Am J Cancer Res.2015 July;5(8):2498-2507

Sprouty2 protein in prediction of post-treatment ascites in epithelial ovarian cancer treated with adjuvant carbotaxol chemotherapy.

 

Samar Masoumi-Moghaddam1, Afshin Amini1, Ai-Qun Wei2, Gregory Robertson3, David L Morris1

1Department of Surgery, St George Hospital, The University of New South Wales, Kogarah, NSW 2217, Sydney, Australia

2Department of Orthopedic Surgery, St George Hospital, The University of New South Wales, Kogarah, NSW 2217, Sydney, Australia

3Department of Gynecology Oncology, St George Hospital, The University of New South Wales, Kogarah, NSW 2217, Sydney, Australia

 

Abstract

Ascites development and resistance to chemotherapy with carbotaxol are common clinical problems in epithelial ovarian cancer, partly due to the activation of MAPK/ERK signaling. Sprouty proteins are negative modulators of MAPK/ERK pathway, but their role in predicting resistance to carbotaxol chemotherapy and ascites development is unknown. In this study, we evaluated the expression of Sprouty protein isoforms by immunohistochemistry. The associations between the Sprouty expression and the clinicopathological features, including chemoresistance and the presence of ascites, were then explored. We found that the decreased expression of Spry2 was correlated with the post-treatment development of ascites and represented an independent predictor of this condition in carbotaxol-treated patients. However, no association was observed between the Sprouty expression and chemoresistance. In conclusion, our results suggest that Spry2 may be useful for patient follow-up and monitoring as it predicts the development of ascites in epithelial ovarian cancer cases treated with carbotaxol.

PMID: 26396926

 

Supplement

Epithelial ovarian cancer (EOC) is the seventh leading cancer in women (accounting for around 3.6% of female cancers) and the second cause of gynecological cancer death worldwide (1). Ascites presents in at least one third of patients and may contribute to the spread of cancer to secondary sites (2). Postoperative treatment with paclitaxel plus carboplatin (carbotaxol) is recommended for patients with early-stage disease with poor prognostic features (3). For advanced-stage disease, the current standard first-line chemotherapy regimen involves intravenous administration of a platinum-based drug (cisplatin/carboplatin) with a taxane, usually paclitaxel, given 3 weekly for six cycles. Lack of novel and specific sets of markers for diagnosis, clinical monitoring, prognosis and prediction of response to treatment is still considered as an unmet need to improve medical management of this disease.

Mitogen-activated protein kinase (MAPK) signaling is among the biological pathways activated in cancer and involved in the development of chemoresistance (4). Members of the Sprouty protein family, including Spry1, Spry2 and Spry4, are known as the downstream modulators of MAPK and key regulators of the eukaryotic cell biology (5). As expected, the Sprouty deregulation has been shown to contribute to the pathophysiology of a variety of diseases, including cancer. We have recently reported the predictive value of Spry1 and Spry2 for overall survival and disease free survival of EOC patients (6, 7). In the present retrospective study, we investigated the possible association of the Sprouty proteins expression with the development of ascites and/or response to carbotaxol chemotherapy, and their significance as a relevant predicting factor in EOC. To this end, we first evaluated the immunohistochemical expression of Spry1, Spry2 and Spry4 proteins, and their correlation with major clinicopathological characteristics in a cohort of 100 patients with EOC (Table 1). We found that recurrent disease, disease stage, and tumor grade were significantly associated with the expressions of Spry1 and Spry2 in an inverse manner.

 

tab1

Table 1 Correlations of the expressions of Sprouty isoforms with clinicopathological characteristics

 

Moreover, there was a significant correlation between Spry2 and history of ascites, in particular post-treatment ascites (Table 2). The expression of Spry4, however, did not show any significant correlations with the clinicopathological characteristics studied. Also, our further analysis of the Sprouty isoforms expression revealed neither a significant correlation with nor a predictive value for the chemorefractory disease.

 

tab2

Table 2 Correlations of the expressions of Sprouty isoforms with history of ascites

 

Then, we evaluated the predictive value of Spry2 for the development of malignant ascites in EOC. In a binary model of the Spry expression, univariate analysis revealed the predictive significance of Spry2 for the development of post-treatment ascites. In multivariate logistic regression analysis, too, Spry2 retained its predictive value and was thus identified as an independent predictor of post-treatment ascites in EOC patients (Table 3).

 

tab3

Table 3 Predictive value of Spry1, Spry2 and Spry4 for response to chemotherapy and post-treatment ascites

 

Next, we performed receiver operating characteristic (ROC) curve analysis to evaluate the sensitivity and specificity of the Spry2 expression in the prediction of post-treatment ascites in our patients (Table 4).

tab4

Table 4 Sensitivity and specificity of Spry2 expression in prediction of post-treatment ascites

 

To justify these findings, one can postulate that Spry2 inhibits the development of post-treatment ascites by hindering tumor growth and development per se, and/or through regulating mechanisms that promote ascites formation. Spry2 inhibition of MAPK/ERK signaling can be a major underlying mechanism. These observations, pertinent hypotheses, and the molecular mechanisms involved need to be further investigated in future studies.

 

References

  1. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.
  2. Puiffe ML, Le Page C, Filali-Mouhim A, Zietarska M, Ouellet V, Tonin PN, Chevrette M, Provencher DM and Mes-Masson AM. Characterization of ovarian cancer ascites on cell invasion, proliferation, spheroid formation, and gene expression in an in vitro model of epithelial ovarian cancer. Neoplasia 2007; 9: 820-829.
  3. Aletti GD, Gallenberg MM, Cliby WA, Jatoi A and Hartmann LC. Current Management Strategies for Ovarian Cancer. Mayo Clinic proceedings. Mayo Clinic 2007; 82: 751-770.
  4. Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007; 63: 12-31.
  5. Masoumi-Moghaddam S, Amini A and Morris D. The developing story of Sprouty and cancer. Cancer Metastasis Rev 2014; 33: 695-720.
  6. Masoumi-Moghaddam S, Amini A, Wei AQ, Robertson G and Morris DL. Sprouty 1 predicts prognosis in human epithelial ovarian cancer. Am J Cancer Res 2015; 5: 1531-1541.
  7. Masoumi-Moghaddam S, Amini A, Wei AQ, Robertson G and Morris DL. Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer. Int J Cancer 2015; 137: 560-570.

 

Contact:

Samar Masoumi-Moghaddam, MD, PhD.

Department of Surgery, St George Hospital, The University of New South Wales

Research and Education Center, 4-10 South Street, Kogarah, NSW 2217, Sydney, Australia

Phone: 0061(2) 9113 1534; Fax: 0061(2) 9113 3967; Email: samar.masoumi@gmail.com

 

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann