10763

NES

nestin;NES;nestin

-

1q23.1

protein-coding

Sentinel lymph node evaluation is a critical component of melanoma staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. One of the well-known diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi, which has been demonstrated in up to 26% of lymphadenectomy specimens and specifically in melanoma patients. Melanocytic markers enhance the sensitivity of melanoma detection in sentinel lymph nodes. However, established markers such as anti-melan-A/MART1, S100 protein and SOX10 antibodies cannot discriminate melanoma metastasis from nodal nevi. Recent studies have demonstrated strong expression of neural stem/progenitor cell markers nestin and SOX2 in melanoma. In this study, we tested the diagnostic utility of nestin and SOX2 in differentiating metastatic melanomas from nodal nevi. Twenty-three lymph nodes with metastatic melanomas and 17 with nodal nevi were examined. Of the 23 metastatic melanomas, 18 showed diffuse and strong (3+) nestin, 4 showed rare cells with strong (3+) nestin, and one showed diffuse but faint (1+) nestin staining. Nuclear SOX2 was positive in 13 metastatic melanomas. In contrast, 15 nodal nevi showed no nestin, and 2 showed rare cells with very faint (<1+) nestin staining. SOX2 was negative in 13 nodal nevi. Overall, nestin was strongly expressed in metastatic melanomas (n=22/23; 96%), but not in nodal melanocytic nevi (n=15/17; 88%; P<0.0001). SOX2 was also expressed in metastatic melanomas (n=13/23; 57%) but not in the majority of nodal melanocytic nevi (n=13/16; 81%; P=0.02). In one lymph node harboring metastatic melan-A-negative desmoplastic melanoma, nestin and SOX2 strongly highlighted the infiltrating tumor cells, suggesting the potential clinical value of these two markers in desmoplastic melanoma lymph node biopsies. This study provides evidence that nestin and SOX2 can effectively differentiate nodal melanocytic nevi from metastatic melanomas and serve as powerful diagnostic adjuncts in melanoma staging.

Stem cell marker nestin has been reported to be activated in various neoplasms, and its expression is correlated with poor prognosis. However, nestin expression in non-small cell lung cancer still remains unclear. The present study aimed to investigate nestin expression in 52 tissue samples of non-small cell lung cancer by immunohistochemical staining and explore its correlation with some clinicopathologic characteristics. The associations of nestin with lymphatic vessel density, microvessel density, vascular endothelial growth factor, vascular endothelial growth factor-C, and cyclooxygenase-2 (COX-2) were further observed to determine the linkage between nestin and lymphangiogenesis. The results showed that nestin expressed in tumor cells of 45 samples. High nestin expression correlated significantly with poor differentiation (P = .007), adenocarcinoma (P = .000), N2 lymph node metastasis (P = .006), high microvessel density (P = .033), and lymphatic vessel density (P = .020). Multivariate analysis of N1 and N2 lymph node metastasis revealed a 1.086-fold increase in hazard ratio of N2 lymph node involvement (P = .011) in patients with high nestin expression in primary tumor. More important, multivariate analysis showed a significant correlation of lymphatic vessel density with nestin and vascular endothelial growth factor-C expression (P = .039 and P = .045), independent of vascular endothelial growth factor, COX-2, and other clinicopathologic characteristics. The results demonstrated that nestin expressed in most tumor cells of non-small cell lung cancer tissue and had a direct linkage to lymph node metastasis and tumor-induced lymphangiogenesis, independent of COX-2 signal pathway.

The intermediate filament protein Nestin identifies stem/progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RV1, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by immunohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgen-independent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread.