The differential gene expression of Notch receptors in primary and metastatic epithelial ovarian cancer sites

Purpose of Investigation: Notch signaling belongs among the candidate pathways for targeted therapies in ovarian cancer. While Notch 3 and Notch 1 overexpression has already been confirmed in ovarian carcinomas compared to their benign counterparts, the expression in metastatic sites is still not well known. The aim of the current study was to compare the relative expression of the four Notch gene receptors between primary and metastatic sites of ovarian carcinomas. Materials and Methods: Seventeen paired couples of tissues, from primary and metastatic sites of epithelial ovarian cancer, were collected during the cytoreductive surgery. For the study of the gene expression Real-Time Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was used. The analysis of the results was performed with the Comparative C_T Method (ΔΔCt Method). Results: Notch 3 and 2 were overexpressed compared to Notch 1 and 4 in both primary and metastatic sites. Notch 3 showed the highest differential expression, yet none of the four Notch genes reached statistical significance due to the differences between different samples. Conclusions: The lack of statistical difference in the expression of all four genes between primary and metastatic sites of epithelial ovarian cancer, potentially predicts same treatment response in all intrabdominal tumours and render Notch pathway a suitable and promising candidate for targeted therapies. The high heterogeneity in the expression between the samples, highlights even more the need of personalized therapies. Further studies should include more patients, examine the absolute expression, extend to all histological types, and focus on the Notch intracellular domain expression.

Notch; Receptors; Ovarian cancer; Expression; Metastasis

[1] Siegel R.L., Miller K.D., Jemal A.: “Cancer statistics, 2015”. CA Cancer J. Clin., 2015, 65, 5.

[2] Eisenkop S.M., Friedman R.L., Wang H.J.: “Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study”. Gynecol. Oncol., 1998, 69, 103.

[3] Bristow R.E., Montz F.J., Lagasse L.D., Leuchter R.S., Karlan B.Y.: “Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer”. Gynecol. Oncol., 1999, 72, 278.

[4] Chang S.J., Bristow R.E., Ryu H.S.: “Impact of complete cytoreduction leaving no gross residual disease associated with radical cytoreductive surgical procedures on survival in advanced ovarian cancer”. Ann. Surg. Oncol., 2012, 19, 4059.

[5] Ang C., Chan K.K., Bryant A., Naik R., Dickinson H.O.: “Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer”. Cochrane Database Syst Rev., 2011, 4, CD007697.

[6] Piccart M.J., Bertelsen K., James K., Cassidy J., Mangioni C., Simonsen E., et al.: “Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results”. J. Natl. Cancer Inst., 2000, 92, 699.

[7] Coleman R.L., Monk B.J., Sood A.K., Herzog T.J.: “Latest research and treatment of advanced-stage epithelial ovarian cancer”. Nat. Rev. Clin. Oncol., 2013, 10, 211.

[8] Herzog T.J., Pothuri B.: “Ovarian cancer: a focus on management of recurrent disease”. Nat. Clin. Pract. Oncol., 2006, 3, 604.

[9] Liu J., Matulonis U.A.: “New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances”. Clin. Cancer Res., 2014, 20, 5150.

[10] Kopan R., Ilagan M.X.: “The canonical Notch signaling pathway: unfolding the activation mechanism”. Cell, 2009, 137, 216.

[11] Miele L. Notch signaling. Clin Cancer Res., 2006, 12, 1074.

[12] Kotsopoulos I.C., Papanikolaou A., Lambropoulos A.F., Papazisis K.T., Tsolakidis D., Touplikioti P., et al.: “Serous ovarian cancer signaling pathways”. Int. J. Gynecol. Cancer, 2014, 24, 410.

[13] Rose S.L.: “Notch signaling pathway in ovarian cancer”. Int. J. Gy- necol. Cancer, 2009, 19, 564.

[14] Lu K.H., Patterson A.P., Wang L., Marquez R.T., Atkinson E.N., Baggerly K.A., et al.: “Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis”. Clin. Cancer Res., 2004, 10, 3291.

[15] Park J.T., Li M., Nakayama K., Mao T.L., Davidson B., Zhang Z., et al.: “Notch3 gene amplification in ovarian cancer”. Cancer Res., 2006, 66, 6312.

[16] Lu C., Bonome T., Li Y., Kamat A.A., Han L.Y., Schmandt R., et al.: “Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma”. Cancer Res., 2007, 67, 1757.

[17] Park J.T., Chen X., Trope C.G., Davidson B., Shih Ie M., Wang T.L.: “Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin”. Am. J. Pathol., 2010, 177, 1087.

[18] Groeneweg J.W., DiGloria C.M., Yuan J., Richardson W.S., Growdon W.B., Sathyanarayanan S., et al.: “Inhibition of notch signaling in combination with Paclitaxel reduces platinum-resistant ovarian tumor growth”. Front Oncol., 2014, 4, 171.

[19] Hopfer O., Zwahlen D., Fey M.F., Aebi S.: “The Notch pathway in ovarian carcinomas and adenomas”. Br. J. Cancer, 2005, 93, 709.

[20] Rose S.L., Kunnimalaiyaan M., Drenzek J., Seiler N.: “Notch 1 signaling is active in ovarian cancer”. Gynecol. Oncol., 2010, 117, 130.

[21] Wang M., Ma X., Wang J., Wang L., Wang Y.: “Pretreatment with the gamma-secretase inhibitor DAPT sensitizes drug-resistant ovarian cancer cells to cisplatin by downregulation of Notch signaling”. Int. J. Oncol., 2014, 44, 1401.

[22] Wang M., Wang J., Wang L., Wu L., Xin X.: “Notch1 expression correlates with tumor differentiation status in ovarian carcinoma”. Med. Oncol., 2010, 27, 1329.

[23] Galic V., Shawber C.J., Reeves C., Shah M., Murtomaki A., Wright J., et al.: “expression is decreased in epithelial ovarian cancer and is related to the tumor histological subtype”. Pathol. Discov., 2013, 1, 4.

[24] Gao M.Q., Choi Y.P., Kang S., Youn J.H., Cho N.H.: “CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells”. Oncogene, 2010, 29, 2672.

[25] Jung S.G., Kwon Y.D., Song J.A., Back M.J., Lee S.Y., Lee C., et al.: “Prognostic significance of Notch 3 gene expression in ovarian serous carcinoma”. Cancer Sci., 2010, 101, 1977.