Phytonutrients in the Treatment of Gastrointestinal Cancer E-Book
53,95 €
Mehr erfahren.
- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2009
Gastrointestinal cancer is one of the most prevalent causes of cancer-related deaths in the world. Recent research demonstrates that phytochemicals are critical in preventing and managing gastrointestinal cancer. The increased intake of phytochemicals could reduce the risk of cancer by inhibiting cancer cell proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis as well as cancer cell metastasis. These mechanisms are also known to counter Helicobacter pylori infection and modulate gut microbiota. There is preliminary data suggesting that daily supplementation with high doses of certain vitamins combined with conventional therapeutic agents may enhance their growth inhibitory effects on tumor cells and protect normal tissues against some of their toxic effects.
This book attempts to fill gaps on the role of phytonutrients in the treatment of cancer in the gastrointestinal tract (GIT). It discusses the action of individual vitamins on cellular and molecular parameters and describes how vitamins inhibit protein kinase C activity, increase the production of certain growth factors, and modulate the expression of a number of oncogenes.
The book is divided into 2 parts. The first part summarizes the pathophysiology of GIT cancers and introduces readers to anticancer phytonutrients. A chapter on the status of FDA approved nutraceuticals rounds up this section. The second part of the book provides a systematic review on the different plant derived chemicals that can be used to treat GIT cancer. Each chapter in this section focuses on a specific type of phytochemical agent and its molecular mechanisms relevant to the disease.
This book will give the reader a holistic view of gastrointestinal cancer treatment and the value of natural compounds in developing functional food and drugs for preventive medicine.
Das E-Book können Sie in Legimi-Apps oder einer beliebigen App lesen, die das folgende Format unterstützen:
Seitenzahl: 557
Ähnliche
BENTHAM SCIENCE PUBLISHERS LTD.
End User License Agreement (for non-institutional, personal use)
This is an agreement between you and Bentham Science Publishers Ltd. Please read this License Agreement carefully before using the ebook/echapter/ejournal (“Work”). Your use of the Work constitutes your agreement to the terms and conditions set forth in this License Agreement. If you do not agree to these terms and conditions then you should not use the Work.
Bentham Science Publishers agrees to grant you a non-exclusive, non-transferable limited license to use the Work subject to and in accordance with the following terms and conditions. This License Agreement is for non-library, personal use only. For a library / institutional / multi user license in respect of the Work, please contact: [email protected].
Usage Rules:
All rights reserved: The Work is the subject of copyright and Bentham Science Publishers either owns the Work (and the copyright in it) or is licensed to distribute the Work. You shall not copy, reproduce, modify, remove, delete, augment, add to, publish, transmit, sell, resell, create derivative works from, or in any way exploit the Work or make the Work available for others to do any of the same, in any form or by any means, in whole or in part, in each case without the prior written permission of Bentham Science Publishers, unless stated otherwise in this License Agreement.You may download a copy of the Work on one occasion to one personal computer (including tablet, laptop, desktop, or other such devices). You may make one back-up copy of the Work to avoid losing it.The unauthorised use or distribution of copyrighted or other proprietary content is illegal and could subject you to liability for substantial money damages. You will be liable for any damage resulting from your misuse of the Work or any violation of this License Agreement, including any infringement by you of copyrights or proprietary rights.Disclaimer:
Bentham Science Publishers does not guarantee that the information in the Work is error-free, or warrant that it will meet your requirements or that access to the Work will be uninterrupted or error-free. The Work is provided "as is" without warranty of any kind, either express or implied or statutory, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. The entire risk as to the results and performance of the Work is assumed by you. No responsibility is assumed by Bentham Science Publishers, its staff, editors and/or authors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products instruction, advertisements or ideas contained in the Work.
Limitation of Liability:
In no event will Bentham Science Publishers, its staff, editors and/or authors, be liable for any damages, including, without limitation, special, incidental and/or consequential damages and/or damages for lost data and/or profits arising out of (whether directly or indirectly) the use or inability to use the Work. The entire liability of Bentham Science Publishers shall be limited to the amount actually paid by you for the Work.
General:
Any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims) will be governed by and construed in accordance with the laws of Singapore. Each party agrees that the courts of the state of Singapore shall have exclusive jurisdiction to settle any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims).Your rights under this License Agreement will automatically terminate without notice and without the need for a court order if at any point you breach any terms of this License Agreement. In no event will any delay or failure by Bentham Science Publishers in enforcing your compliance with this License Agreement constitute a waiver of any of its rights.You acknowledge that you have read this License Agreement, and agree to be bound by its terms and conditions. To the extent that any other terms and conditions presented on any website of Bentham Science Publishers conflict with, or are inconsistent with, the terms and conditions set out in this License Agreement, you acknowledge that the terms and conditions set out in this License Agreement shall prevail.Bentham Science Publishers Pte. Ltd. 80 Robinson Road #02-00 Singapore 068898 Singapore Email: [email protected]
FOREWORD
Professor Khan has compiled an outstanding book covering contemporary issues in gastrointestinal tract cancers and therapy. It discusses Phytonutrients/Nutraceutical as anticancer and their US Food and Drug Administration (FDA) approval process, flavonoids, saponins, terpenoids, plants volatile oils, phytosterols, plant peptides and glycosides in the treatment of gastrointestinal tract cancers.
The book is highly encompassing. Beyond the conceptualization of various topics, it also offers insight into study methods and contemporary tools for research in the subject matter.
The book represents a compilation of multiple topics and should deepen the reader’s understanding of this discipline. Professor Khan has assembled internationally recognized experts in the field, all of whom have made a valiant contribution to the book.
The reader will be treated to the latest developments in this fast-moving field, and updated on the latest scientific breakthroughs in the area.
The book should be of interest to researchers, healthcare providers, and pharmaceutical companies.
PREFACE
Cancers of the gastrointestinal tract (GIT) are the most common human malignancies. The prevalence of esophageal cancer, pancreatic ductal adenocarcinoma, gastric cancer, hepatocellular carcinoma, colorectal cancer and gallbladder cancer are on the rise now a days. Despite advances in cancer treatment, increasing reports are focusing on finding novel therapies possessing lower side effects and higher potency. From the mechanistic point of view, several dysregulated factors are behind the pathophysiology of GIT cancers. Multiple studies have shown molecular targeted therapies in various GIT cancers, including epidermal growth factor receptor pathway (EGFR), vascular endothelial growth factor pathway (VEGF), Wnt/β-catenin pathway and insulin-like growth factor receptor (IGFR). The aforementioned mediators are the critical targets of monoclonal antibodies and small molecules in treating GIT cancers. Accordingly, providing the exact dysregulated mechanisms behind GIT cancers could pave the way in the treatment of cancers.
Phytochemicals have been important resources of preventive and curative entities for various diseases, such as cancer. To a certain extent, enough investigation has been made over the last few decades to investigate natural compounds that possess anti-cancer properties. Phytochemicals used in the management of malignancies appear to be obligatory, serving as the cornerstone for the latest medicine as well as a rich reserve of novel medicines. Phytonutrients are the main principles present in plants that possess a great role in their protection against certain bacteria, viruses, and fungi and as a result of certain detoxification processes within the plant. There are many recommendations to increase the intake of high amounts of fresh colored vegetables and fruits, besides whole grains (cereals) and beans, which contain phytoconstituents that participate in lowering the risk of certain cancers, diabetes, hypertension, in addition to certain heart diseases. The effect of phytonutrients differs according to their chemical class and amount. They may act as antioxidants, which mainly prevent carcinogens' effects on the healthy body.
This book focuses on the types of available phytonutrients and their regimens, comprehensive knowledge about phytonutrients, their targeted mechanism of action in the management of GI cancer, clinical findings of phytonutrients, synergistic effect with other anti-cancer medicines and future prospects of phytonutrients in treating GI carcinoma.
List of Contributors
Pathophysiology of Gastrointestinal Tract Cancers and Therapeutic Status
Fatemeh Abbaszadeh1,2,#,Sajad Fakhri3,*,#,Sana Piri3,Haroon Khan4,*Abstract
Cancers of the gastrointestinal tract (GIT) are the most common human malignancies. The prevalence of esophageal Cancer, pancreatic ductal adenocarcinoma, gastric Cancer, hepatocellular carcinoma, colorectal Cancer and gallbladder Cancer are on the rise now a days. Despite advances in cancer treatment, increasing reports are focusing on finding novel therapies with lower side effects and higher potency. From the mechanistic point of view, several dysregulated factors are behind the pathophysiology of GIT cancers. Multiple studies have shown molecular targeted therapies in various GIT cancers, including epidermal growth factor receptor pathway (EGFR), vascular endothelial growth factor pathway (VEGF), Wnt/β-catenin pathway, and insulin-like growth factor receptor (IGFR).The aforementioned mediators are the critical targets of the existence of monoclonal antibodies and small molecules in treating GIT cancers. Accordingly, providing the exact dysregulated mechanisms behind GIT cancers could pave the road in the treatment of cancers. This chapter reveals dysregulated signaling pathways and potential therapeutic agents in the treatment of GIT cancer.
1. INTRODUCTION
The cancers of gastrointestinal tract (GIT) are heterogeneous malignancies. Of those, pancreatic Cancer (PC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), esophageal cancer (EC), gallbladder cancer (GBC) and liver-bile duct malignancies are common GIT cancers which are on the rise [1, 2]. More than one in six affected patients with GIT cancers experience malignant tumors, leading to life-threatening events [3]. Also, evidence indicated that GIT neoplasm, as the most common mesenchymal tumor [4], arises from interstitial cells in the myenteric plexus followed by platelet-derived growth factor receptor A (PDGFRA), which encode tyrosine kinases receptors towards uncontrolled cell replication [5]. There are different GIT classifications based on tumor size and associated risk of progression, including those with high, intermediate, low, and very low [6].
From the mechanistic point of view, several tumoral signaling pathways play an important function in GIT cancers, such as phosphoinositide 3-kinases (PI3K), mitogen-activated protein kinase (MAPK), transforming growth factor beta (TGF-β), Wnt/β-catenin, and Janus kinase (JAK) /signal transducer and activator of transcription (STAT) [7, 8]. In the Wnt signaling pathway, there are several dysregulated genes, such as β-catenin, phosphatase and tensin homolog (PTEN), Wnt1-inducible signaling protein 3 (WISP3], adenomatous polyposis coli (APC), and T-cell factor 4 (TCF4), which has major functions in carcinogenesis [8]. Based on the experimental evidence, natural killer (NK) cells have cytotoxicity and immune-modulatory properties involved in GIT cancers [9]. They are also activated via the natural killer group 2D receptor and its ligands in GC, indicating that the NK cell has a promising cytotoxicity effect on GC cell line [10]. Studies indicated that interleukin (IL) -15 can increase the maturation and function of NK cells in cancers [11]. In this line, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and IGFR are upstream receptors that begin the aforementioned signaling cascades in GIT cancers [12]. Recently, abnormal DNA methylation has been correlated to GIT tumorigenesis and progression through the regulation of tumor suppressor genes [13, 14]. Consequently, immunotherapy plays critical roles in checkpoint inhibitors of cancers through anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1] and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4] [9]. Evidence suggested that generation of free radicals and reactive oxygen species (ROS) in GI tract can cause oxidative damages in GIT, leading to a variety of different pathological conditions and clinical signs.
Of the therapeutic candidates, although surgery is the critical way of stopping GC, it does not sufficiently work in patients with advanced stages of disease [15]. In such cases, chemotherapy is a suitable candidate; however, the response rate is 20-40%, with a median overall survival (OS) time of 6-11 months. Besides, it could not be ignored the serious side effects of chemotherapy [3]. It urges the need to find novel multi-target agents regarding the modulation of several dysregulated pathways in GIT cancers. Accordingly, providing the exact pathophysiological mechanisms behind GIT cancers could pave the road in cancer therapy.
In the present chapter, we investigate different types of GIT cancers, as well as related epidemiology and precise molecular pathology. Additionally, promising therapeutic targets and associated treatments are provided in GIT cancers.
2. ETIOLOGY AND PATHOLOGY OF GIT CANCERS
Several factors are behind the etiology of GIT cancers, including inflammation, multiple dysregulated pathways, Epstein-Barr virus (EBV), virus mutation of the E-cadherin gene (CDH1), mutations of tumor protein p53 (TP53) and catenin (CTNNB1) genes [16] and Helicobacter pylori (H. pylori). Evidence has shown that H. pylori as a bacteria can be colonized in the gastric mucosa, leading to chronic active gastritis [17]. In this line, H. pylori can disrupt gastric acid secretion and then impair the function of GIT. Additional studies suggested that H. pylori infection can lead to abdominal pain, discomfort, satiation, fullness, epigastric pain and also irritable bowel syndrome [18, 19]. Evidence also observed that H. pylori infection is involved in the progression of esophageal adenocarcinoma (EA) [20]. In an analysis of patients with PC, Guo et al. indicated an increased rate of PC following infection with H. pylori [21]. Other studies indicated that CRC is associated with H. pylori in affected patients [22]. Studies indicated that H. pylori activate a growth factor-like response in gastric cells by complexing with the Src homology 2 domain (SH2)-containing tyrosine phosphatase (SHP-2) in a phosphorylate ion-dependent effects [23].
In addition to the role of H. pylori in GIT cancers, reports indicated that inflammation has an important function in the stomach, development of GC and dysfunction of the GIT [18, 19]. Hypermethylation and increased levels of inflammatory markers (TNF-α, IL-1β) correlated to EBV and H. pylori [24]. El-Omar et al. reported that the levels of IL-1β and IL-1 are increased in GC [25]. It has also been indicated that in PC, there is an elevated expression of cytokeratins 7, 8, 13, 18 [26]. Studies also showed that EBV correlated to GCs [27-29]. Evidence has shown EBV and human herpesvirus 4 (HHV4) are associated with cancers such as gastric/nasopharyngeal carcinoma, transplant lympho proliferative disorder (PTLD), non-Hodgkin and Hodgkin lymphomas [29]. EBV is correlated to hypermethylation in many cancers and also miRNA abnormalities [30, 31]. It also induced several signaling pathways leading to GC [29]. Zhao et al. suggested different pathways such as neuroactive ligand-receptor interaction mediators in Cancer, Wnt, MAPK, cytokine-cytokine receptor interaction, insulin, and calcium signaling pathway [32]. Evidence indicated that there is an increased prevalence of HPV infection in patients with esophageal squamous cell carcinoma; also, several research indicated that HPV DNA positive was present in those samples [33]. In-line studies suggested that HPV infection is associated with elevated CRC [33]; such also happened with John Cunningham Virus [34] and cytomegalovirus [35].
Glucagon-like peptide 1 (GLP-1), a hormone generated by intestinal endocrine cells, can play important functions such as regulating glucose homeostasis, suppressing gastric emptying, and GI motility [36-38]. Herrera-Goepfert et al. investigate a correlation between several genes, such as death-associated protein kinase (DAPK), CDH1, thrombospondin-1 (THBS1), and p14, with H. pylori. They observed that guanine residue methylation of these genes was involved in cell growth, differentiation, and suppression of esophageal tumors [39]. There are two pathways that play a function in cell proliferation such as MAPK and PI3K pathways, as well as mutations in kirsten rat sarcoma virus (KRAS), BRAF, and Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), which affect the MAPK/PI3K pathways in CRC [40]. In addition, researchers observed abnormal induction of the Wnt pathway in CRC. APC has several functions, namely regulation of the Wnt pathway [41].
Also, studies indicated mutations in pancreatic ductal adenocarcinoma (PDAC), such as cyclin dependent kinase inhibitor 2A CDKN2A, KRAS, suppressor of mothers against decapentaplegic SMAD, and TP53 [42]. Evidence has shown that TP53, as a transcription factor, has a protective effect via the induction of cell cycle or apoptosis in damaged cells. This factor is also inactivated in PC [43]. It has been shown that TGF-β binds to receptors and leads to phosphorylate of SMAD2/3 and SMAD4 and other factors for stimulation of transcription genes, which regulate cell growth. SMAD4 as an important mediator for TGF-β signals, and SMAD4 is inactivated in PC [44]. It has been shown that there is abnormal activation of nuclear factor kappa B (NF-κB) and STAT3 in the epithelium of the gastrointestinal tract [45].
3. CLASSIFICATIONS OF GASTROINTESTINAL TRACT (GIT) CANCERS
The GIT is a 25-foot-long tract that extends from the mouth to the anus. GC, EC, PDAC, HCC, GBC, and CRC are GIT cancers described as follows:
3.1. Gastric Cancer (GC)
GC is a disorder in which malignant cells are developed in the tissues of the stomach. The prevalence of this Cancer is twice as common in men, with most cases after 60 years. GC has the highest incidence in East Asian countries [46]. GCs are anatomically classified into two groups non-cardiac (distal GC) and cardiac GC (proximal GC) [47, 48]. Under Lauren's classification, GCs are divided into two subgroups: diffuse or intestinal, while the WHO system classifies GC into four subgroups: mucosal, tubular, papillary, and poorly cohesive [49]. Studies have shown that genetic factors, heredity, Menetrier's disease, radiation exposure, H. pylori infection, the frequent diet of salty foods, and smoking increase the risk of GC [50].
From the mechanistic point of view, HER2 and programmed death-ligand1/2 (PD-L1/2) are prognostic and biomarkers of GCs. HER2 overexpression occurs in about 38% of GC. Expression of PD-L1/2 has been reported mostly in EBV-positive tumors, and it appears that its antagonists may be effective in the treatment of EBV-associated GC [51].
3.2. Esophageal Cancer (EC)
EC is the sixth leading cause of death worldwide among cancers [52]. Risk factors for EC are gender, race, smoking, alcohol, digestive disorder, obesity, Barrett’s esophagus, and genetic aspects [53]. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the most well-known esophageal malignancies. Squamous cell carcinoma begins in squamous cells within the esophagus. It grows at the top and center parts of the esophagus. Adenocarcinoma occurs in the glandular tissue of the inferior part of the esophagus where the esophagus and the stomach meet [54]. In addition, there are other rare types of EC, including epithelial tumors and non-epithelial tumors (lymphoma and gastrointestinal stromal cell tumors) [55].
3.3. Pancreatic Ductal Adenocarcinoma (PDAC)
PDAC, the most common type of PC, is the 7th leading cause of cancer mortality in the world [56]. The best-known risk factors for PDAC are nutritional factors (high intake of fats and alcohol drinking), diabetes mellitus, and a history of chronic pancreatitis [57]. Notable types of PDAC include undifferentiated or anaplastic carcinoma, adenosquamous carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet-ring carcinoma, medullary carcinoma, colloid and hepatoid carcinoma [58]. Pancreatic adenocarcinoma occurs as a result of a series of gradual mutations ranging from normal mucosa to invasive malignancy. Mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, and pancreatic intraepithelial neoplasia are the best-characterized precursors of this malignancy [59]. Serum cancer antigen 19-9 is the approved marker for the management of PC, but it is not reliable in the detection and prediction of the early stage of PDAC [60, 61].
3.4. Hepatocellular Carcinoma (HCC)
HCC is the most common malignancy of the liver. HCC is ranked as the 3rd leading cause of cancer death. Chronic hepatitis B and C, and aflatoxin B1 are risk factors for this Cancer [62]. Metabolic syndrome and obesity, which lead to non-alcoholic fatty liver disease, can also be mentioned, especially in Western countries [63]. It is more common in men than women [64]. HCC is caused by epigenetic modifications and the accumulation of somatic genomic changes in the passenger and driver genes, which explains its enormous molecular heterogeneity [65]. Patients with HCC have different molecular subtypes divided into two categories: proliferative and non-proliferative. The former possesses high serum levels of alpha-fetoprotein, TP53 mutations, poor cell differentiation, chromosomal instability, and activation of oncogenic pathways (MAPK, Akt/mTOR), while nonproliferation class is highlighted with CTNNB1 (beta-catenin) mutations [66, 67].
3.5. Gallbladder Cancer (GBC)
GBC is the prominent malignancy of the biliary tract, which is more common in women [68]. To some extent, estrogen increases cholesterol saturation in the bile and is therefore involved in the pathogenesis of GBC-mediated gallstones [69]. Factors such as inflammation of the bile ducts, gallbladder polyps, high carbohydrate intake, chemical exposure and heavy metals increase the risk of GBC [70]. Chronic inflammation of the bile duct tissue accumulates sequential mutations such as CTNNB1 and K-ras in the genome that lead to malignant transformation. About 90% of histopathological changes in GBC are seen as adenocarcinoma [71].
3.6. Colorectal Cancer (CRC)
CRC is common in both sexes, as the third and second leading cause of Cancer in men and women worldwide, respectively [72]. Environmental risk factors, heredity, obesity, diabetes and long-standing inflammatory bowel disease play a critical part in the development of CRC. CRC is classified according to lymph node involvement (N stage), local invasion depth (T stage), and presence of distant metastases [73]. The process begins with an aberrant crypt, turning into a polyp (a neoplastic precursor lesion) and eventually leading to CRC over an estimated period of several years. Stem cells at the colonic crypts are the result of the gradual accumulation of genetic or epigenetic modifications that inactivate tumor suppressor genes and activate oncogenes [74]. CRC is explained by two pathways, the gatekeeper (genes that regulate growth), and the caretaker (genes that maintain genetic stability) pathway [75]. Carcinoembryonic antigen was first discovered in 1965, and is still the only tumor marker known to be effective in monitoring the treatment of CRC patients [76].
4. MOLECULAR PATHOLOGY OF GASTROINTESTINAL CANCER
Several dysregulated pathways are involved in GIT cancers, including EGFR, VEGF, Wnt/β-catenin pathway, and IGFR.
4.1. Epidermal Growth Factor Receptor Pathway (EGFR)
EGFR is a membrane glycoprotein with intrinsic tyrosine kinase activity, consisting of 1186 amino acids. Its specific ligands are EGF and TGF-α. HERl (EGFR), HER2 (Neu, ErbB-2, CD340), HER3 and 4(ErbB-3,4) are the four main members of this family [77]. The over-expression of EGFR and HER2, especially the latter, has been detected in GIT cells. Their level of expression is directly related to the depth of the tumor attack and is inversely related to the degree of survivorship and tumor differentiation. Fixation of the ligand to the EGFR extracellular domain, ultimately leading to phosphorylation of the intracellular tyrosine kinase domain. It initiates a series of intracellular signals, such as the MAPK/extracellular signal-regulated kinases (ERK) signaling pathway and PI3K/Akt/mTOR [78-80]. These two pathways are closely related, have some overlaps, and activate different targets that result in cell growth, proliferation, differentiation, and survival [81]. Ras is activated through mutation and hyper-phosphorylation. Raf and Ras then form a complex that activates MEK1/2 through phosphorylation. In the following, MEK1/2 is activated through MALAT1 and SLC25A22, which the former induces activation of MAPK, and begins a downstream signaling cascade. MEK1/2 increases the activation of ERK1/2, which activates downstream mediators and increases the proliferation and anti-apoptosis agents. PI3K activates and phosphorylated Akt. Also, SPOCK1 induces the activation and phosphorylation of Akt. It then phosphorylates SPOCK1, which by forming phosphorylated Bax, inactivates the Bax. In addition, upstream effects lead to mTOR hyper-phosphorylation. As a result, enhanced survival is achieved through the PI3K/Akt/mTOR pathway [82]. Phospholipase C, matrix metalloprotease 9 (MMP9), Ca2 +/calmodulin-dependent kinases, and the STAT pathway are also activated in EGFR signaling [83, 84].
The carcinogenic function of H. pylori is mediated by binding of activator proteins 1, c-Jun and c-Fos to the EGFR promoter region and indirectly activating NF-κB-mediated transcription, and secrete TNF-α-inducing proteins, also inhibits the pro-apoptotic proteins [85]. Therefore, drugs that target EGFR and HER2 are expected to improve the therapeutic effect of GIT treatments [80].
4.2. Vascular Endothelial Growth Factor Pathway (VEGF)
A tumor needs new blood vessels to get nutrients and maintain growth. Changes such as increased CO2, cyclooxygenase-2 (COX-2), hypoxia, NO production, and genetic events, such as the loss of some oncogenes, occur in the tumor environment and stimulate the need for new blood vessels. Tumors elevate angiogenesis by enhancing the production/secretion of proteases/angiogenic factors. VEGF is the main stimulant that regulates tumor angiogenesis and is involved in all stages of angiogenesis. VEGF family consists of VEGF(A), VEGF(B), VEGF(C), VEGF(D), VEGF(E), and placental growth factor 1 and 2 (PIGF-1 and -2). VEGR has 4 isoforms that VEGFR-2 is principal in tumor angiogenesis [86, 87]. Proangiogenic factors lead to angiogenesis by activating endothelial cells of tyrosine kinase and eventually the MAPK and PI3K/Akt/mTOR pathways [88]. The expression level of VEGF and neovas-cularization in patients with H. pylori-positive gastritis was markedly higher than in the control group [89]. In this regard, targeting VEGF would be valuable in combating GIT cancers.
4.3. Wnt/β-catenin Pathway
The Wnt pathway or signal transduction pathway is subdivided into two branches: the canonical or β-catenin-dependent pathway and non-canonical pathway or β-catenin-independent pathway. Without Wnt, β-catenin is bound to E-cadherin and is phosphorylated by core proteins AXIN, adenomatous polyposis coli (APC), glycogen synthase kinase (GSK3), and casein kinase 1 (CK1). Binding of Wnt ligands to a Frizzled and LRP-5/6 receptor complex results in the stabilization of hypophosphorylated β-catenin, which binds to T-cell factor (TCF)/lymphoid enhancer factor (LEF) proteins in the nucleus to trigger the transcription. Transfer of β-catenin in the nucleus eventually leads to the transcription of known carcinogenic genes c-myc and cyclin D1 [90]. This is another element to support the link between H. pylori infection and GC. H. pylori have been reported to up-regulate the stem cell markers Lgr5 and CD44 through the activation of the Wnt/β-catenin pathway [91]. MMP7, as another target of the β-catenin/TCF pathway, is expressed in over 90% of CRCs [92]. Approximately 80% of CRCs have nuclear β-catenin accumulation due to mutation in APC [93]. Approximately one-third of tumors in human HCC contain β-catenin mutations in exon 3 [90].
4.4. Insulin-like Growth Factor Receptor (IGFR) Pathway
IGFR is a membrane tyrosine kinase receptor activated by IGF-1 and IGF-2. Their binding causes receptor autophosphorylates and activates multiple pathways, such as the MAPK/ERK and PI3K/Akt-1 pathways. IGFR plays a key role in metastasis, angiogenesis, transformation, and anti-apoptotic. Decreased IGFR causes apoptosis in tumors, but generates growth arrest in untransformed cells [94]. During the fetal period, the human stomach has high levels of IGF-I mRNA [95].
5. MOLECULAR TARGETED THERAPIES IN GASTROINTESTINAL CANCER
5.1. Targeting EGFR
The main classes of EGFR inhibitors are anti-EGFR monoclonal antibodies (mAbs) that bind to extracellular EGFR, which prevent EGF from binding to its receptor and stop cell division, induce apoptosis, and reduce the growth factor production (e.g., inflammatory cytokines, VEGF) [96]. In this line, tyrosine kinase inhibitors also fix the tyrosine kinase domain in the EGFR and stop the activity of the EGFR [97].
Anti-EGFR mAbs are divided into 4 types, including anized, murine, chimeric, and fully human mAbs. The former antibodies were obtained entirely from mice with a high incidence of human anti-mouse antibody (HAMA) reactions. Chimeric mAbs showed a much lower incidence of HAMA, and humanized antibodies are 90% human with 10% mouse protein [98].
Cetuximab and panitumumab are of mAbs approved by the FDA for GIT cancer [99]. Cetuximab targets EGFR and has 5-10 times as much affinity as natural ligands, which inhibits the proliferation of EGFR-expressing cell lines, and elevates the cytotoxic activity of radiation and chemotherapy [100]. Treatment of GIT cancer with cetuximab was associated with cell cycle arrest, cell accumulation in the G1 stage, down-regulating the activities of CDK6, CDK4, and CDK2, accumulation of Bax protein and finally, induction of cancer cell apoptosis [101]. Administration of cetuximab to CRC patients was associated with improved factors, including OS time, response rate, disease progression time, and progression-free survival (PFS) time compared with other treatments [101]. Cetuximab treatment in 55 patients with an EC undergoing a chemotherapy regimen for advanced disease showed the median OS for 4 months, and PFS for 1.8 months [102]. In another study, 45 mg of cetuximab in 28 HCC patients was associated with a PFS and OS of 2.8 and 5.8, respectively [103].
As the second mAb used in GIT cancers, panitumumab binds to different isotopes of EGFR compared to cetuximab, therefore, has different pharmacokinetics and pharmacodynamics [104] and leads to an arrest in the G0-G1 interphase [105]. In patients with gastroesophageal junction cancer (GEJC), PFS and OS were 5.6 and 11 months after treatment with panitumumab plus folinic acid/5-fluorouracil/ oxaliplatin (FOLFOX4) [106]. In the phase II study of panitumumab plus irinotecan in EG patients, the partial response rate was 6%, OS/PFS was 7.2 and 2.9 months, respectively [107].
Erlotinib and gefitinib are EGFR tyrosine kinase inhibitors for GIT cancers. Gefitinib inhibits autophosphorylation, reduces c-FOS mRNA, and finally stops the shift of cells from the S phase into G0/G1 [96]. In a report by Ferry et al., 500mg/d of gefitinib in twenty-seven patients with EC was associated with an OS of 4.5 months and PFS of 1.9 months [108]. In another study on EG patients treated with gefitinib, median OS and PFS were 6.1 and 2.2 months, respectively. Also, partial response rate, stable disease rate, and progression disease rate were 4.9%, 34.1%, and 61.0% [109]. With advanced PC, the combination of gefitinib and gemcitabine treatment was associated with a PFS of 4.1 months and 7.3 months of OS [110]. In a pilot feasibility study, Yamaguchi et al. reported that gefitinib and celecoxib (a COX-2 inhibitor)modulated the disease in 12 patients (40%), and reduced the progression of the disease in 18 patients (60%) [111].
Treatment of PC patients with erlotinib showed a statistically significant improvement in median survival [112]. In patients with GC, Erlotinib showed no tumor response, while patients with gastroesophageal (GE) cancer had a response rate of 9% [113]. 38 HCC patients treated with erlotinib showed OS time of 13 months and PFS at 6 months [114]. Erlotinib plus bevacizumab and FOLFOX4 in CRC patients showed PFS at 9.6 months which was significantly higher than in bevacizumab and FOLFOX4 groups 6.9 months [115].
Pertuzumab is an anti-HER2 mAb that binds to domain II of HER2. This region is essential for dimerization with other receptors in the HER family and signaling, thereby inhibiting ligand-induced dimerization and its downstream signaling [116]. OS (18.7 months) and PFS (10.5) were improved by pertuzumab plus trastuzumab and chemotherapy treatment in Chinese HER2-positive GC/GEJC patients [117]. And pertuzumab plus trastuzumab treatment in CRC showed patient PFS of 2.9 months and median OS of 11.5 months [118].
5.2. Targeting VEGF and VEGFR
Bevacizumab is an anti-VEGF antibody for the treatment of GC. A pivotal phase IItrial using bevacizumab in combination with irinotecan and cisplatin in patients with GC (51%) or GE (49%) adenocarcinoma showed the median time to tumor progression of 8.3 months, a response rate of 65%, and median survival of 12.3 months [119]. The results of a study of 104 CRC patients showed that the administration of bevacizumab increased OS rate by 16.1 months [120]. A randomized phase II study of bevacizumab in combination with chemoradiation on PC OS was 17 months and disease-free survival 11 months [121].
Sunitinib is an oral anti-angiogenic tyrosine kinase inhibitor and is known as a potent inhibitor of VEGFR-2, VEGFR-1, the fetal liver tyrosine kinase receptor 3, PDGFRα, and PDGFRβ [122]. A study of sunitinib in 72 patients with advanced GC showed a more than 6-week stable disease rate of 32.1%, a partial response rate of 2.6%, a PFS of 2.3 months and OS of 6.8 months [123]. Accordingly, 400 mg of sorafenib for 21-day in patients with advanced GC was associated with a response rate of 41%, OS of 13.6 months, and PFS of 5.8 months [124]. In another study, 34 HCC patients were enrolled in a phase II study of sunitinib. 50% of patients showed a stabled disease, and OS and PFS were 9.8 and 3.9 months, respectively [125].
Sorafenib inhibits the activity of tyrosine kinases involved in angiogenesis and tumor, including Flt3, and platelet-derived growth factor receptor (PDGF-R). It also targets B-Raf, and C-Raf involved in the MAPK pathway [126]. Sorafenib showed an OS of 10.7 months compared with placebo (7.9) for patients with advanced HCC; the median time to symptomatic progression was the same in both groups [127]. Treatment with sorafenib in patients with EC and GEJC PFS 3.6 and disease stabilization [128]. In a phase II study of sorafenib in patients with GBC, PFS was 2.3 months, and the median OS was 4.4 months [129].
Apatinib (rivoceranib) is a VEGFR-2 tyrosine kinase inhibitor that prevents phosphorylation and downstream signaling by targeting the intracellular binding site of ATP to the receptor [130]. Treatment with 425 mg of apatinib in patients with GC associated with PFS of 3.4 months and OS4.3 months [131]. In another study, an 850 mg dose of apatinib in patients with GC showed OS at 6.5 months and PFS at 2.6 months [132]. Apatinib with chemotherapy in CRC patients had effective results. The objective response rate was 31.25%, and the disease control rate was 62.5%. Consequently, PFS in apatinib combined with chemotherapy was 12 months compared with apatinib alone of 4.5 months [133]. In a pilot study, associated PFS was 4.8 months, and OS was reported at 10.1 months in CRC patients [134]. Also, apatinib treatment significantly improved PFS (2.6 months) and OS (6.5 months) in patients with gastroesophageal junction adenocarcinoma [135].
Lenvatinib is an oral inhibitor of VEGF1-3, PDGFR α, FGFRs 1–4, RET, and KIT. It is the first-line treatment of HCC in Japan, China, the United States, and Europe [136]. Treating 24mg of lenvatinib in biliary tract cancer showed an objective response rate of 11.5%, PFS 3.19months, as well as OS 7.35months [136]. In an open-label phase 2 trial, lenvatinib plus pembrolizumab in patients with advanced GC was associated with a PFS rate of 7.0 months, and OS of 10.4 months [137]. Lenvatinib was similar to sorafenib in OS of HCC in the Japanese population, but it was significantly better at PFS (7.2 vs. 4.6 months) [138].
Cediranib is an oral small-molecule inhibitor of VEGFR1-3, PDGFR, and c-kit. The results of cediranib plus FOLFOX6 versus bevacizumab plus FOLFOX6 in phase II/III study in 1422 patients with CRC were associated witha PFS 9.9 vs. 10.3 months, and OS 22.8 vs. 21.3 months [139].
Ramucirumab has been approved for the treatment of advanced GC or EC in a second-line setting and has been shown to be effective both as monotherapy and in combination with paclitaxel [140]. Ramucirumab, a VEGFR-2 antagonist, improved OS in a phase III study of HCC patients who were intolerant to sorafenib [141]. Ramucirumab in combination with pembrolizumab in patients with advanced GC was associated with objective response rate (25%), OS (14.6 months), and PFS (5.6 months) [142]. In 26 patients with GBC treated with 8 mg/d of ramucirumab and pembrolizumab intravenously for 3 weeks, OS, and PFS were 6.4 and 1.6 months, respectively. Also, in their study objective response rate was 4% [143].
5.3. Targeting wnt/β-catenin
Curcumin acts via its role in the modulation of the Wnt/β-catenin pathway and the activity of PPARγ levels in cancer treatment [144]. Curcumin down-regulated expression of COX-2, STAT3, and NF-κB in peripheral blood mononuclear cells in PC patients after receiving 8 g/day curcumin for 2 months [145]. Oral administration of curcumin plus FOLFOX chemotherapy was associated with PFS of 9.7 vs. 5.7 and OS time of 16.7 vs. 6.6 in CRC patients [146]. In their study, the PFS and OS were 8.4 and 10.2 months, respectively, in PC patients [147]. Median survival time was 5.3 in PC patients after 8000 mg/day of curcumin together with gemcitabine treatment [148].
Genistein is an isoflavone in soy that targets GSK3β and inhibits the Wnt pathway by producing soluble Wnt inhibitory molecules such as sFRP2. In CRC patients, PFS was 11.5 months after genistein plus chemotherapy treatment [149]. Besides, the OS time was 4.9 months in PC patients [150].
The vitamin D active form, promotes the binding of β-catenin to the vitamin D receptor, and thereby decreases the available β-catenin molecules, which may bind to TCF/LEF transcription factors [151]. Among CRC patients, the prognostic plasma level of 25-hydroxyvitamin D3 was associated with improvement in OS [152].
5.4. Targeting IGR-IR
Figitumumab (CP-751,871) is a humanized IgG2 mAb against IGF-1R. A cohorts’ study on CRC patients showed that OS in doses of 20 and 30 mg/kg of figitumumab were 5.8 and 5.6 months, respectively, and PFS was 1.4 months in both doses [153]. Ganitumab is another inhibitor for IGF-1R. Ganitumab did not improve the OS in PDAC patients [154]. Ganitumab plus a chemotherapy regimen was also not effective in patients with mutant KRAS metastatic CR [155].
5.5. Targeting other Signaling Mediators
Everolimus (RAD001) is a derivative of rapamycin and, as an oral inhibitor of mTOR, has shown clinical effects and tolerable safety profiles in a variety of human cancers and tumor syndrome, which has been approved by the FDA [156]. The results of a Phase II study involving 54 GC patients revealed a 56.0% disease control rate, an OS of 10.1 months, and a PFS of 2.7 months [157]. In 656 patients with GC, OS was 5.4 months and 4.3 months in the everolimus and placebo groups, respectively. Median PFS was 1.7 months with everolimus and 1.4 months with placebo [158]. In another phase II trial study, everolimus in patients with GTI cancer (11 esophagus, 13 gastroesophageal junction and 21 stomach cancers), OS was 3.4 months, and PFS was 1.8 months. A randomized double-blind phase III study on 546 patients showed that the PFS with everolimus was 3.0 months and the placebo was 2.6 months [159].
Marimastat is a low-molecular-weight peptide that acts as an MMP inhibitor. Orally administered marimastatin in combination with gemcitabine to 239 patients with PC showed median survival times of 165.5 days and 1-year survival of 18% [160]. In a randomized, double-blind, placebo-controlled study on GC patients, median survival was 160 days for marimastat and 138 days for placebo, with a 2-year survival of 9% and 3%, respectively. Also, PFS was longer for patients receiving marimastat [161].
Celecoxib selectively inhibits the COX-2 enzyme, reducing pain and inflam-mation. It was evaluated in a phase II study of 47 patients with CRC. Median PFS was 8.7 months and OS was 19.7 months [162]. In a preliminary, three-center, clinical trial study, celecoxib combined with chemotherapy offers OS of 14 months and PFS 7.5 months in patients with GC [163]. Also, celecoxib plus chemotherapy in advanced EC patients was associated with a PFS and OS 8.8 and 19.6 months, respectively [164]. Napabucazine (STAT3 inhibitor) is a small molecule activated by NADPH and cytochrome P450 oxidoreductase, leads to redox cycling and the production of reactive oxygen species (ROS). Increased ROS leads to DNA damage and affects various oncogenic cell pathways, including inhibition of the STAT3 signaling pathway, which is involved in the survival of cancer stem cells [165, 166]. Also, STAT3 regulates the β-catenin expression. Napabucasinin a randomized phase 3 trial CRC patients was associated with OS 4.8 months [167].
Table 1 shows the drugs used in GIT cancers, as well as related mechanisms.
CONCLUSION
In recent decades, our knowledge of GIT cancers increased; however, much remains unclear. Revealing the etiology and basic dysregulated mechanisms in the pathogenesis of GIT cancers may help in providing novel anticancer treatments. Growing evidence is revealing the role of H. pylori, and viruses in dysregulating EGFR, VEGF, IGF, HER, PI3K/Akt/mTOR, JAK/STAT, wnt/β-catenin and MMPs towards the progression of cancer cells during GIT cancers. The aforementioned therapeutic targets are modulated by mAbs, small molecules and anti-inflammatory drugs (Fig. 1). The present chapter reveals GIT cancer types, associated epidemiology, and exact molecular pathology. Besides, the therapeutic targets and associated treatments are provided in GIT cancers.
Such reports will pave the road in the treatment/prevention of GIT cancers. Additional research should cover extensive in-vivo and in-vitro experiments regarding revealing the precise dysregulated signaling pathways followed by well-controlled clinical trials.
Fig.(1))Major therapeutic targets, therapies and pathophysiological mechanisms behind GIT cancers. COX-2: cyclooxygenase-2, CRC: colorectal Cancer, EC: esophageal Cancer, EGFR: epidermal growth factor receptor, ERK: extracellular signal-regulated kinases, GBC: gallbladder cancer.GC: gastric Cancer, GIT: gastrointestinal tract, GSK: glycogen synthase kinase, HCC: hepatocellular carcinoma, HER2: human epidermal growth factor receptor 2, HIF-1: hypoxia-inducible-factor-1 alpha, IGFR: insulin-like growth factor receptor,IL: interleukin, MAPK: mitogen-activated protein kinase, MMP: matrix metalloprotease, NF-κB: nuclear factor kappa B, PC: pancreatic cancer,PI3K: phosphoinositide 3-kinases, STAT: signal transducer and activator of transcription, TNF-α: tumor necrosis factor alpha, VEGF: vascular endothelial growth factor receptor.AUTHOR CONTRIBUTIONS
Conceptualization S.F. and H.K.; drafting the chapter, F.A., S.F., and S.P.; review and editing the chapter, S.F., and H.K; revising; F.A., S.F., and H.K.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENT
Declared none.
