Therapeutic Targets For Inflammation And Cancer: Novel Therapies For Digestive Diseases

Novel Therapies for Digestive Diseases

Chi Hin Cho

• Publisher: WSPC
• Year: 2017
• ISBN:
  9789813148581
• Topic: Médecine
• Subtopic: Oncologie

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This unique book deals with both inflammation and cancer in a single source of publication. They are seldom grouped together although it has been known that both diseases are closely associated, particularly in the gastrointestinal tract and liver. As the book touches on two such major areas of diseases in humans, it should be of interest to a wider audience of researchers and readers. It is noted that the book combines the effort of both basic scientists and clinicians from different countries with extensive experiences in molecular biology and clinical practice to unveil the most updated picture of the pathogenesis and therapeutic strategies in the treatment of inflammation and cancer in the digestive tract. In this regard, potential pathogenic modulators and also therapeutic options are widely discussed. These types of information would definitely broaden our knowledge in better understanding these diseases.

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Section III

Carcinogenesis and Therapeutic Targets in the Gastrointestinal Tract

Chapter 6

Targets of Tumor Epigenetics and Its Microenvironment in Gastrointestinal Cancer

Ssu-Yin Yen, Hong-Meng Chuang, Mao-Hsuan Huang,
Sheng-Feng Tsai, Tzyy-Wen Chiou, Hong-Lin Su,
Li-Ing Ho, Shinn-Zong Lin, and Horng-Jyh Harn

Abstract

Gastrointestinal (GI) cancers, including gastric, liver, pancreatic, and colorectal cancers, are the major cause of death worldwide. One of the carcinogenic pathways associated with GI cancer is chronic inflammation. Also, the tumor microenvironment, including cells like fibroblasts and immune cells and other modulators, such as growth factors, cytokines, and proteins, can support the growth of cancer cells. The interaction between cancer cells and stromal cells is essential for tumor growth, progression, and metastasis. Moreover, tumor progression involves various genetic modifications and epigenetic alterations, leading to gain-of-function in oncogenes and loss of function in tumor suppressor genes. In gastric cancer, Helicobacter pylori infection is probably a predisposing factor. This may cause chronic inflammation. In addition, it has been reported that H. pylori infection enhances irregular DNA methylation in gastric cancer cells and silences tumor suppressor genes to promote gastric carcinogenesis. In this chapter, we shall introduce the mechanism of epigenetics, endoplasmic reticulum stress, cytokine regulation, and epithelial–mesenchymal transition in GI cancer. We believe that targeting the tumor microenvironment or modifying epigenetic changes may be the potential and effective therapeutic strategies in the treatment of GI cancer.

Introduction

Cancer is a difficult issue in the world, and it is also a leading cause of death. In 1863, the German pathologist Virchow was the first suggesting a link between inflammation and cancer. Many scientists demonstrated that inflammation is the initiation and progression of gastrointestinal (GI) cancer. Besides, several genetic and epigenetic alterations have been implicating a strong association between the inflammation mechanism and that might be responsible for cancer carcinogenesis.

The common mechanism involved in inflammation and its association with cancer is the NF-κB (nuclear factor-κ-light-chain-enhancer of activated B cells) pathway. Activation of NF-κB in the GI tract leads to the induction of pro-inflammatory cytokines and plays an important role in tumor development. NF-κB activation in tissues has been found in patients with some GI tract diseases. Targeting cytokines, chemokines, and inflammation responsive transcription factors represents a potential target and promising therapeutic strategy. The mechanisms of epigenetics, endoplasmic reticulum stress, cytokine regulation, and epithelial–mesenchymal transition (EMT) association with inflammation in GI cancer are described in detail below.

Histone Modifications and Inflammation in Gastrointestinal Cancer Epigenetics

Epigenetic change can be influenced by several factors including age, environment, lifestyle and also the disease state. The term epigenetics refers to heritable changes in gene expression (activation of oncogenes and/or inactivation of tumor suppressor genes) that does not involve changes to the underlying DNA sequence (i.e. a change in phenotype without a change in genotype). Currently, it is thought that DNA methylation, histone modification, and non-coding RNA-associated gene silencing are responsible for initiating and sustaining epigenetic change. Epigenetic change can produce more damaging effects that can result in diseases such as cancer. Epigenetic regulation may be involved in tumor progression, metastasis, invasiveness, and the response to chemotherapy. Nowadays, researchers are becoming more aware of the roles of epigenetics in a variety of human disorders, particularly cancer.

Epigenetics in cancer

Cancer is caused by the accumulation of gene aberrations during the multi-step process of carcinogenesis. Abnormal patterns of epigenetic modifications are common in numerous human diseases. The epigenetic modifications involve cell differentiation, cell proliferation, and patient survival during malignant development. In 1983, DNA methylation was first used to investigate human cancer cases, since then, many other diseases have been linked to epigenetics.¹

DNA methylation

DNA methylation is one type of epigenetic modification and is crucial for the following reasons: for maintaining genomic DNA in genome imprinting, for the stability of the chromosome, and in transcriptional silencing of repetitive genes. DNA methylation is mediated by a family of highly related DNA methyltransferase enzymes (DNMT1, DNMT3A, and DNMT3B) which transfers a methyl group from S-adenosyl-L-methionine to cytosines in CpG dinucleotides. Typically, the maintenance of DNA methylation patterns in somatic cells is attributed to DNMT1, whereas de novo DNA methylation during embryonic development is performed by DNMT3A and DNMT3B. However, DNMT1 can also contribute to de novo DNA methylation both in vitro and in vivo, and the maintenance of methylation in certain regions of the genome requires DNMT3A and DNMT3B.² In DNMT3a-null mice, each passage resulted in a lowered differentiation capacity of hematopoietic stem cells. DNMT3a was determined to be indispensable for the proper differentiation of these cells.³ Some contributing factors have been identified in the aberrant methylation pattern in gastric epithelia, such as aging, diet, chronic inflammation, and microbial infection in gastric cancer.^4,5

Histone modification

Epigenetic alterations frequently occur in cancer development and it plays a critical role in cancer pathogenesis. A high expression of histone deacetylase (HDAC) class I enzymes has been reported in different tumor types, including gastric cancer.⁶ In addition, other studies have described a decrease in acetylated histones and overexpression of HDAC2 in gastric cancer patients. Panobinostat (LBH589) is a novel pan-deacetylase inhibitor that overcomes imatinib resistance in preclinical models of GI stromal tumors.^7,8 It belongs to the hydroxamate class of compounds and has potent inhibitory activity at low nanomolar concentrations. LBH589 has shown great promise as a monotherapy for cutaneous T-cell lymphoma and high efficacy in preclinical studies of GI stromal tumors.^9,10 LBH589 has also been proven to cause the regression of colon cancer in animal models, and in phase I trials. This agent has been shown to be well tolerated.⁹

Epigenetic events in inflammation

Inflammation is the physical response of an organism to harmful stimuli such as pathogens, damaged cells, or irritants. Macrophages play an important role in cancer response and allergy response. Recent research data indicated that chromatin modifications are mechanistically crucial when acquiring the macrophage phenotype.¹¹ NF-κB, forkhead box P3 (FOXP3), interferon regulatory factor (IRF), and signal transducer and activator of transcription (STAT) families are involved in epigenetic changes, including DNA methylation and covalent histone modifications. It has been shown to be of great importance in regulating inflammatory genes. Also, epigenetic mechanisms in T-cells and monocytes are controlled by several of these regulatory factors. H. pylori infection induces both acute and chronic gastritis, which leads to superficial mucosal inflammation in the gastric mucosa.¹² Although most infected individuals have no clinical manifestations, approximately 10–20% of patients develop peptic ulcers, and 1% of patients develop gastric cancer.

Regulation of microRNA Profiles by Cytokines and Chemokines in Gastrointestinal Cancer

microRNA in general

microRNA (miRNA) is a new class of regulatory molecule that was recently discovered. They are involved in the process of inflammation and cancer growth, and belong to the group of non-coding RNAs with short 18–24-bp RNA duplex that does not translate to proteins. They function as posttranscriptional regulators of target messenger RNAs (mRNAs), which promotes target mRNA degradation. Primary miRNAs contain 7-methylguanosine and are polyadenylated and transcripted by RNA polymerase II. Primary miRNAs are broken down by the enzyme Drosha, within the nucleus, into 60–80-bp stem-loop precursor miRNAs. The precursor miRNAs are then exported into the cytoplasm, and the RNase Dicer breaks them down further into short 18–24-bp mature miRNAs. The mature miRNAs then synthesize the RNA-induced silencing complex, which leads to the downregulation of specific genes where the binding of complementary sequences in the 3′ untranslated regions (3′-UTRs) of the target mRNAs occur.

microRNAs in gastrointestinal cancer

Several studies have reported that miRNAs are involved in GI cancer development and progression. For example, members of the miR-17-92 cluster, miR-19a and miR-19b, can be upregulated in multidrug resistance (MDR) cell lines, and they can also be modulated in MDR in gastric cancer cells by targeting phosphatase and tensin homolog (PTEN).¹³ Furthermore, miRNA profiling has revealed that miR-153 is highly expressed in colorectal cancer.¹⁴ In colorectal cancer patien...