Proliferation of Immature Tumor Vessels Is a Novel Marker of Clinical Progression in Prostate Cancer

Abstract

Nestin (neuroepithelial stem cell protein) is expressed in immature endothelial cells, and we here introduce coexpression of Nestin and Ki-67 as a novel angiogenesis marker on tissue sections. Including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1A (HIF-1A) expression, we studied relation to disease progression in prostate cancer. Different patient series were included. Sections from 104 radical prostatectomies with long follow-up, 33 castration-resistant prostate cancers, 28 nonskeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias were immunostained for Nestin/Ki-67, VEGF-A, and HIF-1A. Vascular proliferation by Nestin/Ki-67-positive vessels was counted within ''hotspot'' areas. Median vascular proliferation counts were 4-to 5-fold higher in castration-resistant prostate cancers and metastases versus localized cancers and prostatic hyperplasias (P < 0.0005). Among localized cancers, high vascular proliferation was significantly related to adverse clinicopathologic features and was a strong and independent predictor of biochemical failure (P < 0.005), clinical recurrence (P = 0.005), and skeletal metastasis (P = 0.025) in multivariate analysis. Castration-resistant cancers were characterized by reduced VEGF-A and increased HIF-1A expression, and vascular proliferation was associated with reduced patient survival in this group. Thus, vascular proliferation was of independent prognostic importance among prostate cancers. When compared with localized cancers, vascular proliferation was significantly increased in castration-resistant cases and metastatic lesions. The castration-resistant tumors exhibited weak VEGF-A but strong HIF-1A expression. These novel data might have an effect on clinical evaluation and treatment of prostate cancer patients. [Cancer Res 2009;69(11):4708-15]

GRK3 is essential for metastatic cells and promotes prostate tumor progression

“…3D). We then used another metric for tumor angiogenesis, vascular proliferation by costaining for CD31 and Ki-67 (17). Consistent with the MVD analysis, we observed an increase in proliferating microvessels in the primary tumor and significantly also in the metastases formed by GRK3-expressing tumors (Fig.…”

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

“…Although nestin is known to be present in neuroepithelial stem cells [37], it has also been shown to be expressed in cells with endothelial phenotype [38]. To confirm that nestinpositive cells developing in close proximity to ECs are NSPCs, microvessels containing perivascular cells (Fig.…”

Prognostic Significance of Nestin Expression in pT1 High-Grade Bladder Urothelial Carcinoma Patients Treated with Intravesical BCG

“…Increased nestin expression has also been reported in various tumor cells, especially in central nervous system and gastrointestinal tumors as a poor prognostic factor (Eaker and Sallustio., 1994;Toshiyuki et al, 2011). High expression levels in tumor blood vessels and proliferating endothelial cells in certain tumor types suggest a relationship between tumor angiogenesis and nestin (Kim et al, 2002;Teranishi et al, 2007;Gravdal et al, 2009;Eaton et al, 2010). From urological point of view, reduction of nestin expression has been shown to be correlated with decreased invasion and migration capability of prostate cancer cells (Gravdal et al, 2009).…”

“…High expression levels in tumor blood vessels and proliferating endothelial cells in certain tumor types suggest a relationship between tumor angiogenesis and nestin (Kim et al, 2002;Teranishi et al, 2007;Gravdal et al, 2009;Eaton et al, 2010). From urological point of view, reduction of nestin expression has been shown to be correlated with decreased invasion and migration capability of prostate cancer cells (Gravdal et al, 2009). Furthermore, it has been detected as a stem cell marker in 100% of bladder cancer cell cultures which may suggest a possible role in bladder cancer pathogenesis (Bentivegna et al, 2010).…”

“…Nestin is detected in various types of tumors and is involved in malignant processes (Takano et al, 1996;Yang et al, 2000;Almazan et al, 2001;Lardon et al, 2002;Toshiyuki et al, 2011). Proliferating vascular endothelial cells in tumor tissues also highly express nestin and nestin is therefore considered to be closely related with tumor angiogenesis (Gravdal et al, 2009). Ozer et al reported in a previous study that T1 high grade bladder cancers possess higher angiogenetic activity resulting in a greater rate of progression or recurrence rates (Ozer et al, 1999).…”