Eiichi Tahara Hiroshima University, Hiroshima, Japan
1 Introduction 3
2 Genetic and Epigenetic Alterations and Abnormal Growth Factor/Cytokine Network in Esophageal Cancer 4 2.1 Genetic and Epigenetic Alterations in Esophageal SCC 4 2.2 Abnormal Growth Factor/Cytokine Network in Esophageal SCC 6
3 Genetic and Epigenetic Alterations and Abnormal Growth Factor/Cytokine Network in Gastric Cancer 8 3.1 Genetic and Epigenetic Alterations in Gastric Cancer 8 3.2 Factors Associated with Increased Incidence of Gastric Cancer 13 3.3 Abnormal Growth Factor/Cytokine Network in Gastric Cancer 16
4 Genetic and Epigenetic Alterations and Abnormal Growth Factor/Cytokine Network in Colorectal Cancer 18 4.1 Genetic and Epigenetic Alterations in Colorectal Cancer 19 4.2 Factors Associated with Increased Incidence of Colorectal Cancer 21 4.3 Abnormal Growth Factor/Cytokine Network in Colorectal Cancer 22
5 Conclusion 23
Bibliography 24 Books and Reviews 24 Primary Literature 25
Cell Adhesion Molecules
Surface ligands, usually glycoproteins, that mediate cell to cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migration, and metastasis.
Cell Cycle Regulators
Proteins that regulate the cell division cycle. This family of proteins involves a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases as well as their putative substrates, such as chromatine-associated proteins, cytoskeletal proteins, and transcription factors.
Polypeptides secreted by inflammatory leukocytes, macrophages and lymphocytes in response to microbes and other antigens that mediate and regulate immune and inflammatory reactions. They generally act locally in a paracrine or an autocrine manner rather than in an endocrine manner.
Signal molecules that act to control cell growth and differentiation in the receptor-dependent fashion. The alterations of these proteins lead to transformation and the accompanying loss in growth control. Some of the growth factors and their receptors are involved in the products of oncogens.
Genes that can convert cells to cancerous growth by attacking crucial cellular machinery. They encode for growth factors, growth-factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. These genes are constitutively expressed after structural and /or regulatory changes, resulting in uncontrolled cell proliferation. They can be classified into viral oncogenes (v-oncogenes) and cellular oncogenes (proto-oncogenes).
Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase is expressed in the testis and ovary, but repressed in normal human somatic tissues. Telomerase activity is seen in more than 90% of human cancers.
Genes inhibit expression of the tumorigenic phenotype. They are normally involved in holding cellular growth in check. When tumor-suppressor genes are inactivated or lost, a barrier to normal proliferation is removed, leading to unregulated growth.
A large number of molecular events are involved in the development and progression of gastrointestinal carcinomas. Among them, common and distinct events of genetic and epigenetic alterations in oncogenes, tumor-suppressor genes, cell adhesion molecules, DNA repair genes, and genetic instability as well as telomerase activation are observed in esophageal, gastric, and colorectal cancers. In gastric cancer, the pattern of genetic and epigenetic alterations also differs depending on the two histological types, intestinal type or well-differentiated type and diffuse type or poorly differentiated type, indicating that there are two distinct major genetic pathways for gastric carcinogenesis.
In addition to these events, gastrointestinal cancer cells express a broad spectrum of the growth factor/cytokine receptor systems that organize complex cancer-stromal interaction, which confer cell growth, apoptosis, morphogenesis, angiogenesis, progression, and metastasis. However, these abnormal growth factor/cytokine networks also are different among esophageal, gastric, and colorectal cancers, respectively. Importantly, NF-[kappa]B activation induced by inflammation may act as a key player for induction of growth factor/cytokine network in gastrointestinal cancers.
Multiple genetic and epigenetic alterations in oncogenes, tumor-suppressor genes, cell cycle regulations, cell adhesion molecules, DNA repair genes and genetic instability as well as telomerase activation are responsible for the multistep process of human gastrointestinal carcinogenesis. However, a scenario or particular combination of these alterations differs in esophageal, gastric, and colorectal cancers. Namely, common and distinct molecular events are observed in esophageal, gastric, and colorectal cancers, respectively. Moreover, two types of gastric cancer, well-differentiated or intestinal type, and poorly differentiated or diffuse-type carcinomas also exhibit a distinct pattern of genetic pathways.
Besides these genetic and epigenetic events, gastrointestinal cancer cells express a broad spectrum of growth factors, cytokine or both, including epidermal growth factor (EGF) family, transforming growth factor (TGF)-?, heparin binding (HB)-EGF, PDGF, IGF, basic fibroblast growth factor (FGF), interleukin (IL)-1[alpha], IL-6, IL-8 and osteopontin (OPN). These growth factors and cytokines act as autocrine, paracrine, and juxtacrine modulators of the growth of cancer cells, and then organize complex interplay between cancer cells and stromal cells, which plays an important role in cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. Interestingly, the expression of these growth factors, cytokines or both by cancer cells is also different among esophageal, gastric, and colorectal cancers.
This article will provide an overview of the molecular machinery that underlies gastrointestinal carcinogenesis and focuses on abnormal growth factor/cytokine network in gastrointestinal cancers.
2 Genetic and Epigenetic Alterations and Abnormal Growth Factor/Cytokine Network in Esophageal Cancer
Esophageal cancer is the third most frequent gastrointestinal cancer in the world. The most recent estimates are that esophageal cancer is the sixth most common cancer in men (212 600 new cases, 4.9% of all cancers) and the ninth most common in women (103 200 new cases, 2.7% of all cancers). The two main histological types of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma, but SCC is the more prevalent type worldwide. The development of esophageal SCC exhibits a multistep, progressive process. An early indicator of this process is an increased proliferation of esophageal epithelial cells including basal cell hyperplasia, dysplasia, and carcinoma in situ. Thismultistep process requires the accumulation of multiple genetic and epigenetic alterations and overexpression of growth factors/cytokine receptor systems, leading to the evolution of clonal cell populations that possess growth advantages over other cells as demonstrated in the progression model of head and neck cancer. This paragraph thus will describe recent advances in molecular dissection of multi-step tumorigenesis of esophageal SCC and abnormal growth factor/cytokine network that contributes to the development and progression of esophageal SCC.
2.1 Genetic and Epigenetic Alterations in Esophageal SCC
Numerous genetic and epigenetic alterations are implicated in the development and progression of esophageal SCC (Table 1). This cancer is frequently associated with loss of heterozygosity (LOH) at multiple chromosomal loci including 3p, 5q, 9p, 9q, 13q, 17p, 17q, and 18q. No significant differences have been found in the prevalence of LOH at various loci in SCC and adenocarcinoma of the esophagus.
Among these alterations, LOH and mutation of the p53 gene at chromosome 17p13 occur at an early stage of esophageal carcinogenesis, such as dysplasia and carcinoma in situ. About 50% of esophageal SCC harbor mutations of the Tp53 gene, most of which are missense mutations leading to amino acid changes within exons 5-8, which encode the entire DNA binding domain of the p53 molecule and the flanking splice sites. Considering the Growth Factors and Oncogenes in Gastrointestinal Cancers 5 base substitution spectrum, G:C to T:A transversion is common in esophageal carcinoma, similar to that in carcinomas of the lung and liver. This situation is different from the finding that colorectal carcinomas frequently contain G:C to A:T transitions at CpG dinucleotides. This evidence suggests that different environmental and intrinsic factors may affect the tumorigenesis of esophageal and colorectal carcinomas. It is of interest that LOH of the APC, DCC, and Rb genes shows high frequency but these genes are very rarely or never mutated in esophageal SCC.
The retinoic acid receptor (RAR) ? gene is a putative tumor-suppressor gene on chromosome 3p24, where a high frequency of LOH is found in many human cancers, including esophageal cancer. The human RAR? has three isoforms (?1, ?2, ?4). Overexpression of RAR?2 induces inhibition of tumor cell growth and apoptosis in human cancer cell lines including esophageal cancer cells. Moreover, Induction ofRAR?2 suppresses cyclooxygenase-2 (COX2) expression in esophageal cancer cells. More importantly, DNA methylation of RAR?2 promoter CpG sites has been reported to cause the loss of RAR?2 expression in many human cancers including lung, breast, prostate, stomach, head and neck, and esophageal cancers. RAR? is expressed in 90% of normal esophageal mucosa, while it is detected in only 60% of dysplastic lesions and in 50% of SCC. These findings indicate that loss of RAR?, or more specifically, the isoform?2, is an early event associated with esophageal carcinogenesis and the status of squamous differentiation.
p16, an inhibitor of cyclin D1/cyclindependent kinase, is located on chromosome 9p21. It is inactivated by 9p21LOH with de novo p16 promoter hypermethylation in the majority of esophageal SCC. Recent molecular analysis of precancerous laryngeal lesions suggests that loss of p16 protein is an early step toward malignant transformation in head and neck tissues. This protein forms binary complexes with CDK4 and CDK6, inhibiting their ability to phosphorylate the Rb protein. Loss of the p16 protein may bring about increased Rb phosphorylation and allow cells to enter into S-phase. In fact, we have confirmed that homozygous deletion of the p16 gene is closely correlated with the increased expression of cyclin D1, CDK4 and phosphorylated Rb protein in esophageal SCC cell lines.
In 1989, we discovered the coamplification of hst-1 and int-2, both of which are located on chromosome 11q13, in about 50% of primary tumors and in 100% of metastases of esophageal SCC. Gene amplification, however, was not accompanied by overexpression of the two genes. Subsequently, Jiang et al. found that the cyclin D1, which is located on the same locus as hst-1 and int-2 genes, was amplified in 32% of SCC, associated with overexpression. The amplification of the cyclin D1 is closely correlated with tumor staging, depth of tumor invasion, and metastasis. In the esophagus, 71% of SCC and 64% of adenocarcinoma are positive for increased cyclin D1 nuclear staining, indicating that overexpression of cyclin D1 is common in both types of cancer. Cyclin D1 binds to Rb protein and stimulates its phosphorylation. Hyperphosphorylation of Rb in response to overexpressed cyclin D1 may lead to uncontrolled cell cycling and increased cell proliferation.
As for oncogene activation, amplification of the EGF receptor (EGFR) gene occurs in 10-15% of advanced cases of esophageal SCC, accompanied by overexpression of EGFR. The frequency of K-ras mutation is very low in esophageal SCC, whereas it takes place in 50% of sporadic colorectal carcinoma. c-erbB2 is amplified in esophageal adenocarcinoma but not in esophageal SCC. Recently, Inazawa's group reported that ZASC1 encoding a Kruppel-like zinc finger protein is involved in the pathogenesis of esophageal SCC as one of the targets for 3q26 amplification. CIAP1, a number of the IAP (antiapoptotic) gene family, may also be a target for 11q22 amplification.
Telomerase, a ribonucleoprotein enzyme, is necessary for cancer cells to maintain their telomere and to become immortal. Results of a 1998 study on cell immortalization show, however, that activation of telomerase alone is not enough to immortalize certain epithelial cells, and that inactivation of the p16/Rb pathway is needed. More than 80% of gastrointestinal carcinomas exhibit high level of telomerase activity and overexpression of human telomerase reverse transcriptase (hTERT). The expression of hTERT is closely associated with activation of telomerase in vitro and in vivo. It is of interest to note that telomerase activity as well as hTERT expression is detected in about 45% of dysplasia and in 90% of SCC of the esophagus. Telomerase activation may also play a critical role in early stage of esophageal SCC.
Recently, Chen et al. reported that LOH at 13q 33-34 including ING1, a candidate tumor-suppressor gene, was observed in about 60% of esophageal SCC, associated with mutation as well as loss of ING1 protein. ING1, a novel growth inhibitor, cooperates directly with p53 in growth regulation by modulating the ability of p53 to act as a transcriptional activator. Genetic or epigenetic alterations in ING1 may be also involved with esophageal SCC. Sonoda et al. reported that loss of LRP1B (low density lipoprotein receptor-related protein 1B) often occurs in esophageal SCC.
These results overall indicate that accumulation of the above-mentioned genetic and epigenetic alterations is involved in the multistep carcinogenesis and progression of esophageal SCC. Inactivation of tumor-suppressor genes on 3p (ex. RAR?2) and p53, and telomerase activity may be important for converting normal stratified squamous epithelium to dysplasia. Because p16 inactivation and 9q LOH are found occasionally in mild dysplasia, but frequently in severe dysplasia and in carcinoma in situ, these alterations may have implications for transformation to malignancy. Amplification of cyclin D1and EGFR genes, inactivation of tumor-suppressor genes on 5q, 13q, and 18q, and abnormal expression of growth factor/ cytokine receptor system may confer progression and metastasis of esophageal SCC. The genetic progression model of esophageal SCC (Fig. 1) is quite similar to that of head and neck SCC
2.2 Abnormal Growth Factor/Cytokine Network in Esophageal SCC
Esophageal SCC cells express a variety of growth factor/ receptor and cytokines including the EGF family, PDGF, transforming growth factor ? (TGF?), interleukin (IL)-1[alpha] and IL-6. Among them, the EGF/TGF[alpha] receptor system plays a major role in the cell growth and progression of esophageal SCC through signaling of receptor-linked tyrosine kinases.
Excerpted from Encyclopedia of Molecular Cell Biology and Molecular Medicine, 16 Volume Set by Robert A. Meyers Copyright © 2006 by Robert A. Meyers. Excerpted by permission.
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