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Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma

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Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma Vol. 11, 1835–1841, March 1, 2005 Clinical Cancer Research 1835 Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma Stefania Scala,1 Alessandro Ottaiano,1 reached in patients with CXCR4-negative tumors. In the Paolo Antonio Ascierto,1 Manuela Cavalli,1 multivariate analysis, CXCR4 expression, presence of ulcer- Ester Simeone,1 Paola Giuliano,1 ation, and sentinel lymph node status emerged as independent 1 2 prognostic factors. Maria Napolitano, Renato Franco, Conclusions: This article provides the first evidence 2 1,3 Gerardo Botti, and Giuseppe Castello that CXCR4 expression could be an independent and Departments of 1Clinical Immunology and 2Clinical Pathology National powerful prognostic marker in primary cutaneous malig- 3 Cancer Institute, G. Pascale Foundation and Melanoma Cooperative nant melanomas. Group of Naples, Italy INTRODUCTION ABSTRACT Malignant melanoma represents about 2% to 3% of all Purpose: CXCR4 receptor and its unique ligand, the malignancies in the United States and North Europe. The CXCL12 chemokine, have been recently implicated in cancer incidence of malignant melanoma has increased steadily during metastasis. Evidence about the role of CXCR4/CXCL12 axis the last decades with a high mortality rate because of the has been reported in several cancers including melanoma. metastatic dissemination of tumor cells and generation of Our goal was to investigate if CXCR4 expression has a chemoresistance (1). Although surgery can be curative in prognostic value in malignant melanoma. localized disease, a large number of patients develop distant Experimental Design: Immunohistochemical expression metastases. Despite multiple clinical trials that have tested a of CXCR4 was evaluated on 71 specimens of primary wide variety of anticancer strategies, ranging from surgery to cutaneous melanoma with a Breslow tumor thickness of >1 immunotherapy, radiotherapy, and chemotherapy, the average mm after radical resection. Associations between baseline survival rate is of 6 to 10 months. To date, the most important patient features and tumors were analyzed by C2 test. The prognostic factors are Breslow’s tumor thickness, ulceration, and prognostic value of CXCR4 expression was evaluated by lymph node status (2). Diagnosis of malignant melanoma at very univariate and multivariate analyses adjusted by age, sex, early stages (i.e., before the malignant melanocytes become Breslow tumor thickness, presence of ulceration, and sentinel invasive) allows for complete surgical excision of the primary lymph node metastases. tumors. In these cases there is over a 95% success rate at stage Results: CXCR4 expression was detected in 31 of 71 I/II and it can even substantially extend the long term survival of (43.6%) primary cutaneous melanomas. Membrane or patients with lymph node infiltration (stage III; refs. 1, 2). cytoplasmic staining for CXCR4 protein was absent in 56% The migration of tumor cells to a secondary site from their of the tumors. The positive cases were divided into three score primary location one is a key event in cancer metastasis. Many classes according to their staining: low in 15 cases (21%), studies suggest the mechanisms used for homing of leukocytes moderate in 10 (14%), and high in 6 (8%). After a median and hematopoietic progenitors may be appropriated for the follow-up of 38 months, 26 patients progressed (16 of 26 dissemination of tumors via the bloodstream and lymphatics. expressed CXCR4) and 19 died (12 of 19 expressed CXCR4). CXCR4 is a seven-domain trans-membrane chemokine recep- The CXCR4 expression on tumor cells was correlated with an tor predominantly expressed on lymphocytes where it activates unfavorable prognosis with a median disease-free and overall chemotaxis. The CXCR4/CXCL12 pathway has been recently survival of 22 and 35 months, respectively. The hazard ratios involved in stimulating the metastatic process of many different of relapse and death, compared with patients with CXCR4- neoplasms (3), where CXCR4 is able to activate a plethora of negative tumors, were 2.5 (95% confidence interval, 1.2-6.1) phenomena such as chemotaxis, invasion, angiogenesis, and and 3.1 (95% confidence interval, 1.1-7.2), respectively. proliferation. These phenomena have been shown with different Median time-to-event (progression and survival) was not methodologic approaches in breast cancer (4, 5), small cell lung cancer (6), ovarian cancer (7, 8), pancreatic cancer (9), lymphoma (10–12), neuroblastoma (13), glioblastoma (14, 15), Received 9/14/04; revised 12/3/04; accepted 12/13/04. renal cell carcinoma (16), thyroid cancer (17–19), rabdomyo- Grant support: Associazione Italiana per la Ricerca sul Cancro. sarcoma (20), prostate cancer (21), and colorectal cancer (22). The costs of publication of this article were defrayed in part by the The role of CXCR4 receptor in the biology of malignant payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to melanoma has been previously described. CXCR4 expression indicate this fact. was detected in human melanoma cell lines and in patient Note: S. Scala and A. Ottaiano contributed equally. samples. The authors described expression of CXCR3 and Requests for reprints: Stefania Scala, Department of Clinical CXCR4 receptors regulating cell motility during invasion as well Experimental Immunology, National Cancer Institute, via Mariano Semmola, 80131, Naples, Italy. Phone: 39-081-5903678; Fax: 39-081- as cell proliferation and survival (23). Insights into this 5903820; E-mail: [email protected]. mechanism showed that CXCL12 promotes melanoma cell D2005 American Association for Cancer Research. invasion through activation of membrane type I–bound matrix Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2005 American Association for Cancer Research. 1836 CXCR4 in Melanoma metalloproteinase and small GTPase proteins RhoA, Rac1, and negative for CXCR4 expression. Neoplastic cells with CXCR4 CDC42 (24). Interestingly, CXCR4 expression on melanoma cytoplasmatic and/or membrane immunohistochemical expres- cells is increased by transforming growth factor-h1 and specific sion were considered positive cells. Macrophage positivity was inhibition with anti-transforming growth factor-h antibodies used as adequate internal positive control for each case, to blocked CXCR4 expression and melanoma cell invasion toward validate technical procedure. Staining was categorized into four CXCL12 (24). Overexpression of CXCR4 dramatically enhanced semiquantitative classes based on the rate of stained (positive) the metastatic accumulation of B16 melanoma cells in mice lungs tumor cells: absence of staining, <10% positive cells (low), 10% (25). Expression of functional CXCR4 receptor on melanoma to 50% positive cells (moderate), and >50% positive cells (high). cells indicates that it might contribute to cell motility during Topographical expression of CXCR4 was also evaluated. invasion of lymph nodes as well as to regulation of cell Prevalent expression in radial or vertical component was proliferation and survival. considered when expression in such component was twofold The aim of the present study was to evaluate the expression compared with the other. Moreover, CXCR4 expression was of CXCR4 in malignant melanoma patients and its possible evaluated in SLN. In particular, cases were considered positive prognostic value in 71 human primary melanoma samples and when >10% of metastatic cell showed cytoplasmatic and/or relative sentinel lymph nodes (SLN). membrane CXCR4 expression. Slides were evaluated by two blinded observers (G.B. and R.F.); discordant cases were discussed and concordance was then achieved. MATERIALS AND METHODS Statistical Analysis. Correlations between CXCR4 Patients were seen at the Clinical Immunology Department expression, baseline patient features, and tumors were studied of the National Cancer Institute of Naples from 1996 to 2003. by contingency tables and the m2 test. DFS was defined as the The histologic sections were reviewed by two expert patholo- time elapsed from the date of the initial diagnosis to the gists (G.B. and R.F.) to verify the histologic diagnosis of appearance of local relapse or distant metastasis or death, malignant melanoma, before performing immunohistochemistry. whichever occurred first. Overall survival (OS) was defined as Standard therapeutic strategies were applied for these patients, the time elapsed from the date of the initial diagnosis to death or according to SLN status. Patients with soft tissue recurrence or to the date of the last available information on vital status. local disease were treated with surgery. Patients with advanced Kaplan-Meier product limit method was applied to draw DFS disease were mainly treated with palliative chemotherapy. A few and OS curves. Univariate analysis was done with the log-rank selected patients underwent pulmonary metastasectomy in the test. Cox proportional-hazards regression was used to analyze case of a solitary lesion or single lobe involvement and adequate the effect of several risk factors on DFS and OS. The probability disease-free survival (DFS, at least 1 year). Locations of the of the end point (hazard) was estimated with a coefficient: primary tumor were grouped in four classes: head/neck, trunk, exp(b). The quantity exp(b) can be interpreted as the extremities, and feet. Breslow’s tumor thickness in the studied instantaneous relative risk of an event, at any time,
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