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Chemokines and Cancer Progression: A Qualitative Review on the Role of Stromal Cell-derived Factor 1-alpha and CXCR4 in Endometrial Cancer

The goal of this paper was to examine the literature related to stromal cell-derived factor 1-alpha (SDF-1alpha) and its receptor CXCR4 in endometrial cancer, as expression of these biomarkers has been implicated in an aggressive phenotype in other
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  REVIEW PAPER  Chemokines and Cancer Progression: A Qualitative Reviewon the Role of Stromal Cell-derived Factor 1-alphaand CXCR4 in Endometrial Cancer Ashley S. Felix  &  Robert Edwards  &  Robert Bowser  & Faina Linkov Received: 14 January 2010 /Accepted: 29 January 2010 /Published online: 26 February 2010 # Springer Science+Business Media B.V. 2010 Abstract  The goal of this paper was to examine the literaturerelated to stromal cell-derived factor 1-alpha (SDF-1alpha)and its receptor CXCR4 in endometrial cancer, as expressionof these biomarkers has been implicated in an aggressive phenotype in other common epithelial cancers. We conductedaqualitativereviewofallpublishedstudiesexaminingtheroleof SDF-1alpha/CXCR4 in endometrial cancer progressionand prognosis. Pubmed and Ovid MEDLINE databases weresearched in order to identify relevant studies for thisqualitative review. Four studies have examined the role of the SDF-1alpha/CXCR4 pathway on endometrial cancer  progression. The findings were contradictory; two studiesreported an inverse association between overexpression andmortality while two studies reported overexpression to beassociated with hallmarks of aggressive endometrial cancer.Expression of stromal-derived proteins can potentially serveas biomarkers of aggressive disease as well as biomarkers for remission monitoring, however the endometrial cancer liter-ature has lagged behind in this area. Furthermore, the current research suffers from lack of comparability among different studies due to the utilization of different tools and lack of common outcome definitions. Future studies in this areashould use clinically meaningful protein expression catego-ries, widely accepted outcome definitions, and larger samplesof patients. Finally, although standard immunohistochemistryis a mainstay in tumor marker studies, automated detectionmethods may be more suitable as they do not rely onsubjective interpretation. Keywords  Chemokines.CXCR4.Endometrial cancer .Stromalcell-derivedfactor1-alpha.Tumormarkers.Tumormicroenvironment  Introduction Although endometrial cancer is the most common gyneco-logic malignancy, the mortality associated with this diseaseis relatively low. Typically, tumors present as well-differentiated, low stage masses that are confined to theuterus and are effectively managed by hysterectomy [1].The major burden of disease associated with endometrialcancer occurs from aggressive tumors characterized bynonendometrioid histology, high stage, poor differentiation,and metastasis to regional nodes. Patients with these typesof tumors are more likely to suffer from recurrence as wellas have a poor overall survival, and therefore are primecandidates for adjuvant therapy [2]. Despite this knowl-edge, surgical factors alone are not sufficient to makerecommendations regarding specific chemotherapies that would be most beneficial for the individual patient.Moreover, the toxicities associated with these therapies A. S. Felix ( * ) :  F. LinkovDivision of Cancer Prevention and Population Science,University of Pittsburgh Cancer Institute,5150 Centre Avenue, Suite 4-C,Pittsburgh, PA 15232, USAe-mail: asf23@pitt.eduA. S. Felix : F. LinkovDepartment of Epidemiology,University of Pittsburgh Graduate School of Public Health,Pittsburgh, PA 15261, USAR. EdwardsMagee-Womens Hospital of UPMC Health System,300 Halket St,Pittsburgh, PA 15213, USAR. Bowser Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh, PA 15261, USACancer Microenvironment (2010) 3:49  –  56DOI 10.1007/s12307-010-0042-7  require selection criteria that will predict which patientswould most likely benefit from such treatments. Theaddition of tumor markers to the current endometrial cancer  prognostic panel would significantly aid in the stratificationof patients into appropriate subgroups for treatment, similar to the work that has been done in the breast cancer field.The tumor microenvironment is composed of cancer cells as well as stromal cells and the extracellular matrix[3]. Common epithelial mutations which give rise to endometrial tumors include PTEN inactivation, beta-catenin, k- ras , p53, and HER2/  neu  mutations, as well asmicrosatellite instability [4]. Importantly, cancer cells continue to communicate with host stromal cells after acquiring these initial mutations. Moreover, cancer cells are proficient in exploiting a wide array of signaling pathwaysregulated by stromal-derived proteins with the purpose of maintaining cancer proliferation and promoting metastasis;one such class of signaling molecules is the chemokinefamily. Chemokines are chemotactic cytokines that direct the movement of cells; cells which express the appropriatechemokine receptors migrate towards high concentrationsof chemokines along a chemokine gradient [5]. Therefore,their role in tumor invasion and metastasis has beenexplored frequently in the cancer literature. Furthermore,chemokines and their receptors are known to play animportant role in immune responses, and recent evidencesuggests that a particular CXC receptor, CXCR4 (CXCmotif receptor 4), is the predominately expressed chemo-kine receptor in many human cancers [6]. CXCR4 is involved in chemotaxis, hematopoiesis, and tumor metas-tasis in breast, ovarian, and thyroid cancers [5, 7  –  9].The CXCR4 receptor and its ligand, stromal cell-derivedfactor 1-alpha (SDF-1alpha, CXCL12) may potentiallyenhance endometrial tumor progression and metastasis. Invitro studies report that SDF-1alpha is a potent stimulator of endometrial cancer cell proliferation [10, 11], yet the association between expression of these markers and prognostic factors is inconsistent in the literature [12  –  15].Understanding the association between these proteins andclinical factors may inform therapeutic protocols to better impact survival. The goal of this paper was to review theliterature related to endometrial cancer and the SDF-1alpha/ CXCR4 pathway in order to characterize the current state of knowledge regarding this relationship. Methods Literature Search StrategyTo identify published studies on SDF-1alpha/CXCR4 inendometrial cancer, two electronic databases, Pubmed (1950-June8,2009) and Ovid MEDLINE(1966-June 8,2009),wereaccessed through the Health Sciences Library System at theUniversity of Pittsburgh. Three separate searches were performed in each database with the following keywords: 1.)endometrial cancer AND stromal cell-derived factor 2.)endometrial cancer AND CXCL12 3.) endometrial cancer AND CXCR4. No restrictions on language or human subjectswere used. Unpublished reports, including dissertations andconference abstracts, were not considered.Inclusion and Exclusion CriteriaAll titles and abstracts of the retrieved articles from Pubmedand Ovid MEDLINE were reviewed. Studies were includedif the following criteria were met 1.) human tissue (ex vivo)was studied, 2.) mRNA or protein expression of SDF-1alpha or CXCR4 was characterized, and 3.) the association between pathologic variables and/or outcomes in relation toexpression were explored. Some of the ex vivo studies that met the inclusion criteria for this study also included invitro analyses of the migratory and proliferative effects of the markers. When this was the case, these results were alsosummarized in this review.The major reasons for exclusion were 1.) endometrialcancer was not the primary cancer, 2.) studies examined theinvasive or mitogenic capacity of the proteins in endome-trial cancer cell lines only, and 3.) the markers studied werenot SDF-1alpha or CXCR4. Figure 1 outlines the completesearch strategy used for this review.Data ExtractionData from each study included in the review were extracted by one reviewer. Extracted data elements included: sample population, study design and laboratory assays, important covariates, primary results related to expression and prognostic factors, and secondary findings. Table 1 sum-marizes the data elements abstracted from each articleincluded in this review. Results Four studies have analyzed the SDF-1alpha/CXCR4 axis inendometrial cancer, however, the conclusions regarding the prognostic role of these proteins are conflicting. Mizokamiet al. [12] studied the relationship between histologicalgrade, an important prognostic factor in endometrial cancer,and protein expression of SDF-1alpha and CXCR4 in 41endometrial cancer cases. Tissues obtained from hysterec-tomy specimens were analyzed immunohistochemically(IHC) and staining was classified on a 3-level ordinalscale: negative or weakly positive, moderately positive, andstrongly positive. Both SDF-1alpha and CXCR4 expression 50 A.S. Felix et al.  were inversely associated with histological grade in thecarcinoma compartment of the tissue. In grade 1 and 2tumors, the mean level of SDF-1alpha staining was 0.54while grade 3 tumors had a mean level of 0.10, which wasstatistically significant at   p =0.05. The mean level of CXCR4 staining in grade 1 and 2 tumors was 0.73 whilegrade 3 tumors had a mean expression of 0.17 (  p <0.05)[12]. Stromal expression of SDF-1alpha and CXCR4 wasalso assessed with IHC, however no significant differencein stromal SDF-1alpha or CXCR4 expression amongdifferent grade cancers was detected.Similarly, Kodama et al. [16] reported CXCR4 expressionto be significantly lower in patients (  N  =55) with character-istics of advanced endometrial cancer. Protein expressionwas analyzed by IHC and dichotomized as positive or negative. Tissue specimens were labeled as  ‘  positive ’  whentreatment with the appropriate antibody stained more than50% of cells. In the unadjusted models, CXCR4 expressionwas negative in patients with late stage tumors (  p =0.004),deep muscular invasion (  p =0.05), lymph node metastasis(  p =0.03), ovarian metastasis (  p =0.003), and positive perito-neal cytology (  p =0.001); all of which indicate an aggressivecancer phenotype. Additionally, survival following surgerywas examined; CXCR4 expression was not an independent  predictor of either overall or disease-free survival adjustedfor other known endometrial cancer prognostic factors [13].Results from these two studies conflict with the notion that the SDF-alpha/CXCR4 pathway is involved in an aggressiveendometrial cancer phenotype, as tumors with poor prog-nostic traits were less likely to have strong positive staining.The third study to examine this pathway was performed by Tsukamoto et al. [14] which investigatedthe interaction between SDF-1alpha and CXCR4 on theability of endometrial tumors to invade the muscular layer of the endometrium. Muscular infiltration is an important  prognostic factor in endometrial cancer. Regional nodemetastases and distant organ metastases are significantlymore likely to occur as the depth of muscular invasionincreases [15]. Five human endometrial cancer cell linesand endometrial cancer tissues resected from endometrialcancer patients (  N  =34) were examined. CXCR4 proteinexpression was analyzed by IHC and scored on a 3-titeredscale similar to Mizokami et al. [12]. The outcome,muscular invasion, was classified on the basis of depth:more than half of the muscle layer invaded vs. less thanhalf of the muscle layer invaded. Mean expression of CXCR4 was significantly higher in those tumors that invaded more than half of the myometrium compared tothose tumors with superficial invasion (  p <0.05). The invitro assays revealed two key findings: 1.) SDF-1alphaactivates the phosphoinositide 3-kinase/Akt pathway asshown by Western blot analysis using a p-Akt-specificantibody and 2.) Akt activation is required for uterinesmooth muscle cell-induced endometrial cancer cell  Pubmed Search (1950 - June, 2009) Ovid MEDLINE Search (1966 - June, 2009) Endometrial cancer   AND  stromal cell-derived factor (10 articles) Endometrial cancer   AND  CXCL12 (14 articles) Endometrial cancer   AND  CXCR4 (15 articles) N=39 Title/Abstract Review(N=39) Excluded articles: Duplicate articles (N=11) Other malignancies (N=4) Cell line study only (N=13) Articles in Chinese (N=2) Markers not SDF-1alpha/CXCR4 (N=5) Full text article Review(N=4) Articles included in Review(N=4) Fig. 1  Flow chart of searchstrategy for articleidentificationThe Role of SDF-1alpha and CXCR4 in Endometrial Cancer 51  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     a     R    T  -    P    C    R   :    R   e   v   e   r   s   e   t   r   a   n   s   c   r    i   p   t    i   o   n   p   o    l   y   m   e   r   a   s   e   c    h   a    i   n   r   e   a   c   t    i   o   n        b     I    H    C   :    I   m   m   u   n   o    h    i   s   t   o   c    h   e   m    i   s   t   r   y      c     M    A   :    M    i   g   r   a   t    i   o   n   a   s   s   a   y        d     E    L    I    S    A   :   e   n   z   y   m   e  -    l    i   n    k   e    d    i   m   m   u   n   o   s   o   r    b   e   n   t   a   s   s   a   y The Role of SDF-1alpha and CXCR4 in Endometrial Cancer 53
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