Abstract
Over-expression of TROP2 (the trophoblast cell surface antigen 2) was reported to predict poor prognosis in various solid tumors in number of studies. However, the results remained not comprehensive. Therefore, we here carried out this meta-analysis of relevant studies published on this topic to quantitatively evaluate the clinicopathological significance of TROP2 in solid tumors. Relevant articles were identified through searching the PubMed, Web of Science and Embase database. The primary outcomes were overall survival (OS) and disease-free survival (DFS). In this meta-analysis, 16 studies involving 2,569 participants were included and we drew the conclusion that TROP2 overexpression was significantly associated with poor OS (pooled HR = 1.896, 95% CI = 1.599–2.247, P < 0.001) and short DFS (pooled HR = 2.336, 95% CI = 1.596–3.419, P < 0.001). Furthermore, the subgroup analysis revealed that the associations between TROP2 overexpression and the outcome endpoints (OS or DFS) were significant in in patients with female genital system neoplasms, as well in gastrointestine neoplasms. In addition, subgroup analysis found no difference HR across populations of different descent.Taken together, TROP2 overexpression was associated with poor survival in human solid tumors. TROP2 may be a valuable prognosis predictive biomarker and a potential therapeutic target in human solid tumors.
Similar content being viewed by others
Introduction
Trophoblast cell surface antigen 2 (TROP2), also known as GA733-1 or EGP-1 or TACSTD2, was a 36-kDa transmembrane glycoprotein, which was originally defined on normal and malignant trophoblast cells1,2,3. TROP2 has four potential N-linked glycosylation sites and consists of 323 amino acids4. Trop-2 was synthesized in the endoplasmic reticulum, transported to and glycosylated in the Golgi apparatus and then sorted to the cell membrane5. Trop-2 was a calcium signal transducer that drives tumor growth and as quantitative tumor driver3,5. Existing evidences have shown that it plays a functional role in cancer progression and stem cells6,7. Altered expression and/or activity of TROP2 was involved in cancer cell growth, proliferation, migration, invasion and survival8,9,10,11,12,13. An increasing number of studies suggested that TROP2 is highly expressed in solid tumors, including gastric cancer14,15, nasopharyngeal carcinoma16, gallbladder cancer17, cervical cancer18, extranodal NK/T cell lymphoma11, lung cancer9,19, laryngeal squamous cell carcinoma20, colon cancer21,22,23, Hilar Cholangiocarcinoma24, pancreatic cancer25, squamous cell carcinoma of the oral cavity26, endometrioid endometrial carcinoma27, ovarian carcinoma28. These striking evidences on the role of TROP2 in cancer suggest the transmembrane glycoprotein would be further considered as a potential marker for outcome of cancer patients.
Many studies showed that increased TROP2 expression in tumor tissues was correlated with poor survival of patients with various cancer types. However, the results of those individual studies were not comprehensive. In the present study, we performed this comprehensive meta-analysis aiming to clarify the prognostic value of TROP2 in solid tumors and to support that the protein may be a potential therapeutic oncotarget.
Materials and Methods
Publication search
This present meta-analysis was performed under the Preferred Reporting Items for Systematics Reviews and Meta-Analyses guidelines29. A comprehensive literature search was performed using the electronic databases PubMed, Embase and Web of Science databases (up to April 7, 2016) with the search terms: ‘TROP2’, ‘Trophoblast cell surface antigen 2′ and “cancer”/“tumor”/“neoplasm”/“carcinoma” and the following limits: Human, article in English or Chinese. All potentially eligible studies were retrieved and their bibliographies were carefully scanned to identify other eligible studies and extra studies were identified by a hand search of the references cited in the original studies. When multiple studies of the same patient population were identified, we included the published report with the largest sample size.
Inclusion criteria
To be eligible for inclusion in this meta-analysis and data extraction, studies had to: (a) evaluation of TROP2 expression for predicting prognosis in cancer, (b) provide hazard ratios (HRs) with 95% confidence intervals (CIs) or enable calculation of these statistics from the data presented (c) classify TROP2 expression as “high” and “low” or “positive” and “negative”. (d) studies published in English.
Exclusion criteria
Exclusion criteria were: (a) literatures published as letters, editorials, abstracts, reviews, case reports and expert opinions; (b) experiments performed in vitro or in vivo, but not based on patients; (c) articles without the HRs and 95% CI or K-M survival curves dealing with overall survival, disease-free survival; (d) The follow-up duration was shorter than 3 years.
Data extraction
All data from the included studies were extracted independently and carefully by two reviewers using a standardized form. Disagreement was resolved through independently extracting data from the original article by the third author and consensus was reached by discussions. The meta-analysis of TROP2 expression was based on two outcome endpoints: OS and DFS. Several different parameters, if reported, were extracted from each paper, including the first author’s surname, publication year, country of origin, number of patients analyzed, types of measurement and score for TROP2 assessment, cut-off values to determine TROP2 overexpression, OS and DFS. The main features of these eligible studies are summarized in Table 1. OS was defined as the interval between initial diagnosis and death. DFS was the interval between initial diagnosis and recurrent or between disease progress and death. The multivariate HR was extracted to assess prognostic value of TROP2 expression. For the articles in which prognosis was plotted only as the Kaplan-Meier curves, the Engauge Digitizer V4.1 was then used to extract survival data and the estimates of the HRs and 95% CIs were calculated by Tierney’s method30. All studies were assessed by Newcastle-Ottawa Scale (NOS). The quality scores ranged from 6 to 8, suggesting that the methodological quality was high.
Statistical analysis
The data collected from each qualified paper of outcomes was used to evaluate the associations between TROP2 expression and solid cancer prognosis through meta-analysis. Pooled HRs and 95% CIs for two outcome endpoints (OS, DFS) were calculated. Subgroup analysis was performed when there were at least three studies in each subgroup. Statistical heterogeneity was assessed using the Q test and a P value > 0.10 suggested a lack of heterogeneity among studies. We also quantified the effect of heterogeneity using I2 = 100% × (Q − df)/Q. I2 values of <25% may be considered “low”, values of about 50% may be considered “moderate” and values of >75% may be considered “high”31. According to the absence or presence of heterogeneity, random effects model or fixed effects model was used to merge the HR, respectively. Without statistical heterogeneity, a fixed effects model was employed to calculate the pooled HRs, otherwise random effects model was used32. Funnel plots and the Egger’s test were employed to estimate the possible publication bias33. If a publication bias did exist, its influence on the overall effect was assessed by the Duval and Tweedie’s trim and fill method34. Sensitivity analysis was also conducted to find out if certain single article could influence the overall result. Statistical analyses were conducted using Stata 14.0 (StataCorp, College Station, TX). P values for all comparisons were two-tailed and statistical significance was defined as p < 0.05 for all tests, except those for heterogeneity.
Results
Demographic characteristics
A total of 126 articles were retrieved by a literature search of the PubMed, Embase and Web of Science databases, using different combinations of key terms. As showed in the search flow diagram (Fig. 1), 126 records were initially retrieved using the predefined search strategy. Because of repeated data, 50 records were removed. After browsing the retrieved titles and abstracts, 56 records were excluded due to no relevant endpoint provided. The remaining 22 records were downloaded as full-text and carefully accessed one by one. Among them, 6 studies were excluded, including one study that was experimental study, four that without prognosis data, one in chinese. As a result, 16 published studies including 2,569 patients that met the inclusion norm were finally selected for the meta-analysis, which assessed the relevance between TROP2 expression and solid tumor prognosis. The median sample-size was 97, with a wide range from 26 to 620. Among all cohorts, Mongoloid (n = 11) became the major race of literatures, followed by Caucasian (n = 5). As for the cancer type, twostudies evaluated gastric cancer, one study evaluated nasopharyngeal carcinoma, one study evaluated gallbladder cancer, one study evaluated cervical carcinoma, one study evaluated extranodal NK/T cell lymphoma, two studies evaluated lung cancer, one study evaluated laryngeal squamous cell carcinoma, one study evaluated Hilar Cholangiocarcinoma, two studies evaluated colorectal cancer, one study evaluated pancreatic cancer, one study evaluated squamous cell carcinoma of the oral cavity, one study evaluated endometrioid endometrial carcinoma, one study evaluated ovarian carcinoma. Overall, 15 studies focused on OS, 6 studies focused on DFS.
Evidence synthesis
The meta-analysis of TROP2 expression was based on two outcome endpoints: OS, DFS. 15studies were included in the meta-analysis of OS. A fixed effects model was utilized to calculate the pooled hazard ratio (HR) and 95% confidence interval (CI) on account of the heterogeneity test reported a P value of 0.677 and an I2 values of 0.0%. The results suggested that TROP2 overexpression was associated with poor OS of solid tumors (pooled HR = 1.896, 95% CI = 1.599–2.247, P < 0.001) (Fig. 2). 6 studies were included in the meta-analysis of DFS. Owing to the heterogeneity test reported a P value of 0.210 and an I2 values of 30.0%, a fixed-effects model was used. The results show a significant association between TROP2 expression and DFS (pooled HR = 2.336, 95% CI = 1.596–3.419, P < 0.001) (Fig. 3). Subgroup study was then performed, the results suggested that the associations between TROP2 overexpression and poor OS and poor DFS were significant in Mongoloid patients (OS: pooled HR = 1.841, 95% CI 1.507–2.250, P < 0.001; DFS: pooled HR = 2.112, 95% CI = 1.299–3.433, P = 0.003), as well as in Caucasian (OS: pooled HR = 2.042, 95% CI 1.482–2.814, P < 0.001; DFS: pooled HR = 2.745, 95% CI 1.485–5.072, P = 0.001). The results showed that there was no difference OS or DFS HR across populations of different descent. The significant association was also detected between TROP2 overexpression and poor outcome in patients with female genital system neoplasms (OS: pooled HR = 1.989, 95% CI = 1.312–3.015, P = 0.001; DFS: pooled HR = 1.904, 95% CI = 1.227–2.954, P = 0.004) and gastrointestine neoplasms(OS: pooled HR = 1.642, 95% CI = 1.104–2.444, P = 0.014).
Publication bias and sensitivity analysis
Begg’s funnel plot and Egger’s test were utilized to estimate the publication bias of the included literatures. The shapes of the funnel plots for the OS and DFS showed no evidence of obvious heterogeneity (Fig. 4) and Egger’s tests revealed publication bias concerning OS (P = 0.061) but not DFS (P = 0.653). Therefore, we performed trim and fill method to make pooled HR more reliable and the P value was also <0.01(data not shown). Sensitivity analyses were further performed to determine the robustness of the results described above. No individual study dominated this meta-analysis and the removal of any single study had no significant effect on the overall conclusion (Fig. 5).
Discussions
High TROP2 expression had been reported to promote cancer progression and predict of poor prognosis of cancer patients13,18,24,25,35. Many clinical studies investigated the prognostic value of TROP2 over-expression. Most of these studies, however, include only limited numbers of patients and their conclusions remain not comprehensive. This current meta-analysis is the first complete overview of all reported clinical studies exploring the impact of TROP2 expression on prognosis of many solid tumors.
We systematically evaluated survival data of 2,569 solid tumor patients included in 16 different studies. Overall, these results clearly show that high TROP2 expression was a poor prognostic factor in solid tumors, with both results of poor OS (pooled HR = 1.896, 95% CI = 1.599–2.247, P < 0.001) and poor DFS (pooled HR = 2.336, 95% CI = 1.596–3.419, P < 0.001). Similarly, subgroup analysis revealed the associations between TROP2 overexpression and poor OS and DFS were significant within Mongoloid and Caucasian. When data was stratified according to cancer types, the results showed the prognostic value of TROP2 over-expression was significant in female genital system neoplasms and in gastrointestine neoplasms.
To our knowledge, the present study is the first and most full-scale meta-analysis systemically exploring the possible prognostic role of TROP2 up-regulation in solid tumors. Our quantitative results strongly supported the current mainstream viewpoint that an undesirable impact of TROP2 redundancy was correlated with the OS and DFS.
Additionally, several important implications in this meta-analysis were displayed. First, high TROP2 expression may be a general poor prognostic marker in solid tumors. In this meta-analysis, we included thirteen different cancer types, including gastric cancer14,15, nasopharyngeal carcinoma16, gallbladder cancer17, cervical cancer18, extranodal NK/T cell lymphoma11, lung cancer9,19, laryngeal squamous cell carcinoma20, Hilar Cholangiocarcinoma24, colon cancer21,22, pancreatic cancer25, squamous cell carcinoma of the oral cavity26, ovarian carcinoma28, endometrioid endometrial carcinoma27. The pooled results from these cancer types demonstrated that high TROP2 expression was associated with poor OS and DFS and this finding can be extended to all solid tumors. Second, we demonstrated that high TROP2 expression correlated with poor OS and DFS in Mongoloid and Caucasian patients, as well in female genital system neoplasms and in gastrointestine neoplasms. Finally, it underlines the potential to develop TROP2 as a valuable therapeutic target and prognostic biomarker for solid tumors.
Apart from the inspiring outcomes, limitations still lay in this quantitative meta-analysis. First of all, most of the included studies were designed as retrospective studies and such studies are more likely to be published if they have positive results than if they have negative results. Furthermore, the method for assessing TROP2 expression and definition of TROP2 positivity were inconsistent. Besides, some studies did not provide complete data36 or published in English23 were excluded in statistics. Therefore, our estimate of the associations between increased TROP2 and outcomes may have been overestimated.
In conclusion, high TROP2 expression in solid tumor tissues association with poor survival was clearly demonstrated in the present meta-analysis. We suggest that TROP2 may be a useful prognostic biomarker and a promising therapeutic target for solid tumors. Nevertheless, further studies related to specific tumor types and perspectives are required to corroborate the clinical utility of TROP2 expression in solid tumors.
Additional Information
How to cite this article: Zeng, P. et al. Impact of TROP2 expression on prognosis in solid tumors: A Systematic Review and Meta-analysis. Sci. Rep. 6, 33658; doi: 10.1038/srep33658 (2016).
References
Lipinski, M., Parks, D. R., Rouse, R. V. & Herzenberg, L. A. Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proceedings of the National Academy of Sciences of the United States of America 78, 5147–5150 (1981).
Fornaro, M. et al. Cloning of the gene encoding Trop-2, a cell-surface glycoprotein expressed by human carcinomas. International journal of cancer 62, 610–618 (1995).
Ripani, E., Sacchetti, A., Corda, D. & Alberti, S. Human Trop-2 is a tumor-associated calcium signal transducer. International journal of cancer 76, 671–676 (1998).
Cubas, R., Li, M., Chen, C. & Yao, Q. Trop2: a possible therapeutic target for late stage epithelial carcinomas. Biochimica et biophysica acta 1796, 309–314 (2009).
Trerotola, M. et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32, 222–233 (2013).
Goldstein, A. S. et al. Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proceedings of the National Academy of Sciences of the United States of America 105, 20882–20887 (2008).
Okabe, M. et al. Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver. Development (Cambridge, England) 136, 1951–1960 (2009).
Cubas, R., Zhang, S., Li, M., Chen, C. & Yao, Q. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Molecular cancer 9, 253 (2010).
Pak, M. G., Shin, D. H., Lee, C. H. & Lee, M. K. Significance of EpCAM and TROP2 expression in non-small cell lung cancer. World journal of surgical oncology 10, 53 (2012).
Li, Z., Jiang, X. & Zhang, W. TROP2 overexpression promotes proliferation and invasion of lung adenocarcinoma cells. Biochemical and biophysical research communications 470, 197–204 (2016).
Chen, R. et al. Increased expression of Trop2 correlates with poor survival in extranodal NK/T cell lymphoma, nasal type. Virchows Archiv: an international journal of pathology 463, 713–719 (2013).
Trerotola, M. et al. Trop-2 promotes prostate cancer metastasis by modulating beta(1) integrin functions. Cancer research 73, 3155–3167 (2013).
Ning, S. et al. TROP2 expression and its correlation with tumor proliferation and angiogenesis in human gliomas. Neurological sciences: official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 34, 1745–1750 (2013).
Muhlmann, G. et al. TROP2 expression as prognostic marker for gastric carcinoma. Journal of clinical pathology 62, 152–158 (2009).
Zhao, W. et al. Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget 7, 6136–6145 (2016).
Guan, G. F. et al. Prognostic value of TROP2 in human nasopharyngeal carcinoma. International journal of clinical and experimental pathology 8, 10995–11004 (2015).
Chen, M. B. et al. Prognostic value of TROP2 expression in patients with gallbladder cancer. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 35, 11565–11569 (2014).
Liu, T. et al. Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway. PloS One 8, e75864 (2013).
Kobayashi, H. et al. Expression of the GA733 gene family and its relationship to prognosis in pulmonary adenocarcinoma. Virchows Archiv: an international journal of pathology 457, 69–76 (2010).
Wu, H. et al. Potential therapeutic target and independent prognostic marker of TROP2 in laryngeal squamous cell carcinoma. Head & neck 35, 1373–1378 (2013).
Ohmachi, T. et al. Clinical significance of TROP2 expression in colorectal cancer. Clinical cancer research: an official journal of the American Association for Cancer Research 12, 3057–3063 (2006).
Fang, Y. J. et al. Elevated expressions of MMP7, TROP2 and survivin are associated with survival, disease recurrence and liver metastasis of colon cancer. International journal of colorectal disease 24, 875–884 (2009).
Xu, K. Y. & Gu, J. [Expression of TROP2 mRNA in left-sided and right-sided colon cancer and its clinical significance]. Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 12, 285–289 (2009).
Ning, S. et al. TROP2 correlates with microvessel density and poor prognosis in hilar cholangiocarcinoma. Journal of gastrointestinal surgery: official journal of the Society for Surgery of the Alimentary Tract 17, 360–368 (2013).
Fong, D. et al. High expression of TROP2 correlates with poor prognosis in pancreatic cancer. British journal of cancer 99, 1290–1295 (2008).
Fong, D. et al. TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 21, 186–191 (2008).
Bignotti, E. et al. Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma. BMC clinical pathology 12, 22 (2012).
Bignotti, E. et al. Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients. European journal of cancer 46, 944–953 (2010).
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & Group, P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. International journal of surgery 8, 336–341 (2010).
Tierney, J. F., Stewart, L. A., Ghersi, D., Burdett, S. & Sydes, M. R. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8, 16 (2007).
Higgins, J. P., Thompson, S. G., Deeks, J. J. & Altman, D. G. Measuring inconsistency in meta-analyses. Bmj 327, 557–560 (2003).
DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Controlled clinical trials 7, 177–188 (1986).
Egger, M., Davey Smith, G., Schneider, M. & Minder, C. Bias in meta-analysis detected by a simple, graphical test. Bmj 315, 629–634 (1997).
Duval, S. & Tweedie, R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56, 455–463 (2000).
Yang, J. et al. Trop2 regulates the proliferation and differentiation of murine compact-bone derived MSCs. International journal of oncology 43, 859–867 (2013).
Ambrogi, F. et al. Trop-2 is a determinant of breast cancer survival. PloS one 9, e96993 (2014).
Acknowledgements
This work is supported by the National Natural Science Foundation (81472786, 81472305), The Six Talents Peak Project of Jiangsu Province (2012-WSN-012, 2014-WSW-061), Kunshan Science and Technology Program (KS1418, KS1528).
Author information
Authors and Affiliations
Contributions
Conceived and designed the experiments: M.-B.C. and P.-H.L. Analyzed the data: P.Z. and P.-H.L. Prepared Figures: P.Z. and M.-B.C. Contributed to the writing of the paper: P.Z. and M.-B.C. Helped edit the manuscript: L.-N.Z., M.T. and C.-Y.L.
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
About this article
Cite this article
Zeng, P., Chen, MB., Zhou, LN. et al. Impact of TROP2 expression on prognosis in solid tumors: A Systematic Review and Meta-analysis. Sci Rep 6, 33658 (2016). https://doi.org/10.1038/srep33658
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/srep33658
This article is cited by
-
ImmunoPET imaging of Trop2 expression in solid tumors with nanobody tracers
European Journal of Nuclear Medicine and Molecular Imaging (2024)
-
Trop-2 and Nectin-4 immunohistochemical expression in metastatic colorectal cancer: searching for the right population for drugs’ development
British Journal of Cancer (2023)
-
Comparison of Anti-Trop2 Extracellular Domain Antibodies Generated Against Peptide and Protein Immunogens for Targeting Trop2-Positive Tumour Cells
Applied Biochemistry and Biotechnology (2023)
-
Updated Austrian treatment algorithm for metastatic triple-negative breast cancer
Wiener klinische Wochenschrift (2023)
-
TROP-2 is widely expressed in vulvar squamous cell carcinoma and represents a potential new therapeutic target
Journal of Cancer Research and Clinical Oncology (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.