Novel therapeutic targets in esophageal cancer: impact of chemokine receptor CXCR4
Ines Gockel†, Carl C Schimanski, Markus Moehler & Theodor Junginger†Author for correspondenceJohannes Gutenberg-University of Mainz, Department of General and Abdominal Surgery, Langenbeckstr. 1,55131 Mainz, Germany Tel.: +49 6131 177 291;Fax: +49 6131 176 630;[email protected]
‘The interaction between esophageal cancer-expressed CXCR4 and SDF-1α may have
a key role in directing malignant cells to ‘homing’ organs … thus, this
mechanism may account for metastasis.’
Esophageal cancer is the eighth most commoncancer and the sixth most common cause ofcancer-related deaths worldwide, with a chang-ing epidemiology reflecting a rapid rise in the inci-dence of adenocarcinoma of the esophagus [1,2].Owing to invasive local growth and aggressivespread, as in the presence of lymph node meta-stases and vascular invasion, esophageal cancer ischaracterized by a potential for high malignancy.
Surgery as the treatment of choice offers5-year survival rates of only 30%, even with therecent improved techniques [3]. Neoadjuvant oradjuvant (radio-) chemotherapy regimes exerteda modest impact on prognosis and overall sur-vival. Two meta-analyses confirmed a survivalbenefit at 3 years from neoadjuvant concurrentchemoradiation without compromising the abil-ity to undergo surgical resection and without anincrease in perioperative mortality negating theobserved benefit [4,5]. As the results of conven-tional treatments tended to be rather disappoint-ing, the development of novel molecular targetshas extended the field of oncology widely.
Novel therapeutic targets in esophageal cancer Advancing knowledge of molecular pathways incancer biology has enabled the identification ofnovel molecular targets and facilitated the rationaldevelopment of selectively targeting agents.Owing to their specificity, an advantage as com-pared with traditional nonselective cytotoxics, istheir reduced toxicity.
Several classes of novel targets have beendescribed for esophageal cancer, including inter-ference with growth regulation (epidermalgrowth factor receptors [EGFR, HER-2/Neu]and Ki-67), angiogenesis (vascular endothelialgrowth factor [VEGF]), inflammation (cyclo-oxygenase [Cox]-2 pathway), cell-cycle control
(p16, p21 and cyclin D1), apoptosis (p53, baxand bcl-2) and inhibition of invasion and meta-stasis (matrix metalloproteinase inhibitors andE-cadherin). Targeted therapies should be con-sidered for patients with esophageal cancer in thesearch for more effective treatments.
EGFRs are integral components of the principalsignaling cascade involved in regulating thegrowth of solid tumors. Esophageal cancer oftenexhibits the overexpression of EGFR andHER-2/Neu (p185), correlating with prolifer-ation, invasion, metastasis formation, angiogenesis,protection from apoptosis and poor prognosis [6].
‘Surgery as the treatment of choice offers 5-year survival rates of only 30%.’
Monoclonal antibodies (mABs) and the lowmolecular weight tyrosine kinase inhibitors(TKIs) have been developed to block this path-way. Whereas mABs bind to the extracellulardomain of the receptor and compete with the nat-ural ligands (transforming growth factor [TGF]-αand epidermal growth factor [EGF]) of the recep-tor, TKIs compete with ATP binding to the tyro-sine kinase portion of the endodomain of thereceptor and, thereby, abrogate the receptor’s cata-lytic activity. Among the available anti-EGFRmABs, the chimeric immunoglobulin (Ig)G1cetuximab, is furthest ahead in terms of clinicaldevelopment [7] and has been approved toenhance the antitumor effect of both topotecanand irinotecan in colorectal cancer cell lines invitro and in murine xenograft models, but no clin-ical trial has been performed in esophageal cancer.Matuzumab as a humanized IgG1 mAB withhigh affinity is currently in Phase I and II develop-ment and displays a prolonged half-life, allowingfor a less frequent administration schedule.
The proto-oncogene HER-2/Neu encodes atransmembrane tyrosine kinase growth factorreceptor, similar to EGFR. Trastuzumab is ahumanized IgG1 antibody and results in thedownregulation of HER-2 expression, inductionof G1 cell-cycle arrest and apoptosis and the ini-tiation of antibody-dependent cell-mediated, aswell as of complement-dependent, cytotoxicity.The data on squamous cell carcinoma of the
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esophagus and HER-2/Neu expression are limitedwith reported overexpression rates of between 0and 52%. Thus, its value as an independent prog-nostic factor has not been validated [8]. In adeno-carcinoma of the esophagus, HER-2/Neuoverexpression has been observed in 0–73% ofpatients, correlating with advanced tumor stagesand worse prognosis [9].
VEGF receptor plays a crucial role in tumorangiogenesis. The biologic effects produced byVEGF, in addition to increased vascular permea-bility and maintenance of survival for newlyformed blood vessels, include endothelial cellmitogenesis, migration and activation of protein-ases. VEGF belongs to the platelet-derivedgrowth factor superfamily and consists of sevenrelated glycoprotein ligands (VEGF-A, -B, -C,-D and -E, and the placenta growth factor-1 and-2) [10]. VEGF is overexpressed in 30–60% ofpatients with esophageal cancer and high levels ofVEGF expression in esophagectomy specimenshave been demonstrated to correlate with advancedtumor stage and poor overall survival [11]. VEGFblockade is classified as either direct or indirectinhibition of angiogenesis. The direct blockadetargets the microvascular endothelial cells that arerecruited to the tumor bed and prevent themfrom responding to various endothelial mitogensand motogens. By contrast, indirect angiogenesisinhibitors target proteins – such as EGF tyrosinekinase and its ligands’ basal fibroblast growthfactor, VEGF and TGF-α. Among the angio-genesis inhibitors, bevacizumab, a recombinanthumanized mAB, has been studied most exten-sively. It binds to all isoforms of human VEGFwith high affinity and prevents the binding ofVEGF to its receptor [12]. The clinical data foresophageal cancer remain limited and the major-ity of trials do not clearly distinguish betweendistal (Barrett’s) adenocarcinoma and esophago-gastric junction adenocarcinoma, including car-diac and subcardiac carcinoma and, thus,representing real gastric carcinoma as a differententity. However, VEGF blockade appears to playan important role in the neoadjuvant chemora-diation concepts in patients with locally advancedesophageal cancer. Enhancing chemotherapy totumors through the reduction of tumor interstitialpressure and vascular permeability, the radio-sensitizing effect of VEGF antibodies has beendemonstrated in several xenograft models,including esophageal adenocarcinoma [13].
Cox-2, an inducible enzyme that catalyzesprostaglandin synthesis from arachidonic acid,affects several pathways in carcinogenesis,
including those of inflammation, immunesurveillance, angiogenesis and apoptosis. Theresults from a recent meta-analysis of existingobservational studies indicate a protective effect ofnonsteroidal anti-inflammatory drugs for bothesophageal adenocarcinoma and squamous cellcarcinoma [14]. Although there is a rationale for theassociation between Cox-2 and tumor develop-ment, the role of Cox-2 inhibitors in the treatmentof esophageal cancer is largely unsubstantiated.
Thus, there is growing evidence that prosta-glandins modulate the cellular injury induced byionizing radiation [15]. The results of a Phase II trialof preoperative therapy with cisplatin, irinotecanplus the Cox-2-inhibitor, celecoxib and concurrentradiation demonstrated that of 25 of 36 patientsundergoing surgery, partial complete response wasobserved in 11 patients (44%), microscopic resid-ual disease in five patients (20%), and 84% of thepatients were down-sized [16]. Ongoing studies willclarify the toxicity and effective targeting ofCox-2-inhibitors in esophageal cancer.
‘...disruption of cell-cycle progression by the inhibition of CDK activity is a promising anticancer strategy.’
Regulators of the cell cycle, such as cyclin-dependent kinases (CDKs), can be targeteddirectly with small molecules. Their activity isfurther enhanced in the presence of chemo- orradiotherapy in a time-sequence-dependentmanner. Flavopiridol, a synthetic flavone, is thefirst selective CDK inhibitor to enter clinicaltrials. Its antiproliferative effect is mediated bythe induction of cell-cycle arrest at the G1-S orG2-M phases through the direct inhibition ofCDK1, -2 and -4, the depletion of cyclin D1,apoptosis and angiogenesis [17]. The disruptionof cell-cycle progression by the inhibition ofCDK activity is a promising anticancer strategy.
Nuclear factor (NF)-κB activation has beenimplicated as an important anti-apoptotic signal.As a ubiquitous transcription factor, its functionis controlled at a molecular level. Upon induc-tion by chemotherapy or radiation, NF-κB relo-cates to the nucleus, binds to a specific site onthe DNA and ultimately leads to the transcrip-tion of a wide array of genes responsible for cellproliferation, tumor development and trans-formation. The direct inhibition of NF-κB,combined with chemotherapy, represents a noveland potentially more effective approach to thetreatment of esophageal cancer [18]. Bortezomibis a small-molecule proteasome inhibitor, which
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Novel therapeutic targets in esophageal cancer: impact of CXCR4 – EDITORIAL
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prevents NF-κB activation by preventing pro-teasome-mediated inhibitor (I)κB degradation.Its role in reducing resistance to chemoradiationand its activity in advanced disease remains tobe elucidated.
Matrix metalloproteinase inhibitors (MMPs)are zinc-dependent proteolytic enzymes that playan important role in normal processes of growth,differentiation and repair. Abberant MMPexpression contributes to the invasive localgrowth and spread in different tumor types.Inhibition of MMPs may therefore represent asuccessful strategy for the treatment of esopha-geal cancer. Marimastat is an orally active MMPinhibitor and has been demonstrated to improvedisease-free survival in patients with unresectablegastroesophageal adenocarcinoma – unfortu-nately this study did not distinguish betweenesophageal and gastric adenocarcinoma [19].
Inhibition of esophageal cancer progression by CXCR4 antagonistsChemokines are chemotactic factors regulating thedevelopment and migration of various cell types.They are classified into four subgroups (C, CC,CXC and CX3C) based on the positioning of theirfirst two cysteine (C) residues in the amino acidsequence. CXCR4 is a seven-transmembrane Gprotein-coupled receptor and is also known as a co-receptor used by X4 strains for HIV type 1.CXCL12, also known as stem-cell derived factor(SDF)-1α, the natural ligand for CXCR4, is amember of the CXC chemokine family that haschemotactic activity for hematopoietic progenitor
cells. Chemokine receptor activation can lead togrowth, adhesion and directional migration. Sig-naling results in the transcription of target genesthat are involved in cell invasion, motility, inter-actions with the extracellular matrix and sur-vival. Expression of chemokine receptor CXCR4has been shown to play a key role in migrationand metastasis with associated tumor progressionand poor prognosis in several malignancies.
Our own data, based on 102 consecutivepatients undergoing esophagectomy for esopha-geal cancer, showed a high CXCR4 expression ratein both types of esophageal cancer – squamous cellcarcinoma (94.1%) and adenocarcinoma(89.1%). Furthermore, Koishi and colleaguesdemonstrated that persistent positive CXCR4expression implicated tumor aggressiveness andpoor prognosis in squamous cell carcinoma of theesophagus after neoadjuvant chemoradiotherapyand that chemo–radiotherapy may improve theprognosis via the CXCL12–CXCR4 signalingpathway [20].
In conclusion, the interaction between esopha-geal cancer-expressed CXCR4 and SDF-1α mayhave a key role in directing malignant cells to‘homing’ organs, such as lymph nodes, bonemarrow, liver and lung and, thus, this mechanismmay account for metastasis. However, the exactbiological functions of CXCR4 in terms of tumordissemination in esophageal cancer is not yetthoroughly determined.
The inhibition of esophageal cancer progres-sion using CXCR4 antagonists might represent apromising therapeutic target in the near future.
Executive summary
Novel therapeutic targets in esophageal cancer
• Classes of novel therapeutic targets in esophageal cancer interfere with:– Growth regulation (endothelial growth factor receptor HER-2/Neu)– Angiogenesis (vascular endothelial growth factor)– Inflammation (cyclo-oxygenase-2)– Cell-cycle control (CDK)– Apoptosis (nuclear factor-κB)– Inhibition of invasion and metastasis (matrix metalloproteinase)– Blockade of chemokine receptor (CXCR)4
• Expression of chemokine receptor CXCR4 has been shown to play a key mechanism in migration and metastasis with associated tumor progression and poor prognosis.
• High CXCR4 expression is evident in both types of esophageal cancer – squamous cell carcinoma and adenocarcinoma.
Conclusion
• The interaction between esophageal cancer-expressed CXCR4 and stem cell-derived factor-1α may have a key role in directing malignant cells to homing organs.
Future perspective
• Inhibition of esophageal cancer progression using CXCR4 antagonists represents a promising therapeutic target in the near future.
Future Oncol. (2007) 3(2) future science groupfuture science group
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Affiliations• Ines Gockel, MD
Johannes Gutenberg-University of Mainz, Department of General & Abdominal Surgery, Langenbeckstr. 1, 55131 Mainz, Germany Tel.: +49 6131 177 291;Fax: +49 6131 176 630;[email protected]
• Carl C Schimanski, MD
Johannes Gutenberg-University of Mainz, First Medical Clinic, Interdisciplinary Translational Oncologic Laboratory (ITOL), GermanyTel.: +49 6131 177 276;Fax: +49 6131 175 595;[email protected]
• Markus MoehlerJohannes Gutenberg-University of Mainz, First Medical Clinic, Interdisciplinary Translational Oncologic Laboratory (ITOL), GermanyTel.: +49 6131 177 276;Fax: +49 6131 175 595;[email protected]
• Theodor Junginger, MD
Johannes Gutenberg-University of Mainz, Department of General & Abdominal Surgery, Interdisciplinary Translational Oncologic Laboratory (ITOL), GermanyTel.: +49 6131 177 291;Fax: +49 6131 176 630;[email protected]
