna Nimmakayala, Jawed A. Siddiqui, Koelina Ganguly, Imayavaramban Lakshmanan, Jesse L. Cox, Kavita Mallya, Sukhwinder Kaur, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure.

METHODS: MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in …

Spectrum Of Germline Cancer Susceptibility Gene Mutations In Turkish Colorectal Cancer Patients: A Single Center Study, Haktan Bağiş Erdem, Taha Bahsi̇

Turkish Journal of Medical Sciences

Background/aim: Quarter of colorectal cancer patients have a family history and 6% of these comprise hereditary cancer syndromes. For developing national health strategies for genetic screening, it is crucial to determine the spectrum of damaging alterations in causative genes and to describe frequent founder mutations. Materials and methods: One hundred and thirty six unrelated colorectal cancer cases were investigated. Qiagen large hereditary cancer panel and Hereditary Cancer Solution v1.1 panel were used for sequencing. The sequencing process was performed on the Illumina MiSeq system. The data analyses were performed on QIAGEN Clinical Insight (QCITM) Analyze software and Sophia DDM software. …

Efficacy Of The Population-Based Pilot Colorectal Cancer Screening, Csongrád County,Hungary, 2015, Mariann Rutka, Renáta Bor, Tamás Molnár, Klaudia Farkas, Anna Fábián, Márk Györffy, Anita Bálint, Ágnes Milassin, Mónika Szücs, László Tiszlavicz, Ferenc Nagy, Zoltán Szepes

Turkish Journal of Medical Sciences

Background/aim: In Hungary, a nationwide colorectal screening program is about to be introduced in order to improve the high mortality rate of colorectal cancer (CRC). The aim was to summarize experiences from and assess short-term efficacy of the populationbased pilot colorectal screening program in 2015 in Csongrád county, Hungary. Materials and methods: Asymptomatic individuals between the ages of 50 and 70 with average risk of colorectal cancer participated in the program that was based on the two-step screening method: immune fecal blood test and colonoscopy. The short-term efficacy was assessed as the change in total CRC incidence and initial tumor …

N-Glycosylation-Defective Splice Variants Of Neuropilin-1 Promote Metastasis By Activating Endosomal Signals, Xiuping Huang, Qing Ye, Min Chen, Aimin Li, Wenting Mi, Yuxin Fang, Yekaterina Y. Zaytseva, Kathleen L. O'Connor, Craig W. Vander Kooi, Side Liu, Qing-Bai She

Markey Cancer Center Faculty Publications

Neuropilin-1 (NRP1) is an essential transmembrane receptor with a variety of cellular functions. Here, we identify two human NRP1 splice variants resulting from the skipping of exon 4 and 5, respectively, in colorectal cancer (CRC). Both NRP1 variants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes. This increased endocytic trafficking of the two NRP1 variants, upon HGF stimulation, is due to loss of N-glycosylation at the Asn150 or Asn261 site, respectively. Moreover, these NRP1 variants enhance interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provides persistent …

Macrophages And Associated Inflammation Differentially Impact Obesity, Colorectal Cancer And Obesity-Enhanced Colorectal Cancer, Jackie Bader

Theses and Dissertations

Colorectal Cancer (CRC) is the third-most common malignancy for men or women, with chronic inflammation considered as a primary risk factor. Obesity is also considered a chronic inflammatory disease and is associated with increased CRC incidence. Further, obesity and CRC occur in men and women differently with the highest incidence of either disease found in men, suggesting that female sex hormones may play a protective role in inflammatory diseases. Macrophages can promote inflammation and are a driving force in obesity-associated metabolic dysfunction. Conversely, macrophages also contribute to pro-tumoral responses including, proliferation, angiogenesis and tissue remodeling. This heterogeneity of macrophage behavior …

Silencing The Guca2a-Gucy2c Tumor Suppressor Axis In Cin, Serrated, And Msi Colorectal Neoplasia., Babar Bashir, Dante J. Merlino, Jeff A. Rappaport, Esteban Gnass, Juan P. Palazzo, Ying Feng, Eric R R. Fearon, Adam E. Snook, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Colorectal cancers (CRCs) initiate through distinct mutations, including in APC pathway components leading to tubular adenomas (TAs); in BRAF, with epigenetic silencing of CDX2, leading to serrated adenomas (SAs); and in the DNA mismatch repair machinery driving microsatellite instability (MSI). Transformation through the APC pathway involves loss of the hormone GUCA2A that silences the tumor-suppressing receptor GUCY2C. Indeed, oral hormone replacement is an emerging strategy to reactivate GUCY2C and prevent CRC initiation and progression. Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC. Here, we defined …

Split Tolerance Permits Safe Ad5-Gucy2c-Padre Vaccine-Induced T-Cell Responses In Colon Cancer Patients., Adam E. Snook, Trevor R. Baybutt, Bo Xiang, Tara S. Abraham, John C. Flickinger, Terry Hyslop, Tingting Zhan, Walter K. Kraft, Takami Sato, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy.

Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity …

The Anti-Cancer Effect Of Retinoic Acid Signaling In Crc Occurs Via Decreased Growth Of Aldh+ Colon Cancer Stem Cells And Increased Differentiation Of Stem Cells, Shirin R. Modarai, Anindita Gupta, Lynn M. Opdenaker, Ryan Kowash, Gabriel Masters, Vignesh Viswanathan, Tao Zhang, Jeremy Z. Fields, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and …

The Guanylate Cyclase C-Cgmp Signaling Axis Opposes Intestinal Epithelial Injury And Neoplasia., Jeffrey A. Rappaport, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses …

Alcohol Consumption Promotes Colorectal Carcinoma Metastasis Via A Ccl5-Induced And Ampk-Pathway-Mediated Activation Of Autophagy, Haodong Zhao, Danlei Chen, Rui Cao, Shiqing Wang, Dandan Yu, Yakun Liu, Yu Jiang, Mei Xu, Jia Luo, Siying Wang

Pharmacology and Nutritional Sciences Faculty Publications

There is a definite relationship between alcohol consumption and colorectal cancer (CRC) development. We investigated effect of alcohol consumption on CRC patients’ progression and prognosis by utilizing epidemiological data and found patients with alcohol consumption increased risks of tumor-node-metastasis (TNM), organ metastasis and poorer prognosis. Because their tumor tissues displayed increased expression of C-C chemokine ligand 5 (CCL5), we hypothesized CCL5 might participate in cancer progression in such patients. Ethanol increased the secretion of CCL5 in two CRC cell lines, HT29 and DLD-1. Treatment with CCL5 directly increased migratory ability of these cells, whereas neutralization or knockdown of CCL5 can …

Preclinical Evaluation Of Novel Fatty Acid Synthase Inhibitors In Primary Colorectal Cancer Cells And A Patient-Derived Xenograft Model Of Colorectal Cancer, Yekaterina Y. Zaytseva, Piotr G. Rychahou, Anh-Thu Le, Timothy L. Scott, Robert M. Flight, Ji Tae Kim, Jennifer Harris, Jinpeng Liu, Chi Wang, Andrew J. Morris, Theru A. Sivakumaran, Teresa Fan, Hunter Moseley, Tianyan Gao, Eun Young Lee, Heidi L. Weiss, Timothy S. Heuer, George Kemble, B. Mark Evers

Toxicology and Cancer Biology Faculty Publications

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial.

However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition.

CRC cells and PDXs …