J Mol Hist DOI 10.1007/s10735-014-9574-3
ORIGINAL PAPER
The prognostic value of osteopontin expression in non-small cell lung cancer: a meta-analysis Tao Zhang • Dong-Ming Zhang • Da Zhao • Xiao-Ming Hou • Xiao-Jun Liu • Xiao-Ling Ling Shou-Cheng Ma
•
Received: 10 March 2014 / Accepted: 22 April 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To investigate the association of Osteopontin (OPN) expression in tumor tissue with clinicopathological features of non-small cell lung carcinoma (NSCLC) patients. Publications assessing the clinicopathological characteristics and prognostic significance of OPN in expression NSCLC were identified up to March 2014. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between OPN expression and these clinical parameters. A total of eleven studies met the inclusion criteria, and included 1536 cases of NSCLC tumor tissue and 340 cases of normal lung tissue. The OPN expression rate in NSCLC tissue was higher than normal tissue [Odds ratio (OR) 6.427; 95 % confidence interval (CI) 4.689–8.808; P = 0.000]. Simultaneously, we also found that OPN expression was positively associated with stage (OR 0.332; 95 % CI 0.250–0.440; P = 0.000), lymph node metastasis (OR 3.094; 95 % CI 2.295–4.172; P = 0.000), tumor size (tumor size \3 cm vs. C3 cm; OR 0.484; 95 % CI 0.303–0.773; P = 0.002) and pathology (OR 0.611; 95 % CI 0.466–0.800; P = 0.000). It was unrelated that OPN expression in NSCLC tissue with and degree of differentiation and other clinical features (P [ 0.05). Experimental Tao Zhang and Dong-Ming Zhang have contributed equally to this paper. T. Zhang D. Zhao (&) X.-M. Hou X.-J. Liu X.-L. Ling S.-C. Ma Department of Oncology, The First Hospital of Lanzhou University (The Branch Hospital of Donggang), Lanzhou 730000, Gansu Province, China e-mail: [email protected] D.-M. Zhang Department of Respiratory, The Second People’s Hospital of Pingliang, Pingliang 744000, Gansu Province, China
findings indicate that, OPN plays a crucial role in the development of NSCLC. Keywords Carcinoma Non-small cell lung Osteopontin Clinicopathological characteristics Metaanalysis
Introduction Lung cancer is currently recognized as one of the leading cancers with the highest morbidity and mortality (Jema et al. 2011) with approximately 1.6 million new cases and at least 1.3 million deaths worldwide each year. Non-small cell lung cancer (NSCLC) accounts for approximately 80 % of all lung cancers, which include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (Collins et al. 2007). Invasion and metastasis, which are the most important biological characteristics of malignant tumors and the main causes of death in patients, rapidly develop in NSCLC patients; thus, their 5-year survival rate is generally low (Alberg et al. 2007). The mechanism of invasion and metastasis of NSCLC remains unclear; thus, exploring the biological indicators for invasion and metastasis, especially for the prognosis of NSCLC, is particularly important. Osteopontin (OPN) is a protein secreted by bone stromal cells and is rich in sialic acid. It serves as a bridge between cells and its substrates. Studies have associated the upregulation of this newly discovered cytokine in breast cancer, renal cancer, esophageal cancer, endometrial cancer, and a variety of digestive tract tumors with the growth, migration, and invasion of tumor cells (Thorat et al. 2013; Etiz et al. 2013; Sim et al. 2012; Cao et al. 2012). Some studies have argued that the abnormal expression of OPN is
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strongly associated with clinical pathologic characteristics of NSCLC such as the clinical staging of the tumor, histological grade, and lymph node metastasis, thus suggesting that it might also influence its prognosis. On the other hand, there are also researchers that consider the high expression of OPN to be unrelated to the clinicopathological characteristics of NSCLC. For example, (Ane et al. 2012), Jin et al. (2012), and Li et al. (2009) reported that there was no relationship between the high expression of OPN and the size or pathological stage of the tumor. Based on these findings, the present study collected data from related published literature and conducted a meta-analysis of the relationship between OPN expression and NSCLC, aiming to provide evidence for the treatment and prognosis of NSCLC.
Methods Inclusion and exclusion criteria The inclusion criteria were as follows: published related literature on the correlation between OPN expression in primary tumor tissues and NSCLC and pathological features; cases with complete clinical data and not subjected to radiotherapy or chemotherapy prior to selection; similar research topic and research method, wherein immunohistochemistry was used as the detection method of OPN; and the expression results were judged by scoring the amount or strength of staining of cells. The exclusion criteria were as follows: literature showing an inconsistent judgment standard for positive OPN expression and OPN expression in non-primary tumor tissues of NSCLC patients (OPN detection in patient’s blood circulation); literature presenting repeated or duplicated documents and poor quality; and literature involving animal experiments or literature reviews. Literature retrieval and data extraction Literature retrieval was conducted in PubMed, EMBASE, and Web of Science and the search-terms ‘‘Osteopontin’’, ‘‘OPN non-small cell lung cancer’’ and ‘‘NSCLC’’ were used. Retrieval of the combined key words and free words and the time was from the day when the database was established to March 2014, without language restrictions. Based on these conditions, references from the included literature and related conference paper collections were manually retrieved. Literature screening was independently performed by two reviewers (Tao Zhang and DM Zhang). First, by reading the title and abstract, the literature that obviously did not satisfy the inclusion criteria were eliminated, and the reports that were difficult to judge were
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further assessed by reading the entire text. All reports were jointly assessed by the two evaluators, and when there were different opinions, a discussion was held with a third person (Da Zhao). Relevant information, including title, author, year of publication, general details of the included cases, OPN expression in the tumor tissues, pathological type, diameter of tumor, degree of differentiation, lymph node metastasis, and clinical staging were extracted from the reports. Statistical analysis Comprehensive Meta-Analysis software (Version 2.0) was used to perform meta-analysis; the Q test was used to examine heterogeneity among the included research results. When statistical homogeneity was detected in the reports (P [ 0.1), a fixed effect model was used; furthermore, when statistical heterogeneity was observed in the articles (P \ 0.1), a random effect model was employed for the analysis or only a qualitative description was performed. A Begg’s funnel plot was generated to examine any underlying publication bias. Odds ratio (OR) and a 95 % confidence interval (CI) were used as the combined statistic for all results and P \ 0.05 was considered statistically significant.
Result Retrieval results Total of 85 reports satisfied the established inclusion criteria; then according to inclusion and exclusion criteria, the Medical Literature King software was used to exclude 35 reports that were deemed repeat publications; 19 articles were excluded based solely on reading the title and abstract; 20 reports were discarded on the basis of reading the entire text and analysis, for the following reasons:(1) the level of OPN was continuous variable data (Stemberger et al. 2013; Schneider et al. 2004); (2) OPN was evaluated on blood sample (Ostheimer et al. 2013; Karadag et al. 2011; Blasberg et al. 2010; Liang et al. 2009; Takenaka et al. 2013; Mack et al. 2008; Joseph et al. 2012; Han et al. 2013; Isa et al. 2009; Liang et al. 2011; Chang et al. 2007; Terpos et al. 2009); (3) evaluation criteria are inconsistent with other literature or unable extract data (Boldrini et al. 2005; Donati et al. 2005; Rud et al. 2013; Chambers et al. 1996; Ane et al. 2012); (4) may contain duplicate patients (Hu et al. 2005). Finally, 11 articles were selected for metaanalysis (Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Yu et al. 2006, 2014; Zhang et al. 2007; Fig. 1).
J Mol Hist Fig. 1 Flow chart for selection of studies for inclusion in this meta-analysis. Characteristics of included researches
Table 1 The general characteristics of studies included in the meta-analysis
ICH Immunohistochemistry, TMT Tissue microarray technology, A The control benign tissue, B Tumor size, C Histology, D Stage, E Differentiation, F Lymph node metastasis, G Distant metastasis
Study
Year of publication
Stage
Number of NSCLC tissues
Measurement method
Cut-off of ICH
Outcome
BC
Ane et al. (2012)
2012
I–IV
196
ICH
Score C3
Gui et al. (2007)
2007
I–IV
41
ICH
Score C1
AC
Hu et al. (2007)
2007
I–IV
555
ICH ? TMT
C25 % positive cells
ACDF
Jin et al. (2012)
2012
I–IV
136
ICH
C10 % positive cells
ABCDEF
Li et al. (2009)
2009
I–IV
48
ICH ? TMT
Score C3
ABCDEF
Sun et al. (2013)
2013
I–III
159
ICH
Score C1
CDEFG
Wu et al. (2012)
2012
I–IV
89
ICH
Score C1
ACDEF
Yang et al. (2007)
2007
I–IV
65
ICH
C10 % positive cells
CD
Yu et al. (2006)
2006
I–III
69
ICH
Score C1
ABCDEF
Yu et al. (2014)
2014
I–III
120
ICH
Score C1
ABCDEF
Zhang et al. (2007)
2007
–
58
ICH
Score C3
AF
Characteristics of included researches The 11 reports included in the meta-analysis involved a total of 1,536 cases of NSCLC tumors and 340 cases of normal lung tissues. Among these, seven studies (Jin et al. 2012; Li et al. 2009; Gui et al. 2007; Hu et al. 2007; Wu et al. 2012; Yu et al. 2006, 2014) discussed the expression of OPN in NSCLC and normal lung tissues and 5 studies
(Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Yu et al. 2006, 2014) analyzed the relationship between the expression of OPN and tumor size. Except for two studies (Hu et al. 2007; Yu et al. 2014), other reports described OPN expression in different pathological types. Several studies described the relationship between the abnormal expression of OPN and tumor differentiation, lymph node metastasis, and clinical staging (Table 1).
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J Mol Hist Fig. 2 Forest plot showed OPN expression in NSCLC and normal tissue
Meta-analysis results
Publication bias
Our meta-analysis did not detect any obvious heterogeneity among the published reports (P = 0.331). The fixed effect model was used to analyze the relationship between OPN expression and the clinical characteristics of NSCLC. Seven reports compared the OPN expression in NSCLC and in normal lung tissues, which showed that the OPN expression rate in NSCLC tissues was higher than that in normal lung tissues (OR 6.427; 95 % CI 4.689–8.808; P = 0.000) (Fig. 2). With respect to OPN positivity, statistically significant results were demonstrated between stage I–II patients and stage III–IV patients (OR 0.332; 95 % CI 0.250–0.440; P = 0.000) (Fig. 3) and between patients with lymph node metastasis and patients without lymph node metastasis (OR 3.094; 95 % CI 2.295–4.172; P = 0.000) (Fig. 4). Significant differences in OPN expression among different tumor sizes was observed (tumor size \3 cm vs. C3 cm; OR 0.484; 95 % CI 0.303–0.773; P = 0.002) (Fig. 5). Compared to adenocarcinomas, a significant positive correlation between OPN expression and lung squamous cell carcinomas was observed (OR 0.611; 95 % CI 0.466–0.800; P = 0.000) (Fig. 6). No correlation between OPN expression and clinicopathological parameters such as the degree of tumor differentiation (Well/Moderate vs. Poor; OR 0.784; 95 % CI 0.555–1.109; P = 0.169) was observed. The results of our meta-analysis suggested that OPN expression in NSCLC tissues has no association with clinical features (including age, gender, and smoking status; P [ 0.05). Among 11 studies included in this metaanalysis, only two studies (Sun et al. 2013; Wu et al. 2012) which investigated the relationship between OPN expression and prognosis of patients with NSCLC. They suggested that positive expression of OPN is associated with poor prognosis in patients with NSCLC.
Begg’s funnel plot was generated to assess publication bias among the included reports. The shapes of the funnel plots did not indicate any evidence of obvious asymmetry (Fig. 7).
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Discussion Several studies have shown that the abnormal expression of OPN is closely associated with the occurrence and development of colon cancer, breast cancer, liver cancer, and some gynecological malignant tumors. Reports have also suggested that OPN plays a role in neovascularization, chemotactic transfer, and adhesion of cytokines, as well as in extracellular matrix degradation, inhibition of cellular apoptosis in tumor cells (Thorat et al. 2013; Etiz et al. 2013; Sim et al. 2012; Cao et al. 2012; Mrochem-Kwarciak et al. 2011; Davidson et al. 2011). OPN is a secreted phosphorylated glycoprotein harboring an a9b1/a4b1 combined domain, with several binding sites for ligands such as Ca2?, a thrombin cracking site, which is responsible for various life activities, and a C terminal that is coupled with the transmembrane glycoprotein, CD44. OPN induces the return of immune cells to their sites of origin, which in turn facilitates metastasis and distant invasion of malignant tumor cells (Davidson et al. 2011; Matusˇan-Ilijasˇ et al. 2013). The abnormal expression of OPN is cell-specific and follows a certain organization; it is regulated by several factors such as cancer suppressor genes, hormones, carcinogenic promoting materials, proto-oncogenes, and growth factors. In normal tissues, OPN expression occurs in the respiratory, breast, digestive tract, normal body fluid, and urinary tissues. Its main physiological functions include the following (Etiz et al. 2013; Cao et al. 2012; Wu
J Mol Hist Fig. 3 Forest plot showed that OPN expression was associated with stage of NSCLC
Fig. 4 Forest plot showed that OPN expression was associated with lymph node metastasis of NSCLC
Fig. 5 Forest plot showed that OPN expression was associated with tumor size of NSCLC
et al. 2012; Chen et al. 2012; Rittling 2011; Zhang et al. 2011; Courter et al. 2010): (1) combining with integrin receptors on the surface of cell membrane and extracellular
matrix to promote adhesion and distant metastasis; (2) promoting vascular endothelial growth factor, assisting in the migration of endothelial cells, and inducing the
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J Mol Hist Fig. 6 Forest plot showed that OPN expression was associated with pathological of NSCLC
Fig. 7 Funnel plot of the meta-analysis
endothelial generation of neovascularization; (3) serving as an essential component of bone mineralization by combining with substrate adhesion molecules to regulate the formation or reconstruction of bone tissues or calcified materials; (4) induction of inflammation and immune responses through Th1, Th2, and IL-12; (5) activation of nuclear factors such as jB to further inhibit cell apoptosis; and (6) interaction with integrin to induce the transduction of normal cell-mediated signals. There are a growing number of reports describing the detection of OPN-positive cancer cells in NSCLC (Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Hu et al. 2005; Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Yu et al. 2006, 2014). However, the role of OPN is relation to the clinicopathological characteristics and prognosis of NSCLC remains elusive. Some reports suggest that OPN in NSCLC might be associated with factors that predict poor prognosis such as histology, tumor stage, grade, and metastatic disease (Ane
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et al. 2012; Jin et al. 2012; Li et al. 2009; Yu et al. 2014), whereas others showed otherwise (Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Zhang et al. 2007). The methods used to detect OPN expression also varied, which included IHC (Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Yu et al. 2006, 2014; Zhang et al. 2007) and tissue microarray (Li et al. 2009; Sun et al. 2013). Based on these discrepancies, a systematic evaluation method was used in the present study. Through literature retrieval and the development and implementation of inclusion and exclusion criteria, reports on the relationship between OPN expression and the pathological and clinical characteristics of NSCLC were screened. A total of 11 reports involving 1,536 cases of NSCLC tumor tissues and 340 cases of normal lung tissues were subjected to quantitative analysis. The results of our meta-analysis showed that OPN expression in NSCLC tissues was markedly higher than that in normal lung tissue. OPN expression was also associated with tumor size, lymph node metastasis, and clinical staging, but no association with pathological types, degree of tumor differentiation, or other clinical features (including age, gender, and smoking status) was detected. Evidence-based medicine has been used to confirm that the abnormal expression of OPN is associated with external invasion growth and distant metastasis, but does not enhance the continuous proliferation of tumor in a fixed position and cannot affect the formation of an ecological niche before metastasis. We analyzed the phenomenon that OPN promotes the formation of tumor blood vessels and lymphatic vessels, increases vascular permeability, and further causes metastatic tumors in lymphatic and blood vessels.
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Although our meta-analysis generated positive results, the present study has a number of limitations. First, the inclusion and exclusion criteria of the present study selected studies that solely focused on tissue OPN expression; thus, studies involving serum OPN expression were excluded. Thus, the role of serum OPN levels in the prognosis of tumor progression should be analyzed in terms of its use in evidence-based medicine and other clinical methods. Second, the number of reports included in the meta-analysis was relatively low, and some of the original data were not perfect. The low number of reports might also increase the risk of publication bias in our meta-analysis. Third, gray reports were not included in the study and, thus, articles with negative results were omitted, which ultimately points to publication bias. In addition, the experiments of the included reports were mostly conducted in China, thus decreasing the probability of representing a patient population consisting of various ethnicities. Finally, most reports did not conduct any follow-up studies on the survival of NSCLC patients or include data on the impact of OPN expression on longterm survival of patients. To summarize, OPN plays an important role in the occurrence and development of NSCLC and our metaanalysis further confirms its value in the prognosis of NSCLC. However, further rigorous and high-quality investigations on the effectiveness of OPN as a therapeutic target for NSCLC are warranted. Conflict of interest peting interests.
The authors declare that they have no com-
References Alberg AJ, Ford JG, Samet JM (2007) Epidemiology of lung cancer: ACCP evidence- based clinical practice guidelines (2nd edition). Chest 132(3 Suppl):29S–55S Ane KR, Marius L, Gisle B et al (2012a) Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer. BMC Cancer 12:333 Ane KR, Marius L, Gisle B et al (2012b) Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer. BMC Cancer 12:333 Blasberg JD, Pass HI, Goparaju CM et al (2010) Reduction of elevated plasma Osteopontin levels with resection of non-smallcell lung cancer. J Clin Oncol 28(6):936–941 Boldrini L, Donati V, Dell’Omodarme M et al (2005) Prognostic significance of osteopontin expression in early-stage non-smallcell lung cancer. Br J Cancer 93(4):453–457 Cao DX, Li ZJ, Jiang XO et al (2012) Osteopontin as potential biomarker and therapeutic target in gastric and liver cancers. World J Gastroenterol 18(30):3923–3930 Chambers AF, Wilson SM, Kerkvliet N et al (1996) Osteopontin expression in lung cancer. Lung Cancer 15(3):311–323 Chang YS, Kim HJ, Chang J et al (2007) Elevated circulating level of osteopontin is associated with advanced disease state of nonsmall cell lung cancer. Lung Cancer 57(3):373–380
Chen CH, Shiu LY, Su LJ et al (2012) FLJ10540 is associated with tumor progression in nasopharyngeal carcinomas and contributes to nasopharyngeal cell proliferation, and metastasis via osteopontin/CD44 pathway. J Transl Med 10:93 Collins LG, Haines C, Perkel R et al (2007) Lung cancer: diagnosis and management. Am Fam Physician 75(1):56–63 Courter D, Cao H, Kwok S et al (2010) The RGD domain of human osteopontin promotes tumor growth and metastasis through activation of survival pathways. PLoS ONE 5(3):e9633 Davidson B, Holth A, Moripen L et al (2011) Osteopontin expression in ovarian carcinoma effusions is related to improved clinical outcome. Hum Pathol 42(7):991–997 Donati V, Boldrini L, Dell’Omodarme M et al (2005) Osteopontin expression and prognostic significance in non-small cell lung cancer. Clin Cancer Res 11(18):6459–6465 Etiz D, Ataizi FC, Bayman E et al (2013) Prognostic value of osteopontin in patients treated with primary radiotherapy for head and neck cancer. Asian Pac J Cancer Prev 14(9):5175–5178 Gui SY, Li HH, Zuo L et al (2007) Protein and mRNA expression of osteopontin in lung cancer and clinical significance thereof. Zhonghua Yi Xue Za Zhi 87(45):3219–3223 Han SS, Lee SJ, Kim WJ et al (2013) Plasma osteopontin is a useful diagnostic biomarker for advanced non-small cell lung cancer. Tuberc Respir Dis (Seoul) 75(3):104–110 Hu Z, Lin D, Yuan J et al (2005) Overexpression of osteopontin is associated with more aggressive phenotypes in human non-small cell lung cancer. Clin Cancer Res 11(13):4646–4652 Hu Z, Xiao T, Lin DM et al (2007) Over-expression of osteopontin in non-small cell lung cancers: its clinical significance. Zhonghua Zhong Liu Za Zhi 29(8):591–595 Isa S, Kawaguchi T, Teramukai S et al (2009) Serum osteopontin levels are highly prognostic for survival in advanced non-small cell lung cancer: results from JMTO LC 0004. J Thorac Oncol 4(9):1104–1110 Jema A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90 Jin Y, Tong DY, Tang LY et al (2012) Expressions of osteopontin (OPN), amb3 and Pim-1 associated with poor prognosis in nonsmall cell lung cancer (NSCLC). Chin J Cancer Res 24(2):103–108 Joseph S, Harrington R, Walter D et al (2012) Plasma osteopontin velocity differentiates lung cancers from controls in a CT screening population. Cancer Biomark 12(4):177–184 Karadag F, Gulen ST, Karul AB et al (2011) Osteopontin as a marker of weight loss in lung cancer. Scand J Clin Lab Invest 71(8):690–694 Li T, Zhou J, Deng Z et al (2009) Expression of FGF-2 and osteopontin in non-small cell lung cancer. Zhong Nan Da Xue Xue Bao Yi Xue Ban 34(11):1114–1119 Liang Y, Li H, Hou SC et al (2009) The expression of galectin-3 and osteopontin in occult metastasis of non-small cell lung cancer. Zhonghua Wai Ke Za Zhi 47(14):1061–1063 Liang Y, Li H, Hu B et al (2011) Elevated circulating levels of osteopontin are associated with metastasis in advanced nonsmall cell lung cancer. Chin J Cancer Res 23(1):64–68 Mack PC, Redman MW, Chansky K et al (2008) Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 26(29):4771–4776 Matusˇan-Ilijasˇ K, Damante G, Fabbro D et al (2013) EGFR expression is linked to Osteopontin and Nf-jB signaling in clear cell renal cell carcinoma. Clin Transl Oncol 15(1):65–71 Mrochem-Kwarciak J, Mrochen-Domin I, Wojcieszek A et al (2011) Usefulness of osteopontin (OPN) determinations in ovarian cancer patients who underwent first-line chemotherapy. Ginekol Pol 82(12):911–917
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J Mol Hist Ostheimer C, Bache M, Gu¨ttler A, et al. A pilot study on potential plasma hypoxia markers in the radiotherapy of non-small cell lung cancer : Osteopontin, carbonic anhydrase IX and vascular endothelial growth factor. Strahlenther Onkol, 2013, s00066013-0484-1 Rittling SR (2011) Osteopontin in macrophage function. Expert Rev Mol Med 13:e15 Rud AK, Boye K, Oijordsbakken M et al (2013) Osteopontin is a prognostic biomarker in non-small cell lung cancer. BMC Cancer 13(1):540 Schneider S, Yochim J, Brabender J et al (2004) Osteopontin but not osteonectin messenger RNA expression is a prognostic marker in curatively resected non-small cell lung cancer. Clin Cancer Res 10(5):1588–1596 Sim SH, Messenger MP, Gregory WM et al (2012) Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma. Br J Cancer 107(7):1131–1137 Stemberger C, Matusˇan-Ilijasˇ K, Avirovic´ M et al (2013) Osteopontin is associated with decreased apoptosis and av integrin expression in lung adenocarcinoma. Acta Histochem S0065–1281(13): 00148 Sun BS, Li Y, Zhang ZF et al (2013) Osteopontin combined with CD44v6, a novel prognostic biomarker in non-small cell lung cancer undergoing curative resection. Ann Thorac Surg 96(6):1943–1951 Takenaka M, Hanagiri T, Shinohara S et al (2013) Serum level of osteopontin as a prognostic factor in patients who underwent surgical resection for non-small-cell lung cancer. Clin Lung Cancer 14(3):288–294
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Terpos E, Kiagia M, Karapanagiotou EM et al (2009) The clinical significance of serum markers of bone turnover in NSCLC patients: surveillance, management and prognostic implications. Anticancer Res 29(5):1651–1657 Thorat D, Sahu A, Behera R et al (2013) Association of Osteopontin and cyclooxygenase-2 expression with breast cancer subtypes and their use as potential biomarkers. Oncol Lett 6(6):1559–1564 Wu J, Zhang X, Zhu YN (2012a) Expression osteopontin and MMP-2 in non-small cell lung cancer. J Clin Exp Pathol 28(8):924–926 Wu Y, Jiang W, Wang Y et al (2012b) Breast cancer metastasis suppressor 1 regulates hepatocellular carcinoma cell apoptosis via suppressing osteopontin expression. PLoS ONE 7(8):e42976 Yang Y, Cheng D, Li X et al (2007) Expression and clinicopathological significance of OPN and CD44v6 in lung cancer. Zhongguo Fei Ai Za Zhi 10(2):98–101 Yu J, Pan T, Li J et al (2006) Expression and clinicopathologic significance of OPN, CD44v6 and MMP-2 in squamous cell carcinoma and adenocarcinoma of the lung. Zhongguo Fei Ai Za Zhi 9(4):325–328 Yu TT, Han ZG, Shan L et al (2014) Expression of osteopontin in non-small cell lung cancer and correlative relation with microvascular density. Asian Pac J Cancer Prev 15(1):29–32 Zhang X, Xue S, Zheng J et al (2007) Correlation between OPN and P21 in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 10(4):288–290 Zhang Y, Forootan SS, Kamalian L et al (2011) Suppressing tumourigenicity of prostate cancer cells by inhibiting osteopontin expression. Int J Oncol 38(4):1083–1091
ORIGINAL PAPER
The prognostic value of osteopontin expression in non-small cell lung cancer: a meta-analysis Tao Zhang • Dong-Ming Zhang • Da Zhao • Xiao-Ming Hou • Xiao-Jun Liu • Xiao-Ling Ling Shou-Cheng Ma
•
Received: 10 March 2014 / Accepted: 22 April 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To investigate the association of Osteopontin (OPN) expression in tumor tissue with clinicopathological features of non-small cell lung carcinoma (NSCLC) patients. Publications assessing the clinicopathological characteristics and prognostic significance of OPN in expression NSCLC were identified up to March 2014. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between OPN expression and these clinical parameters. A total of eleven studies met the inclusion criteria, and included 1536 cases of NSCLC tumor tissue and 340 cases of normal lung tissue. The OPN expression rate in NSCLC tissue was higher than normal tissue [Odds ratio (OR) 6.427; 95 % confidence interval (CI) 4.689–8.808; P = 0.000]. Simultaneously, we also found that OPN expression was positively associated with stage (OR 0.332; 95 % CI 0.250–0.440; P = 0.000), lymph node metastasis (OR 3.094; 95 % CI 2.295–4.172; P = 0.000), tumor size (tumor size \3 cm vs. C3 cm; OR 0.484; 95 % CI 0.303–0.773; P = 0.002) and pathology (OR 0.611; 95 % CI 0.466–0.800; P = 0.000). It was unrelated that OPN expression in NSCLC tissue with and degree of differentiation and other clinical features (P [ 0.05). Experimental Tao Zhang and Dong-Ming Zhang have contributed equally to this paper. T. Zhang D. Zhao (&) X.-M. Hou X.-J. Liu X.-L. Ling S.-C. Ma Department of Oncology, The First Hospital of Lanzhou University (The Branch Hospital of Donggang), Lanzhou 730000, Gansu Province, China e-mail: [email protected] D.-M. Zhang Department of Respiratory, The Second People’s Hospital of Pingliang, Pingliang 744000, Gansu Province, China
findings indicate that, OPN plays a crucial role in the development of NSCLC. Keywords Carcinoma Non-small cell lung Osteopontin Clinicopathological characteristics Metaanalysis
Introduction Lung cancer is currently recognized as one of the leading cancers with the highest morbidity and mortality (Jema et al. 2011) with approximately 1.6 million new cases and at least 1.3 million deaths worldwide each year. Non-small cell lung cancer (NSCLC) accounts for approximately 80 % of all lung cancers, which include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (Collins et al. 2007). Invasion and metastasis, which are the most important biological characteristics of malignant tumors and the main causes of death in patients, rapidly develop in NSCLC patients; thus, their 5-year survival rate is generally low (Alberg et al. 2007). The mechanism of invasion and metastasis of NSCLC remains unclear; thus, exploring the biological indicators for invasion and metastasis, especially for the prognosis of NSCLC, is particularly important. Osteopontin (OPN) is a protein secreted by bone stromal cells and is rich in sialic acid. It serves as a bridge between cells and its substrates. Studies have associated the upregulation of this newly discovered cytokine in breast cancer, renal cancer, esophageal cancer, endometrial cancer, and a variety of digestive tract tumors with the growth, migration, and invasion of tumor cells (Thorat et al. 2013; Etiz et al. 2013; Sim et al. 2012; Cao et al. 2012). Some studies have argued that the abnormal expression of OPN is
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strongly associated with clinical pathologic characteristics of NSCLC such as the clinical staging of the tumor, histological grade, and lymph node metastasis, thus suggesting that it might also influence its prognosis. On the other hand, there are also researchers that consider the high expression of OPN to be unrelated to the clinicopathological characteristics of NSCLC. For example, (Ane et al. 2012), Jin et al. (2012), and Li et al. (2009) reported that there was no relationship between the high expression of OPN and the size or pathological stage of the tumor. Based on these findings, the present study collected data from related published literature and conducted a meta-analysis of the relationship between OPN expression and NSCLC, aiming to provide evidence for the treatment and prognosis of NSCLC.
Methods Inclusion and exclusion criteria The inclusion criteria were as follows: published related literature on the correlation between OPN expression in primary tumor tissues and NSCLC and pathological features; cases with complete clinical data and not subjected to radiotherapy or chemotherapy prior to selection; similar research topic and research method, wherein immunohistochemistry was used as the detection method of OPN; and the expression results were judged by scoring the amount or strength of staining of cells. The exclusion criteria were as follows: literature showing an inconsistent judgment standard for positive OPN expression and OPN expression in non-primary tumor tissues of NSCLC patients (OPN detection in patient’s blood circulation); literature presenting repeated or duplicated documents and poor quality; and literature involving animal experiments or literature reviews. Literature retrieval and data extraction Literature retrieval was conducted in PubMed, EMBASE, and Web of Science and the search-terms ‘‘Osteopontin’’, ‘‘OPN non-small cell lung cancer’’ and ‘‘NSCLC’’ were used. Retrieval of the combined key words and free words and the time was from the day when the database was established to March 2014, without language restrictions. Based on these conditions, references from the included literature and related conference paper collections were manually retrieved. Literature screening was independently performed by two reviewers (Tao Zhang and DM Zhang). First, by reading the title and abstract, the literature that obviously did not satisfy the inclusion criteria were eliminated, and the reports that were difficult to judge were
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further assessed by reading the entire text. All reports were jointly assessed by the two evaluators, and when there were different opinions, a discussion was held with a third person (Da Zhao). Relevant information, including title, author, year of publication, general details of the included cases, OPN expression in the tumor tissues, pathological type, diameter of tumor, degree of differentiation, lymph node metastasis, and clinical staging were extracted from the reports. Statistical analysis Comprehensive Meta-Analysis software (Version 2.0) was used to perform meta-analysis; the Q test was used to examine heterogeneity among the included research results. When statistical homogeneity was detected in the reports (P [ 0.1), a fixed effect model was used; furthermore, when statistical heterogeneity was observed in the articles (P \ 0.1), a random effect model was employed for the analysis or only a qualitative description was performed. A Begg’s funnel plot was generated to examine any underlying publication bias. Odds ratio (OR) and a 95 % confidence interval (CI) were used as the combined statistic for all results and P \ 0.05 was considered statistically significant.
Result Retrieval results Total of 85 reports satisfied the established inclusion criteria; then according to inclusion and exclusion criteria, the Medical Literature King software was used to exclude 35 reports that were deemed repeat publications; 19 articles were excluded based solely on reading the title and abstract; 20 reports were discarded on the basis of reading the entire text and analysis, for the following reasons:(1) the level of OPN was continuous variable data (Stemberger et al. 2013; Schneider et al. 2004); (2) OPN was evaluated on blood sample (Ostheimer et al. 2013; Karadag et al. 2011; Blasberg et al. 2010; Liang et al. 2009; Takenaka et al. 2013; Mack et al. 2008; Joseph et al. 2012; Han et al. 2013; Isa et al. 2009; Liang et al. 2011; Chang et al. 2007; Terpos et al. 2009); (3) evaluation criteria are inconsistent with other literature or unable extract data (Boldrini et al. 2005; Donati et al. 2005; Rud et al. 2013; Chambers et al. 1996; Ane et al. 2012); (4) may contain duplicate patients (Hu et al. 2005). Finally, 11 articles were selected for metaanalysis (Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Yu et al. 2006, 2014; Zhang et al. 2007; Fig. 1).
J Mol Hist Fig. 1 Flow chart for selection of studies for inclusion in this meta-analysis. Characteristics of included researches
Table 1 The general characteristics of studies included in the meta-analysis
ICH Immunohistochemistry, TMT Tissue microarray technology, A The control benign tissue, B Tumor size, C Histology, D Stage, E Differentiation, F Lymph node metastasis, G Distant metastasis
Study
Year of publication
Stage
Number of NSCLC tissues
Measurement method
Cut-off of ICH
Outcome
BC
Ane et al. (2012)
2012
I–IV
196
ICH
Score C3
Gui et al. (2007)
2007
I–IV
41
ICH
Score C1
AC
Hu et al. (2007)
2007
I–IV
555
ICH ? TMT
C25 % positive cells
ACDF
Jin et al. (2012)
2012
I–IV
136
ICH
C10 % positive cells
ABCDEF
Li et al. (2009)
2009
I–IV
48
ICH ? TMT
Score C3
ABCDEF
Sun et al. (2013)
2013
I–III
159
ICH
Score C1
CDEFG
Wu et al. (2012)
2012
I–IV
89
ICH
Score C1
ACDEF
Yang et al. (2007)
2007
I–IV
65
ICH
C10 % positive cells
CD
Yu et al. (2006)
2006
I–III
69
ICH
Score C1
ABCDEF
Yu et al. (2014)
2014
I–III
120
ICH
Score C1
ABCDEF
Zhang et al. (2007)
2007
–
58
ICH
Score C3
AF
Characteristics of included researches The 11 reports included in the meta-analysis involved a total of 1,536 cases of NSCLC tumors and 340 cases of normal lung tissues. Among these, seven studies (Jin et al. 2012; Li et al. 2009; Gui et al. 2007; Hu et al. 2007; Wu et al. 2012; Yu et al. 2006, 2014) discussed the expression of OPN in NSCLC and normal lung tissues and 5 studies
(Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Yu et al. 2006, 2014) analyzed the relationship between the expression of OPN and tumor size. Except for two studies (Hu et al. 2007; Yu et al. 2014), other reports described OPN expression in different pathological types. Several studies described the relationship between the abnormal expression of OPN and tumor differentiation, lymph node metastasis, and clinical staging (Table 1).
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J Mol Hist Fig. 2 Forest plot showed OPN expression in NSCLC and normal tissue
Meta-analysis results
Publication bias
Our meta-analysis did not detect any obvious heterogeneity among the published reports (P = 0.331). The fixed effect model was used to analyze the relationship between OPN expression and the clinical characteristics of NSCLC. Seven reports compared the OPN expression in NSCLC and in normal lung tissues, which showed that the OPN expression rate in NSCLC tissues was higher than that in normal lung tissues (OR 6.427; 95 % CI 4.689–8.808; P = 0.000) (Fig. 2). With respect to OPN positivity, statistically significant results were demonstrated between stage I–II patients and stage III–IV patients (OR 0.332; 95 % CI 0.250–0.440; P = 0.000) (Fig. 3) and between patients with lymph node metastasis and patients without lymph node metastasis (OR 3.094; 95 % CI 2.295–4.172; P = 0.000) (Fig. 4). Significant differences in OPN expression among different tumor sizes was observed (tumor size \3 cm vs. C3 cm; OR 0.484; 95 % CI 0.303–0.773; P = 0.002) (Fig. 5). Compared to adenocarcinomas, a significant positive correlation between OPN expression and lung squamous cell carcinomas was observed (OR 0.611; 95 % CI 0.466–0.800; P = 0.000) (Fig. 6). No correlation between OPN expression and clinicopathological parameters such as the degree of tumor differentiation (Well/Moderate vs. Poor; OR 0.784; 95 % CI 0.555–1.109; P = 0.169) was observed. The results of our meta-analysis suggested that OPN expression in NSCLC tissues has no association with clinical features (including age, gender, and smoking status; P [ 0.05). Among 11 studies included in this metaanalysis, only two studies (Sun et al. 2013; Wu et al. 2012) which investigated the relationship between OPN expression and prognosis of patients with NSCLC. They suggested that positive expression of OPN is associated with poor prognosis in patients with NSCLC.
Begg’s funnel plot was generated to assess publication bias among the included reports. The shapes of the funnel plots did not indicate any evidence of obvious asymmetry (Fig. 7).
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Discussion Several studies have shown that the abnormal expression of OPN is closely associated with the occurrence and development of colon cancer, breast cancer, liver cancer, and some gynecological malignant tumors. Reports have also suggested that OPN plays a role in neovascularization, chemotactic transfer, and adhesion of cytokines, as well as in extracellular matrix degradation, inhibition of cellular apoptosis in tumor cells (Thorat et al. 2013; Etiz et al. 2013; Sim et al. 2012; Cao et al. 2012; Mrochem-Kwarciak et al. 2011; Davidson et al. 2011). OPN is a secreted phosphorylated glycoprotein harboring an a9b1/a4b1 combined domain, with several binding sites for ligands such as Ca2?, a thrombin cracking site, which is responsible for various life activities, and a C terminal that is coupled with the transmembrane glycoprotein, CD44. OPN induces the return of immune cells to their sites of origin, which in turn facilitates metastasis and distant invasion of malignant tumor cells (Davidson et al. 2011; Matusˇan-Ilijasˇ et al. 2013). The abnormal expression of OPN is cell-specific and follows a certain organization; it is regulated by several factors such as cancer suppressor genes, hormones, carcinogenic promoting materials, proto-oncogenes, and growth factors. In normal tissues, OPN expression occurs in the respiratory, breast, digestive tract, normal body fluid, and urinary tissues. Its main physiological functions include the following (Etiz et al. 2013; Cao et al. 2012; Wu
J Mol Hist Fig. 3 Forest plot showed that OPN expression was associated with stage of NSCLC
Fig. 4 Forest plot showed that OPN expression was associated with lymph node metastasis of NSCLC
Fig. 5 Forest plot showed that OPN expression was associated with tumor size of NSCLC
et al. 2012; Chen et al. 2012; Rittling 2011; Zhang et al. 2011; Courter et al. 2010): (1) combining with integrin receptors on the surface of cell membrane and extracellular
matrix to promote adhesion and distant metastasis; (2) promoting vascular endothelial growth factor, assisting in the migration of endothelial cells, and inducing the
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J Mol Hist Fig. 6 Forest plot showed that OPN expression was associated with pathological of NSCLC
Fig. 7 Funnel plot of the meta-analysis
endothelial generation of neovascularization; (3) serving as an essential component of bone mineralization by combining with substrate adhesion molecules to regulate the formation or reconstruction of bone tissues or calcified materials; (4) induction of inflammation and immune responses through Th1, Th2, and IL-12; (5) activation of nuclear factors such as jB to further inhibit cell apoptosis; and (6) interaction with integrin to induce the transduction of normal cell-mediated signals. There are a growing number of reports describing the detection of OPN-positive cancer cells in NSCLC (Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Hu et al. 2005; Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Yu et al. 2006, 2014). However, the role of OPN is relation to the clinicopathological characteristics and prognosis of NSCLC remains elusive. Some reports suggest that OPN in NSCLC might be associated with factors that predict poor prognosis such as histology, tumor stage, grade, and metastatic disease (Ane
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et al. 2012; Jin et al. 2012; Li et al. 2009; Yu et al. 2014), whereas others showed otherwise (Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Zhang et al. 2007). The methods used to detect OPN expression also varied, which included IHC (Ane et al. 2012; Jin et al. 2012; Li et al. 2009; Gui et al. 2007; Hu et al. 2007; Sun et al. 2013; Wu et al. 2012; Yang et al. 2007; Yu et al. 2006, 2014; Zhang et al. 2007) and tissue microarray (Li et al. 2009; Sun et al. 2013). Based on these discrepancies, a systematic evaluation method was used in the present study. Through literature retrieval and the development and implementation of inclusion and exclusion criteria, reports on the relationship between OPN expression and the pathological and clinical characteristics of NSCLC were screened. A total of 11 reports involving 1,536 cases of NSCLC tumor tissues and 340 cases of normal lung tissues were subjected to quantitative analysis. The results of our meta-analysis showed that OPN expression in NSCLC tissues was markedly higher than that in normal lung tissue. OPN expression was also associated with tumor size, lymph node metastasis, and clinical staging, but no association with pathological types, degree of tumor differentiation, or other clinical features (including age, gender, and smoking status) was detected. Evidence-based medicine has been used to confirm that the abnormal expression of OPN is associated with external invasion growth and distant metastasis, but does not enhance the continuous proliferation of tumor in a fixed position and cannot affect the formation of an ecological niche before metastasis. We analyzed the phenomenon that OPN promotes the formation of tumor blood vessels and lymphatic vessels, increases vascular permeability, and further causes metastatic tumors in lymphatic and blood vessels.
J Mol Hist
Although our meta-analysis generated positive results, the present study has a number of limitations. First, the inclusion and exclusion criteria of the present study selected studies that solely focused on tissue OPN expression; thus, studies involving serum OPN expression were excluded. Thus, the role of serum OPN levels in the prognosis of tumor progression should be analyzed in terms of its use in evidence-based medicine and other clinical methods. Second, the number of reports included in the meta-analysis was relatively low, and some of the original data were not perfect. The low number of reports might also increase the risk of publication bias in our meta-analysis. Third, gray reports were not included in the study and, thus, articles with negative results were omitted, which ultimately points to publication bias. In addition, the experiments of the included reports were mostly conducted in China, thus decreasing the probability of representing a patient population consisting of various ethnicities. Finally, most reports did not conduct any follow-up studies on the survival of NSCLC patients or include data on the impact of OPN expression on longterm survival of patients. To summarize, OPN plays an important role in the occurrence and development of NSCLC and our metaanalysis further confirms its value in the prognosis of NSCLC. However, further rigorous and high-quality investigations on the effectiveness of OPN as a therapeutic target for NSCLC are warranted. Conflict of interest peting interests.
The authors declare that they have no com-
References Alberg AJ, Ford JG, Samet JM (2007) Epidemiology of lung cancer: ACCP evidence- based clinical practice guidelines (2nd edition). Chest 132(3 Suppl):29S–55S Ane KR, Marius L, Gisle B et al (2012a) Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer. BMC Cancer 12:333 Ane KR, Marius L, Gisle B et al (2012b) Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer. BMC Cancer 12:333 Blasberg JD, Pass HI, Goparaju CM et al (2010) Reduction of elevated plasma Osteopontin levels with resection of non-smallcell lung cancer. J Clin Oncol 28(6):936–941 Boldrini L, Donati V, Dell’Omodarme M et al (2005) Prognostic significance of osteopontin expression in early-stage non-smallcell lung cancer. Br J Cancer 93(4):453–457 Cao DX, Li ZJ, Jiang XO et al (2012) Osteopontin as potential biomarker and therapeutic target in gastric and liver cancers. World J Gastroenterol 18(30):3923–3930 Chambers AF, Wilson SM, Kerkvliet N et al (1996) Osteopontin expression in lung cancer. Lung Cancer 15(3):311–323 Chang YS, Kim HJ, Chang J et al (2007) Elevated circulating level of osteopontin is associated with advanced disease state of nonsmall cell lung cancer. Lung Cancer 57(3):373–380
Chen CH, Shiu LY, Su LJ et al (2012) FLJ10540 is associated with tumor progression in nasopharyngeal carcinomas and contributes to nasopharyngeal cell proliferation, and metastasis via osteopontin/CD44 pathway. J Transl Med 10:93 Collins LG, Haines C, Perkel R et al (2007) Lung cancer: diagnosis and management. Am Fam Physician 75(1):56–63 Courter D, Cao H, Kwok S et al (2010) The RGD domain of human osteopontin promotes tumor growth and metastasis through activation of survival pathways. PLoS ONE 5(3):e9633 Davidson B, Holth A, Moripen L et al (2011) Osteopontin expression in ovarian carcinoma effusions is related to improved clinical outcome. Hum Pathol 42(7):991–997 Donati V, Boldrini L, Dell’Omodarme M et al (2005) Osteopontin expression and prognostic significance in non-small cell lung cancer. Clin Cancer Res 11(18):6459–6465 Etiz D, Ataizi FC, Bayman E et al (2013) Prognostic value of osteopontin in patients treated with primary radiotherapy for head and neck cancer. Asian Pac J Cancer Prev 14(9):5175–5178 Gui SY, Li HH, Zuo L et al (2007) Protein and mRNA expression of osteopontin in lung cancer and clinical significance thereof. Zhonghua Yi Xue Za Zhi 87(45):3219–3223 Han SS, Lee SJ, Kim WJ et al (2013) Plasma osteopontin is a useful diagnostic biomarker for advanced non-small cell lung cancer. Tuberc Respir Dis (Seoul) 75(3):104–110 Hu Z, Lin D, Yuan J et al (2005) Overexpression of osteopontin is associated with more aggressive phenotypes in human non-small cell lung cancer. Clin Cancer Res 11(13):4646–4652 Hu Z, Xiao T, Lin DM et al (2007) Over-expression of osteopontin in non-small cell lung cancers: its clinical significance. Zhonghua Zhong Liu Za Zhi 29(8):591–595 Isa S, Kawaguchi T, Teramukai S et al (2009) Serum osteopontin levels are highly prognostic for survival in advanced non-small cell lung cancer: results from JMTO LC 0004. J Thorac Oncol 4(9):1104–1110 Jema A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90 Jin Y, Tong DY, Tang LY et al (2012) Expressions of osteopontin (OPN), amb3 and Pim-1 associated with poor prognosis in nonsmall cell lung cancer (NSCLC). Chin J Cancer Res 24(2):103–108 Joseph S, Harrington R, Walter D et al (2012) Plasma osteopontin velocity differentiates lung cancers from controls in a CT screening population. Cancer Biomark 12(4):177–184 Karadag F, Gulen ST, Karul AB et al (2011) Osteopontin as a marker of weight loss in lung cancer. Scand J Clin Lab Invest 71(8):690–694 Li T, Zhou J, Deng Z et al (2009) Expression of FGF-2 and osteopontin in non-small cell lung cancer. Zhong Nan Da Xue Xue Bao Yi Xue Ban 34(11):1114–1119 Liang Y, Li H, Hou SC et al (2009) The expression of galectin-3 and osteopontin in occult metastasis of non-small cell lung cancer. Zhonghua Wai Ke Za Zhi 47(14):1061–1063 Liang Y, Li H, Hu B et al (2011) Elevated circulating levels of osteopontin are associated with metastasis in advanced nonsmall cell lung cancer. Chin J Cancer Res 23(1):64–68 Mack PC, Redman MW, Chansky K et al (2008) Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 26(29):4771–4776 Matusˇan-Ilijasˇ K, Damante G, Fabbro D et al (2013) EGFR expression is linked to Osteopontin and Nf-jB signaling in clear cell renal cell carcinoma. Clin Transl Oncol 15(1):65–71 Mrochem-Kwarciak J, Mrochen-Domin I, Wojcieszek A et al (2011) Usefulness of osteopontin (OPN) determinations in ovarian cancer patients who underwent first-line chemotherapy. Ginekol Pol 82(12):911–917
123
J Mol Hist Ostheimer C, Bache M, Gu¨ttler A, et al. A pilot study on potential plasma hypoxia markers in the radiotherapy of non-small cell lung cancer : Osteopontin, carbonic anhydrase IX and vascular endothelial growth factor. Strahlenther Onkol, 2013, s00066013-0484-1 Rittling SR (2011) Osteopontin in macrophage function. Expert Rev Mol Med 13:e15 Rud AK, Boye K, Oijordsbakken M et al (2013) Osteopontin is a prognostic biomarker in non-small cell lung cancer. BMC Cancer 13(1):540 Schneider S, Yochim J, Brabender J et al (2004) Osteopontin but not osteonectin messenger RNA expression is a prognostic marker in curatively resected non-small cell lung cancer. Clin Cancer Res 10(5):1588–1596 Sim SH, Messenger MP, Gregory WM et al (2012) Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma. Br J Cancer 107(7):1131–1137 Stemberger C, Matusˇan-Ilijasˇ K, Avirovic´ M et al (2013) Osteopontin is associated with decreased apoptosis and av integrin expression in lung adenocarcinoma. Acta Histochem S0065–1281(13): 00148 Sun BS, Li Y, Zhang ZF et al (2013) Osteopontin combined with CD44v6, a novel prognostic biomarker in non-small cell lung cancer undergoing curative resection. Ann Thorac Surg 96(6):1943–1951 Takenaka M, Hanagiri T, Shinohara S et al (2013) Serum level of osteopontin as a prognostic factor in patients who underwent surgical resection for non-small-cell lung cancer. Clin Lung Cancer 14(3):288–294
123
Terpos E, Kiagia M, Karapanagiotou EM et al (2009) The clinical significance of serum markers of bone turnover in NSCLC patients: surveillance, management and prognostic implications. Anticancer Res 29(5):1651–1657 Thorat D, Sahu A, Behera R et al (2013) Association of Osteopontin and cyclooxygenase-2 expression with breast cancer subtypes and their use as potential biomarkers. Oncol Lett 6(6):1559–1564 Wu J, Zhang X, Zhu YN (2012a) Expression osteopontin and MMP-2 in non-small cell lung cancer. J Clin Exp Pathol 28(8):924–926 Wu Y, Jiang W, Wang Y et al (2012b) Breast cancer metastasis suppressor 1 regulates hepatocellular carcinoma cell apoptosis via suppressing osteopontin expression. PLoS ONE 7(8):e42976 Yang Y, Cheng D, Li X et al (2007) Expression and clinicopathological significance of OPN and CD44v6 in lung cancer. Zhongguo Fei Ai Za Zhi 10(2):98–101 Yu J, Pan T, Li J et al (2006) Expression and clinicopathologic significance of OPN, CD44v6 and MMP-2 in squamous cell carcinoma and adenocarcinoma of the lung. Zhongguo Fei Ai Za Zhi 9(4):325–328 Yu TT, Han ZG, Shan L et al (2014) Expression of osteopontin in non-small cell lung cancer and correlative relation with microvascular density. Asian Pac J Cancer Prev 15(1):29–32 Zhang X, Xue S, Zheng J et al (2007) Correlation between OPN and P21 in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 10(4):288–290 Zhang Y, Forootan SS, Kamalian L et al (2011) Suppressing tumourigenicity of prostate cancer cells by inhibiting osteopontin expression. Int J Oncol 38(4):1083–1091
