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The Oncologist, Vol. 12, No. 10, 1165-1177, October 2007; doi:10.1634/theoncologist.12-10-1165
© 2007 AlphaMed Press

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Gastrointestinal Cancer

Activation of Growth Factor Receptors in Esophageal Cancer—Implications for Therapy

Simon Ekmana, Michael Bergqvista, Carl-Henrik Heldinb, Johan Lennartssonb

aDepartment of Oncology, University Hospital, Uppsala, Sweden; bLudwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden

Key Words. Esophageal squamous cancer • Targeted therapy • Growth factor receptors • Esophageal adenocarcinoma

Correspondence: Simon Ekman, M.D., Ph.D., Department of Oncology, Uppsala University Hospital, S-751 85 Uppsala, Sweden. Telephone: 46-18-611-2259; Fax: 46-18-611-5528; e-mail: Simon.Ekman{at}onkologi.uu.se

Received April 23, 2007; accepted for publication July 24, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
 References
 
Esophageal cancer is a highly aggressive disease and is the seventh most common cause of cancer-related death in the western world. Worldwide, it ranks as the sixth most frequent cause of cancer death. Despite advances in surgical techniques and treatment, the prognosis of esophageal cancer remains poor, with very few long-term survivors. The need for novel strategies to detect esophageal cancer earlier and to improve current therapy is urgent.

It is well established that growth factors and growth factor receptor–mediated signaling pathways are important components of the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are emerging possibilities to use growth factor signal transduction pathways in targeted therapy. This review provides a summary of the role of growth factors and their receptors in esophageal cancer and discusses their potential roles as biomarkers and as targets in therapy.


   INTRODUCTION
Top
 Abstract
 Introduction
Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
 References
 
Esophageal carcinoma is the sixth most common cause of cancer-related death, and 462,000 new cases were diagnosed during 2002 [1, 2]. The dominant presenting symptom of esophageal carcinoma is dysphagia, which is present in approximately 70% of all patients at diagnosis [3]. Histologically, esophageal cancer can be divided into adenocarcinoma and squamous cell carcinoma. Known risk factors for squamous cell cancer include smoking, alcohol, and achalasia, while Barrett's esophagus predisposes to adenocarcinoma. The relative incidence of adenocarcinoma has increased from 10% to 25% of all esophageal cancers over the last decade. The causes of esophageal adenocarcinoma are not well known; thus, reasons for the increasing incidence are not clear, but hypotheses include population trends in obesity that increase the risk for gastroesophageal reflux, as well as the continuing decline in Helicobacter pylori infections [4].

Survival rates are poor for patients with esophageal carcinoma. One contributing factor to the poor prognosis is the fact that the majority of patients do not seek medical attention until the tumor has already gained substantial volume or even disseminated [5]. Only a subpopulation of patients seems to benefit from treatment, which is generally either surgery or a combination of radiation and chemotherapy for localized tumors. The development of new surgical techniques and better postoperative care has improved the prognosis for patients undergoing surgery as the sole treatment, with 2-year survival rates in the range of 35%–42% and 5-year survival rates of 15%–24% [3]. The combination of radiotherapy and concurrent chemotherapy with cisplatin and fluorouracil has led to long-term survival in approximately 25% of patients, an outcome similar to that associated with surgery alone. In a recent meta-analysis of survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in esophageal carcinoma, Gebski et al. [6] demonstrated a significant survival benefit for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the esophagus. However, patients with advanced metastatic disease that are treated with palliative chemotherapy have a median survival duration of <1 year, and the 5-year survival rate of all diagnosed patients is only 14%. Thus, there is a need for novel strategies to detect esophageal cancer earlier, which may be more appropriate in high incidence areas such as China, and to improve current therapy. Subversion of growth factor–mediated signaling pathways is an important event in the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are emerging possibilities to use antagonists of growth factor signal transduction pathways in targeted therapy (Table 1). This review summarizes the role of growth factors and their receptors in esophageal cancer, and discusses their potential usefulness as biomarkers and as targets for novel therapy.


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  		Table 1. Signal transduction inhibitors in clinical use: Examples of drugs targeting different growth factors and their receptors and mechanisms of action

 

   GROWTH FACTOR SIGNALING
Top
 Abstract
 Introduction
 Growth Factor Signaling
The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
 References
 
Growth factors are polypeptide molecules that regulate many cellular responses, most notably cell proliferation. They exert their effects on the cell by binding to specific receptors on the cell surface; many of these receptor types are activated by ligand-induced receptor dimerization [7]. Growth factor receptors are often associated with tyrosine kinase activity, either intrinsically or by forming a complex with an intracellular tyrosine kinase. The interaction of the growth factors with the receptors leads to activation of their tyrosine kinase activities and phosphorylation of specific residues in the intracellular parts of the receptors. These phosphorylated tyrosine residues then act as docking sites for downstream signal transduction molecules containing Src homology 2 (SH2) domains (for a review, see Pawson et al. [8]), activating signaling pathways that alter gene-expression patterns, thus influencing cell proliferation and survival; if deregulated, these pathways can promote tumorigenesis (Figure 1).


Figure 1
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  		Figure 1. Schematic presentation of growth factor–mediated signaling pathways. The picture illustrates signaling pathways downstream of PDGF receptors, activated by ligand-induced dimerization. Other tyrosine kinase receptors induce similar pathways. Arrows indicate activation; inhibitory interactions are indicated by blunted lines.

Abbrevations: DAG, diacyl glycerol; ERK, extracellular signal–related kinase; GAP, GTPase activating protein; Grb2, growth factor receptor–bound 2; IP3, inositol phosphate 3; Jak, janus kinase; KSR, kinase suppressor of RAS; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MKP, MAP kinase phosphatase 1; PDGF, platelet-derived growth factor; PDK1, phosphoinositide-dependent kinase 1; PI3-K, phosphatidyl inositol 3'-kinase; PIP2(3), phosphatidyl inositol phosphate 2(3); PKC, protein kinase c; PLC-{gamma}, phospholipase C-{gamma}; SHP2, SH2 domain-containing tyrosine phosphatase 2; Sos, son of sevenless; STAT, signal transducer and activator of transcription.

 
Aberrant regulation of growth factors or their receptors can occur in many different forms during tumorigenesis. In some cases, the cells produce a growth factor for which they carry the corresponding receptor, resulting in autocrine stimulation of the receptors. In addition, tumor cells may also be stimulated by growth factor receptor ligands derived from the stromal compartment, so-called paracrine stimulation. This intercellular communication involves interactions among tumor cells, hematopoietic cells, blood vessels, and extracellular matrix fibers. In other cases, the receptors are present in too great a quantity or carry mutations, rendering them constitutively active even in the absence of growth factor. There are also chromosomal translocations giving rise to fusion proteins between a growth factor receptor and another protein, leading to ligand-independent dimerization and activation of the receptor. Furthermore, there exist examples of tumors in which intracellular components that would normally be controlled by growth factors are overactive, thus promoting cell proliferation.

There are several approaches used to inhibit growth factor signaling, including neutralizing antibodies against growth factors or recombinant ligand binding domains acting as ligand traps, blockade of growth factor receptors by receptor antibodies or low molecular weight inhibitors targeting receptor tyrosine kinases and downstream signal transduction pathways, or small interfering RNA (siRNA) (Fig 2). The technique of siRNA is based on the fact that by introducing short double-stranded RNA into the cell it is possible to specifically silence the expression of a gene containing a complementary nucleotide sequence. The efficacy of these methods has been tested in various tumor models.


Figure 2
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  		Figure 2. Different therapeutic strategies to interfere with growth factor–mediated cell signaling.

 

   THE HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR FAMILY
Top
 Abstract
 Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
 References
 
The human epidermal growth factor receptor (HER) family of growth factor receptors is comprised of four members, that is, EGFR (HER-1, ErbB-1), HER-2 (ErbB-2, Neu), HER-3 (ErbB-3), and HER-4 (ErbB-4) [9]. These receptors are tyrosine kinases that are activated by ligand-induced dimerization. There are several ligands for the receptors in the HER family, and these have different binding specificities, resulting in formation of homo- or heterodimeric receptor complexes. Interestingly, HER-2 does not have a ligand but is used as a heterodimeric partner by the other receptors. However, overexpression of HER-2 may induce formation of homodimers, and in fact HER-2 has oncogene properties when overexpressed. HER family members are commonly activated in several cancers [10] by autocrine stimulation, by mutations, or by overexpression. A consequence of unregulated and improper receptor activation is induction of signals that promote proliferation, survival, migration, and angiogenesis—events that are all central for tumor development and progression.

The Role of EGFR in Esophageal Cancer
EGFR is often overexpressed in esophageal cancers, both squamous cell carcinoma and adenocarcinoma, which in certain cases also express the ligands EGF or transforming growth factor {alpha} (TGF-{alpha}), establishing autocrine growth-promoting loops [11–20]. In fact, EGFR overexpression has been demonstrated to correlate with poor prognosis [16, 21–24]. However, not all studies have found such a connection [19].

The EGF and TGF-{alpha} ligands serve as mitogens for esophageal tumor cells [25]. It has been shown that EGF may also have an antiproliferative effect on some esophageal cancer cells, which is dependent on the presence of EGFR [26]. This growth inhibitory ability of EGF has been suggested to involve signaling through the signal transducer and activator of transcription 1 (STAT-1) pathway [27, 28], possibly through STAT-1–mediated upregulation of the p21WAF1/CIP1 cyclin-dependent kinase inhibitor [29]. Thus, loss of STAT-1 may increase the malignancy of the tumor.

Activation of EGFR signaling has been implicated in metastasis via modulation of cell adhesion, angiogenesis, invasion, and migration. For example, it has been observed in some, but not all, esophageal tumor cell lines that activation of EGFR may increase the expression of matrix metalloproteases (MMPs), which are important for the degradation of the extracellular matrix that is necessary for tumor invasion and metastasis [30, 31]. Moreover, in the esophageal cancer cell line TE-2R it was shown that EGF induces relocalization of E-cadherin from the lateral adhesion sites to a more uniform distribution over the cell surface, which was correlated with changed cell morphology and increased invasiveness [32]. In a recent report from Wijnhoven et al. [33], p120-catenin, a component of the E-cadherin–catenin cell–cell adhesion complex, was found to be lost from the cell surface as the disease progressed from Barrett's metaplasia to tumor formation and lymph node metastasis. Furthermore, reduced p120-catenin expression correlated with poor prognosis, which may be a result of a greater tendency of the tumor to form metastases. In addition, EGF can increase the expression of {alpha}2ß1 and {alpha}3ß1 integrins in esophageal cells overexpressing EGFR, which may lead to greater adhesion of the tumor cell to the vessel wall, and thus promote metastasis [34]. The adaptor protein growth factor receptor–bound protein 7 (Grb7) was first identified as a protein interacting with activated EGFR [35]. Grb7 shows homology with the C. elegans protein Mig-10, which is involved in migration of neuronal cells during embryonic development [36]. Interestingly, Grb7 was found to be overexpressed in metastatic esophageal cancer [37]. Moreover, a novel splice form of Grb7, denoted Grb7V, has been found in invasive esophageal carcinoma [38]. Reducing Grb7 expression using antisense oligonucleotides decreased the invasive phenotype of the esophageal carcinoma cells.

Strategies attempting to therapeutically target the EGFR include antibodies binding to the extracellular domain, such as cetuximab, or low molecular weight inhibitors blocking the kinase activity, such as gefinitib (Iressa®; AstraZeneca Pharmaceuticals, Wilmington, DE) and erlotinib (Tarceva®; Genentech, Inc., South San Francisco, CA). In a phase II study of cetuximab in combination with 5-fluorouracil, leucovorin, and irinotecan (the FOLFIRI regimen) in patients with untreated gastric or gastroesophageal junction (GEJ) adenocarcinoma, Pinto et al. [39] demonstrated activity of this treatment in both nonintestinal and intestinal adenocarcinoma with similar overall response rates (41.6% and 45.4%, respectively). No correlation between the EGFR expression level in the target tumor and treatment activity was found, a result in agreement with another study in metastatic colorectal cancer [40]. Investigating cetuximab as a potential radiation sensitizer in patients with esophageal adenocarcinoma or squamous cell carcinoma, a phase II trial showed that, compared with other trials of irinotecan, cisplatin, radiation therapy, and surgery in similar groups of esophageal cancer patients, adding cetuximab to this treatment combination resulted in a lower complete response rate and higher overall toxicity [41]. However, another study evaluated the safety and efficacy of the addition of cetuximab to concurrent chemoradiation for patients with esophageal and gastric cancer, and concluded that cetuximab can be safely administered with chemoradiation for patients with esophageal cancer [42]. Other EGFR antibodies include matuzumab, for which Trarbach et al. [43] reported on a phase I study in combination with cisplatin, 5-fluorouracil, and leucovorin in patients with advanced esophagogastric (EG) adenocarcinoma, concluding that this combination treatment demonstrated some promise of antitumor activity and might be well tolerated in the first-line treatment of these patients. In a phase I trial by Vanhoefer et al. [44], treatment with matuzumab, in patients with advanced solid tumors expressing EGFR, was well tolerated, and it showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors, including one of two patients with esophageal cancer demonstrating a partial response (PR). A recent trial, the MATRIX EG (Matuzumab Treatment with ECX in Esophago-Gastric Cancer) phase II study, evaluated matuzumab in combination with epirubicin, cisplatin, and capecitabine (the ECX regimen) as first-line treatment in patients with metastatic esophagogastric adenocarcinoma, and data from that trial are pending. Panitumumab (ABX-EGF), a fully human IgG2 monoclonal antibody (mAb), is another high-affinity anti-EGFR mAb that is in clinical development. Results from the initial phase I study revealed that one patient with esophageal cancer had stable disease (SD) for 7 months [45].

Gefitinib has been shown to induce growth arrest of human esophageal cancer cell lines [46, 47]. Teraishi et al. [46] found no correlation between response to gefitinib and the level of EGFR expression, but in gefitinib-responsive cells they observed a dose-dependent increase in cell cycle arrest at the G1 phase. Moreover, the antitumor effect of the death receptor ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) was enhanced by gefitinib treatment, even in cells considered to be TRAIL resistant [46]. The mechanism for this was shown to involve inhibition of EGFR-mediated Akt phosphorylation by gefitinib, leading to Bcl-xL inactivation and caspase-9 activation, thereby promoting apoptosis of cells through a mitochondrial-dependent apoptotic pathway. Importantly, gefitinib has been demonstrated to increase the effect of radiotherapy; the mechanism for this is believed to be inhibition of the Akt and extracellular signal–related kinase survival pathways downstream of the EGFR and subsequent sensitization of the cell to radiation-induced apoptosis [48]. In an abstract presented at the American Society of Clinical Oncology 2004 Annual Meeting, Ferry et al. [49] reported on a phase II trial of gefitinib in advanced adenocarcinoma of the esophagus, revealing that gefitinib is an active treatment with a disease control rate (PR or SD) of 58%. Recently, Janmaat et al. [50] published the results of a phase II trial in which gefitinib was given to advanced esophageal cancer patients. Unfortunately, gefitinib had only limited antitumor activity. However, female patients with high EGFR expression or squamous cell carcinoma showed a better response.

Furthermore, a mutation in the kinase domain of EGFR, S768I, that confers greater sensitivity toward gefitinib in esophageal carcinoma cell lines has been found in fresh frozen tissue from primary esophageal carcinoma, as well as in the esophageal cancer cell line KYSE-450 [51]. Although more primary esophageal tumors remain to be screened for mutations in the tyrosine kinase domain of EGFR, gefitinib may be worth further investigation as a potential therapeutic intervention for esophageal cancers. Thus, future clinical trials may benefit from patient selection based on tumor type, EGFR expression, and the presence of this mutation.

Erlotinib is a low molecular weight inhibitor targeting the enzymatic activity of EGFR. Studies on esophageal cancer cell lines have demonstrated a growth inhibitory effect of erlotinib [52]. Two different phase II trials have reported on the effect of erlotinib in esophageal and GEJ cancers, respectively. In a 22-patient cohort with metastatic, pretreated esophageal squamous cell carcinoma or adenocarcinoma, Tew et al. [53] demonstrated a disease control rate of 54.5% (PR, 9%; SD, 45.5%) using erlotinib, 150 mg daily. Both patients with PRs had squamous cell histology and EGFR overexpression. In a Southwest Oncology Group trial, patients with gastric or GEJ adenocarcinomas were treated with erlotinib, 150 mg daily [54]. In the GEJ stratum with 43 patients, the results showed one complete response, three confirmed PRs, and five SDs (including one unconfirmed PR), giving an overall response rate of 9%. All responses occurred in the GEJ stratum. No EGFR mutations were found in either study. A recent phase I trial using erlotinib in combination with radiation, 5-fluorouracil, and cisplatin showed that this combination therapy was tolerated [55]. Furthermore, a phase II trial has now been initiated at the Sarah Cannon Research Institute, evaluating erlotinib in the neoadjuvant setting, with the aim of studying preoperative concurrent chemotherapy and radiation therapy plus bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA) and erlotinib in the treatment of localized esophageal cancer. In conclusion, it is possible that the combination of EGFR kinase inhibitors and mAbs may give positive results as sensitizers for classic radio- or chemotherapy.

The Role of HER-2 in Esophageal Cancer
The data on HER-2 expression in esophageal cancer are variable, with most reports showing HER-2 overexpression in 9%–60% of cases [19, 22, 56–63], whereas other studies have failed to observe HER-2 expression [64]. The differences among reported overexpression rates might depend on stage of the disease, tumor histology (adenocarcinoma versus squamous cell carcinoma), or methodology, that is, interpretation of immunohistochemistry results. Furthermore, there are reports indicating that HER-2 expression may change during tumor progression. For example, Sauter et al. [65] reported that HER-2 expression is lost during the development of esophageal adenocarcinomas from normal epithelium. Other studies proposed that HER-2 overexpression is a late event in the formation of esophageal adenocarcinomas [66–68]. Clearly, more work is warranted to clarify the expression of HER-2 in different types and stages of esophageal cancer.

The relationship between HER-2 expression and the prognosis of patients with esophageal cancer is not clear. It has been demonstrated that HER-2 overexpression correlates with tumor invasion and lymph node metastasis, and thus indicates a poor prognosis [68–71]. Akamatsu et al. [72] found HER-2 expression to be a predictor of chemoresistance in esophageal squamous cell carcinoma. In contrast, others have shown that HER-2 expression predicts a favorable response to chemo- or radiotherapy and thus improves survival [73]. The reasons for these contradictory results need to be addressed in future studies. It has been proposed that coexpression of the adaptor protein Grb7 and HER-2 may contribute to an invasive tumor phenotype [37, 67], consistent with a role for Grb7 in cell migration.

HER-2 can be used as a therapeutic target using humanized mAbs such as trastuzumab (Herceptin®; F. Hoffmann-La Roche, Basel, Switzerland) and pertuzumab (Omnitarg®; Genentech, Inc., South San Francisco, CA). Studies on esophageal cell lines have suggested cytotoxic as well as growth inhibitory effects of trastuzumab in both adenocarcinoma and squamous cell carcinoma cell lines [60, 74, 75]. Furthermore, in a phase I trial on esophageal adenocarcinomas, Safran et al. [61] studied trastuzumab given in combination with cisplatin, paclitaxel, and radiation. HER-2 expression was evaluated by immunohistochemistry, and HER-2–positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab, whereas HER-2–negative patients received the same chemoradiation without trastuzumab. Results showed that 12 of 36 screened patients (33%) overexpressed HER-2 by immunohistochemistry, and the correlation between the intensity of immunohistochemistry staining and the number of HER-2 genes by fluorescence in situ hybridization is similar in esophageal adenocarcinoma and breast cancer. In this small study, it was not possible to estimate whether the addition of trastuzumab improved locoregional or distant control. The authors concluded that full-dose trastuzumab can be incorporated with paclitaxel, cisplatin, and radiation without cardiotoxicity or a higher incidence of esophagitis. Thus, in addition to their use in isolation, HER-2–targeting agents may also act as sensitizers for conventional chemo- or radiotherapy.

Lapatinib is an oral tyrosine kinase inhibitor (TKI) that targets both EGFR and HER-2 [76] and has been shown to inhibit the growth of tumor cells overexpressing these receptors, both in vitro and in vivo. Phase II and phase III studies investigating lapatinib treatment of breast cancer in various stages are currently being performed with promising results (reviewed by Johnston and Leary [77]). A phase II trial using lapatinib for metastatic or recurrent esophageal squamous cell carcinoma is ongoing at the University of Michigan Cancer Center, and another phase II study run by GlaxoSmithKline is examining the efficacy and safety of lapatinib in patients with HER-2–positive tumors, including esophageal adenocarcinoma.


   INSULIN-LIKE GROWTH FACTOR-1
Top
 Abstract
 Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
 References
 
Insulin-like growth factor-1 (IGF-1) exerts its cellular effects by binding to the {alpha}-subunit of the IGF-1 receptor (IGF-1R), resulting in the activation of the receptor kinase of the ß-subunit of the receptor and autophosphorylation of tyrosine residues in its intracellular part. IGF-1R is important for the growth of malignant cells and for the prevention of apoptosis. Several oncogene products depend on intact IGF-1R to achieve their transforming activity [78]. The abundant expression of IGF-1R in cancer cells and tissues combined with its crucial roles in cancer cell growth makes this receptor an attractive target for therapy of malignant diseases.

The Role of IGF-1 in Esophageal Cancer
Tumor cells of esophageal cancer have been shown to express the IGF-1R [79, 80], but its contribution to the malignant phenotype has still not been completely investigated. Chen et al. [17] demonstrated overexpression of IGF-1R and found evidence suggestive of autocrine growth regulation of esophageal carcinoma cells. Later, Liu and coworkers suggested that an IGF-1 autocrine system in human esophageal carcinoma cells could stimulate tumor growth [80]. They also found that IGF-1 prevented the apoptosis of esophageal carcinoma cells induced by chemotherapeutic drugs, such as cisplatin, 5-fluorouracil, and camptothecin. Oku et al. [25] also established IGF-1 as an important mitogen for human esophageal cancer cells. They showed that the growth of esophageal cancer cells in a protein-free medium was significantly stimulated by insulin and IGF-1 or IGF-2. Moreover, the growth induced by IGF-1, IGF-2, or insulin was markedly inhibited by an anti-IGF-1R antibody. In a study on Barrett's neoplasia, Iravani et al. [81] found indications that expression levels of three different proteins, including IGF-1R, are coordinately elevated in Barrett's-associated neoplasia, suggesting an important role in the malignant progression of Barrett's-associated neoplasia.

Sohda et al. [82] found that serum IGF-1 and IGF binding protein-3 levels were significantly elevated in patients with esophageal cancer. There was a significant correlation between IGF-1 level and depth of tumor invasion and pathological stage. Poor prognosis was significantly correlated with increasing IGF-1 levels. The survival rate of patients with high IGF-1 expression in immunohistochemical analyses was poorer than that of low expression patients [82].

Various approaches have been used to inhibit the function of IGF-1R in malignant cells.

Targeting of IGF-1R signaling may be achieved by interference with ligand–receptor interactions, receptor synthesis and expression, receptor tyrosine kinase activity, or combinations of these strategies. The strategies include the use of neutralizing antibodies, dominant negative receptor, IGF-1R antisense/siRNA, as well as small molecule receptor TKIs. Preclinical studies of IGF-1R–targeting strategies have provided evidence of efficacy comparable with that obtained for other antineoplastic strategies that have subsequently been found to be clinically useful. So far, three different phase I studies using human mAbs against IGF-1R in patients with advanced solid tumors have been reported, indicating mild and clinically manageable treatment-related toxicities and giving promise for future clinical trials [83–85].


   PLATELET-DERIVED GROWTH FACTOR
Top
 Abstract
 Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
Vascular Endothelial Growth...
 Conclusions
 References
 
Platelet-derived growth factor (PDGF) exerts its effects on target cells through interaction with {alpha}- and ß-receptors that are equipped with tyrosine kinase activities (for a review, see Heldin et al. [86]). PDGF is a family of dimeric isoforms of related A-, B-, C-, or D-polypeptide chains. The B- and D-chains bind to ß-receptors with high affinity, and the A-, B-, and C-chains bind to {alpha}-receptors. Thus, the different PDGF isoforms induce different dimeric receptor complexes; {alpha}{alpha} receptor dimers can be formed by PDGF-AA, PDGF-AB, PDGF-BB, and PDGF-CC, {alpha}ß receptor heterodimers by PDGF-AB and PDGF-BB, and ßß receptor dimers by PDGF-BB and PDGF-DD. In addition, PDGF-CC and PDGF-DD have been shown to activate ß- and {alpha}-receptors, respectively, in cells expressing both receptor types [87–90]. The PDGF-AB isoform has been reported to possess the strongest ability to induce a mitogenic response in cells expressing both {alpha}- and ß-receptors [91, 92].

The Role of PDGF in Esophageal Cancer
The role of PDGF and its receptors in esophageal cancer is still unclear. PDGF isoforms are important mitogens for mesenchymal cells. PDGF receptors (PDGFRs) are not normally expressed in epithelial cells under normal physiological conditions. However, Liu et al. [93] found that PDGF-BB induced c-Jun expression and promoted the growth of a human esophageal carcinoma cell line. Their results suggest autocrine PDGF stimulation, providing a growth advantage and also preventing apoptosis, of esophageal carcinoma cells. Another study used immunohistochemical analyses to show that the expression level of PDGFR-ß is significantly higher in tumor tissues than in normal tissues [94].

Another study also used immunohistochemical analyses to show that the expression level of PDGFR-ß is significantly higher in tumor tissues than in normal tissues [22]; in gastric carcinomas, the expression of PDGFR-ß was detected in 53% of the tumor tissues and its expression was closely related to the occurrence of fibrous stroma in the tumor [95], which was not the case in the esophageal carcinomas. On the other hand, analyses of PDGFR expression in a panel of esophageal squamous carcinoma cell lines could not demonstrate significant expression at the protein level (unpublished results).

The importance of PDGF in relation to esophageal cancer has not yet been tested in a therapeutic setting. However, inhibition of the PDGFR tyrosine kinase is part of treatment strategies in other forms of tumors. In 1996, Druker et al. [96] reported the development of the experimental drug CGP57148B, which is known as imatinib mesylate (Gleevec®; Novartis Pharmaceuticals Corporation, East Hanover, NJ). Imatinib inhibits the Abl tyrosine kinase [96, 97] as well as PDGFRs and the stem cell factor receptor (Kit). It has demonstrated considerable activity in chronic myeloid leukemia by inhibiting the breakpoint cluster region–Abelson (BCR-ABL) fusion protein, and in gastrointestinal stromal tumors (GISTs), which are predominantly driven by activating mutations in Kit. Sunitinib malate (Sutent®; Pfizer, Inc., New York), a multitargeting TKI that potently inhibits vascular endothelial growth factor receptors (VEGFRs) and PDGFRs, was recently approved for the second-line treatment of patients with metastatic renal cell carcinoma (RCC), as well as GIST. Another TKI, sorafenib (Nexavar®; Bayer Pharmaceuticals Corporation, West Haven, CT), inhibits the activity of VEGFR-2, VEGFR-3, PDGFR-ß, Flt-3, and c-Kit, as well as several Raf isoforms, and it also has been approved for the treatment of metastatic RCC [98]. However, the importance of the above-mentioned tyrosine kinase inhibitors in the treatment of esophageal cancer remains to be established.


   VASCULAR ENDOTHELIAL GROWTH FACTOR
Top
 Abstract
 Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
Conclusions
 References
 
The VEGF family consists of several closely related members, including VEGF-A, VEGF-B, VEGF-C, and VEGF-D as well as placental growth factor. VEGF-A, normally referred to as VEGF, is the most potent endothelial growth factor. VEGF regulates vascular permeability and proliferation and is also believed to interfere with apoptosis, thus providing antiapoptotic protection to endothelial cells [99]. Direct VEGF stimulation of tumor cells in an autocrine or paracrine fashion results in tumor cell proliferation, increased survival, and migration. Tumor blood vessels formed under the influence of VEGF are disorganized and leaky, resulting in high interstitial pressure and reducing access for chemotherapies. Inhibiting VEGF could potentially reduce the vessel abnormality and increase the permeability of the tumor to chemotherapies [100]. VEGF isoforms exert their functions through activation of members of the VEGFR family of tyrosine kinases. This family consists of VEGFR-1 and VEGFR-2, which mediate growth factor signals for blood vascular endothelial cells, and VEGFR-3, which mainly regulates lymphatic endothelial cells. Expression of VEGFR-1 and VEGFR-2 is mainly restricted to the vascular endothelium [101].

The Role of VEGF in Esophageal Cancer
VEGF is overexpressed in 30%–60% of patients with esophageal cancers, and several studies have demonstrated a correlation among a high level of VEGF expression, advanced stage, and poor overall survival in patients undergoing potentially curative esophagectomy [102, 103]. The prognostic value of VEGF in patients treated with preoperative chemoradiotherapy is less clear. Studies in patients with esophageal squamous cell carcinoma and adenocarcinoma found no significant association between VEGF expression and treatment response or overall survival [104, 105]. This discrepancy may be explained in part by the potential induction of VEGF and increased angiogenic activity that may occur with the delivery of preoperative chemoradiotherapy. Antitumoral treatment can induce the development of more aggressive and resistant tumor phenotypes that might weaken potential associations among pretreatment VEGF level, treatment response, and overall survival [106, 107]. However, other studies of preoperative chemoradiotherapy in patients with esophageal cancer have suggested an association between high VEGF level and poor prognosis [108, 109]. Dreilich et al. [110] concluded that the use of angiogenic factors, including VEGF, as pretherapy prognostic factors in patients with esophageal carcinoma treated with chemoradiotherapy appears limited.

Lymph node metastasis, including lymph node micrometastasis (LMM), is one of the most important prognostic factors in esophageal squamous cell carcinoma, and VEGF-C plays a key role in the process of lymphangiogenesis [111, 112]. Matsumoto et al. [113] found that VEGF-C overexpression was significantly correlated with depth of tumor invasion, lymphatic invasion, and lymph node metastasis. High microvessel density was also correlated with lymphatic invasion and lymph node metastasis. They concluded that, in esophageal squamous cell carcinoma with submucosal invasion, VEGF-C overexpression by the primary tumor is a risk factor for lymph node metastasis, including LMM. In another study, VEGF expression was significantly correlated with angiolymphatic invasion, lymph node metastasis, and shorter survival in patients with adenocarcinoma [114]. Additionally, plasma VEGF has been found to be elevated in patients with bone marrow micrometastases [115].

Production of VEGF-C and VEGF-D has been observed not only in esophageal carcinomas but also in dysplastic lesions in both squamous cell carcinoma and adenocarcinoma, raising the possibility that VEGF-C and VEGF-D might promote tumorigenesis in the early stage of esophageal carcinogenesis [116]. This was also indicated in work by Kitadai et al. [117], who demonstrated an initial increase in vessel density and enhanced expression of VEGF and platelet-derived endothelial cell growth factor, another angiogenic factor, in dysplastic epithelium of esophageal squamous cell carcinomas. Auvinen et al. [118] compared Barrett's dysplasia with normal esophageal mucosa, finding that Barrett's-specific glandular epithelium secretes VEGF-A, in addition to a mixture of sialomucin and sulfated mucins. The receptor of VEGF-A (VEGFR-2) is strongly expressed on angiogenic blood vessels feeding the Barrett's epithelium. The results suggest an interesting functional interplay between angiogenic glandular epithelium and new invading blood vessels in neovascularization of Barrett's epithelium. However, another study indicated that neovascularization has an important impact on the survival of patients with Barrett's carcinoma, but VEGF does not appear to be the vascular growth factor stimulating neovascularization in Barrett's carcinoma patients [119]. There was also a highly significant greater level of expression of both VEGF and basic fibroblast growth factor in adenocarcinoma tissues compared with normal esophageal mucosa or Barrett's esophagus [120].

VEGF blockade may be a promising way to slow down or even stop tumor progression in esophageal cancer. SU6668 is an antiangiogenic agent that acts as a TKI for VEGFR. Nakamura et al. [121] treated xenografted A-431 cells, a human squamous cell carcinoma cell line, with SU6668 and found that both the tumor volume and the number of vessels were significantly less in the treatment group than in the control group, demonstrating a potential use in the treatment of patients with squamous cell carcinoma. Two different TKIs, sunitinib and sorafenib, acting as multitargeted TKIs, including VEGFR, were recently approved for the second-line treatment of patients with metastatic RCC or GISTs and for the treatment of metastatic RCC, respectively [98].

In another study, Gu et al. [122] found that angiogenesis and the tumorigenicity of human esophageal squamous cell carcinoma were effectively inhibited by VEGF165 antisense RNA, demonstrated by a lower microvessel density and smaller tumor volume.

Among VEGF inhibitors, bevacizumab is the one that has been the most well studied. It is a recombinant humanized mAb that binds to all isoforms of human VEGF with high affinity and prevents the binding of VEGF to its receptor [123]. More than 200 clinical trials with bevacizumab in human cancers are ongoing or completed, with various designs, including bevacizumab as monotherapy or in combination with chemotherapy, radiotherapy, other antiangiogenic agents, or targeted agents. In particular, bevacizumab combined with an irinotecan-based regimen (irinotecan, fluorouracil, and leucovorin) resulted in a longer overall survival time, compared with placebo (20.3 months versus 15.6 months) in metastatic colon cancer patients, and was thus subsequently approved by the U.S. Food and Drug Administration [124].

For esophageal cancer, bevacizumab is in the early stages of clinical development. As a result of the life-threatening hemoptysis described in bevacizumab-treated patients with squamous cell carcinoma of the lung [125], most trials have been limited to adenocarcinomas. Because many patients with locally advanced esophageal cancer are treated with concurrent chemoradiation, there may be a possible role for VEGF blockade in this setting. The radiosensitizing effect of VEGF antibody has been demonstrated in several xenograft models, including those of esophageal adenocarcinoma [107]. Encouraging results were reported in a phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or GEJ adenocarcinoma [126], showing a median time to progression of 8.3 months, an improvement over historical controls by 75%. The overall response rate of 65% and median survival duration of 12.3 months were also promising. A phase II trial with neoadjuvant bevacizumab, cisplatin, irinotecan, and concurrent radiation followed by surgery and adjuvant bevacizumab in locally advanced esophageal adenocarcinoma is currently ongoing at Memorial Sloan-Kettering Cancer Center. Another phase II trial conducted at the Sarah Cannon Research Institute is evaluating preoperative concurrent chemotherapy and radiation therapy plus bevacizumab and erlotinib in the treatment of localized esophageal cancer. Recently, it was found that treatment with bevacizumab in patients with upper aerodigestive malignancies may cause tracheoesophageal fistula formation, which has led to a change in the product label of bevacizumab. This finding may hamper our ability to study VEGF-targeted agents in future clinical trials.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
References
 
Esophageal cancer has a dismal prognosis: half of all patients given curative treatment suffer recurrence within 1 year. The need for novel treatment options is urgent. Growth factors and growth factor receptor–mediated signaling pathways are important components of the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are new possibilities to use growth factor signal transduction pathway antagonists in targeted therapy and the range of potential targets is increasing rapidly. Future research trials involving targeted therapies of growth factor signaling will aim at improving chemotherapy in metastatic esophageal cancer, acting as a radiosensitizer in combined chemoradiotherapy and even preventing tumor progression in early-stage disease such as Barrett's esophagus.


   REFERENCES
Top
 Abstract
 Introduction
 Growth Factor Signaling
 The Human Epidermal Growth...
 Insulin-Like Growth Factor-1
 Platelet-Derived Growth Factor
 Vascular Endothelial Growth...
 Conclusions
 References
 

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