Emerging Role of Nestin as an Angiogenesis and Cancer Stem Cell Marker in Epithelial Ovarian Cancer: Immunohistochemical Study

Abstract

Ovarian cancer is the most fatal gynecologic malignancy and the existing second-line treatments have not been confirmed to be effective. Cancer stem cells research has a leading role to explore promising therapeutic applications. Nestin was postulated to reflect cancer stem cell properties in various tumors, correlating with poor prognosis. Furthermore, nestin is proposed as a reliable neovascularization marker. This study aimed to elucidate the status of nestin expression in various epithelial ovarian cancers (EOCs), its neoangiogenic properties, and investigate its potential association with clinicopathologic parameters. A total of 80 primary EOCs (37 serous, 20 Mucinous, 13 endometrioid, and 10 clear cell carcinomas) were immunohistochemically stained with nestin. Staining intensity and automated microvascular density (MVD) were assessed. Positive nestin expression was defined in ≈47.5% of all EOC; more commonly in ≈60% of the serous tumors. It was noticeably expressed in tumor spheroids. Nestin expression significantly correlated with overall tumor grade, lymph node, distant metastasis, and stage. Nestin neoangiogenesis was detectable in all cases (average=60.1). The nestin expression in tumor cells significantly correlated with Nestin/MVD. The average Nestin/MVD was significantly an independent predictor of high tumor stage. As a stem cell marker, nestin is expressed in cells of EOC including those growing as spherules and correlated with poor prognosis. Thus, nestin may be a novel therapeutic target for tumor angiogenesis and a combination therapy that includes nestin-targeting agents may be an effective therapeutic approach. In addition, detection of Nestin/stem cells and Nestin/MVD can be used as predictors of disease.

A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein

“…In the adult cardiovascular system, nestin is expressed in actively proliferating endothelial cells (EC), but is considered absent from mature vasculature 6 , 18 , 19 . Thus, it has been suggested as a potential therapeutic target for tumour-associated angiogenesis 18 , 20 – 23 and a prognostic marker 24 – 26 .…”

Proliferation and maturation of intratumoral blood vessels in women with malignant ovarian tumors assessed with cancer stem cells marker nestin and platelet derived growth factor PDGF-B

“…Expression of nestin in tumor cells was not associated with MVD-nestin (p > 0.05). In lesions with low expression pattern median values of nestin-positive MVD was slightly higher than in samples where staining reaction was moderate or high (22/HPF; range 13-37 vs. 19/HPF; range [12][13][14][15][16][17][18][19][20]. No significant correlation between MVD-CD34 and nestin-positive MVD (r = 0.14; p = 0.19) was found.…”

“…Nestin could serve not only as a reliable neovascularization marker but also may reflect cancer stem cell properties in different types of malignant masses, correlating with poor prognosis. Osman et al [20] found the expression of nestin in almost 50% of all epithelial ovarian cancers and this neurofilament protein was expressed more often (60%) in serous type of tumors. In our study nestin expression pattern in microvessels did not correlate with nestin expression in tumor cells.…”

Prognostic significance of TEM7 and nestin expression in women with advanced high grade serous ovarian cancer

“…Correlation between nestin expression in tumor tissue and the clinical course of the disease was reported for breast and ovarian cancers, as well as for gastrointestinal tumors, germ cell tumors, osteosarcomas and melanomas [10]. In some tumor types, increased nestin expression correlates with the tumor grade and indicates an immature and invasive phenotype of transformed cells [11,12]. Interestingly, the use of nestin as a predictive marker of a poor response to conventional therapy and to novel therapeutic agents was reported for multiple myeloma [13].…”

“…in tissue repair processes through proliferating vascular endothelial cells or in various malignant tumors. Previous studies showed that nestin could be another specific indicator of ovarian cancer aggressive and clinically advanced forms [11,12]. Correlation between nestin expression in tumor tissue and the clinical course of the disease was reported for breast and ovarian cancers, as well as for gastrointestinal tumors, germ cell tumors, osteosarcomas and melanomas [10].…”