Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue

Shih, Shyh-Jen; Dall′Era, Marc; Westphal, Johan R.; Yang, Jinghua; Sweep, Fred C.G.J.; Gandour‐Edwards, Regina; Evans, Christopher P.

doi:10.1038/sj.pcan.4500637

Cited by 19 publications

(9 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the future, immunohistochemical techniques [50,51] might elucidate more on the nature of the false readings. There are indications that (co-occurring) prostatitis or BPH might be responsible for false positives, as these diseases are known to also promote angiogenesis [52,53]. Qualitative inspection of the false negatives revealed that these were indeed invisible to the naked eye on all US modalities.…”

Section: Discussionmentioning

confidence: 99%

Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics

et al. 2019

View full text Add to dashboard Cite

Objectives The aim of this study was to assess the potential of machine learning based on B-mode, shear-wave elastography (SWE), and dynamic contrast-enhanced ultrasound (DCE-US) radiomics for the localization of prostate cancer (PCa) lesions using transrectal ultrasound. Methods This study was approved by the institutional review board and comprised 50 men with biopsy-confirmed PCa that were referred for radical prostatectomy. Prior to surgery, patients received transrectal ultrasound (TRUS), SWE, and DCE-US for three imaging planes. The images were automatically segmented and registered. First, model-based features related to contrast perfusion and dispersion were extracted from the DCE-US videos. Subsequently, radiomics were retrieved from all modalities. Machine learning was applied through a random forest classification algorithm, using the co-registered histopathology from the radical prostatectomy specimens as a reference to draw benign and malignant regions of interest. To avoid overfitting, the performance of the multiparametric classifier was assessed through leave-one-patient-out cross-validation. Results The multiparametric classifier reached a region-wise area under the receiver operating characteristics curve (ROC-AUC) of 0.75 and 0.90 for PCa and Gleason > 3 + 4 significant PCa, respectively, thereby outperforming the best-performing single parameter (i.e., contrast velocity) yielding ROC-AUCs of 0.69 and 0.76, respectively. Machine learning revealed that combinations between perfusion-, dispersion-, and elasticity-related features were favored. Conclusions In this paper, technical feasibility of multiparametric machine learning to improve upon single US modalities for the localization of PCa has been demonstrated. Extended datasets for training and testing may establish the clinical value of automatic multiparametric US classification in the early diagnosis of PCa. Key Points • Combination of B-mode ultrasound, shear-wave elastography, and contrast ultrasound radiomics through machine learning is technically feasible. • Multiparametric ultrasound demonstrated a higher prostate cancer localization ability than single ultrasound modalities. • Computer-aided multiparametric ultrasound could help clinicians in biopsy targeting.

show abstract

Section: Discussionmentioning

confidence: 99%

Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Of note, neprilysin-expressing LNCaP cells do not produce measurable amounts of FGF-2, in contrast to non-neprilysin-expressing, androgen-independent PC-3 and DU-145 cells (34). Fibroblast growth factor-2 is highly expressed in prostate cancer tissues (35)(36)(37), and expression correlates with neovascularization in prostate cancer tissue specimens (38). Patients with prostate cancer have significantly elevated serum FGF-2 levels compared with healthy controls that increase on progression to androgen-independent disease (35).…”

Section: Discussionmentioning

confidence: 99%

Neprilysin Inhibits Angiogenesis via Proteolysis of Fibroblast Growth Factor-2

Goodman

Febbraio

Simantov

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Neprilysin is a cell surface peptidase that catalytically inactivates neuropeptide substrates and functions as a tumor suppressor via its enzymatic function and multiple protein-protein interactions. We investigated whether neutral endopeptidase could inhibit angiogenesis in vivo utilizing a murine corneal pocket angiogenesis model and found that it reduced fibroblast growth factor-2-induced angiogenesis by 85% (p < 0.01) but had no effect on that of vascular endothelial growth factor. Treatment with recombinant neprilysin, but not enzymatically inactive neprilysin, resulted in a slight increase in basic fibroblast growth factor electrophoretic mobility from proteolytic cleavage between amino acids Leu-135 and Gly-136, which was inhibited by the neutral endopeptidase inhibitor CGS24592 and heparin. Cleavage kinetics were rapid, comparable with that of other known neprilysin substrates. Functional studies involving neprilysin-expressing vascular endothelial cells demonstrated that neutral endopeptidase inhibition significantly enhanced fibroblast growth factor-mediated endothelial cell growth, capillary array formation, and signaling, whereas exogenous recombinant neprilysin inhibited signaling. Recombinant constructs confirmed that cleavage products neither promoted capillary array formation nor induced signaling. Moreover, mutation of the cleavage site resulted in concomitant loss of cleavage and increased the potency of fibroblast growth factor-2 to induce capillary array formation. These data indicate that neprilysin proteolytically inactivates fibroblast growth factor-2, resulting in negative regulation of angiogenesis.Neprilysin (neutral endopeptidase 24.11, CD10) is a 90 -110-kDa cell surface peptidase normally expressed by a variety of tissues, including epithelial cells of the prostate, kidney, intestine, endometrium, adrenal glands, and lung. This enzyme cleaves peptide bonds on the amino side of hydrophobic amino acids and inactivates a variety of physiologically active peptides, including atrial natriuretic factor, substance P, bradykinin, oxytocin, Leu-and Met-enkephalins, neurotensin, bombesin, endothelin-1, and ␤-amyloid. Loss or a decrease in neprilysin expression has been reported in a variety of malignancies, including renal cancer, invasive bladder cancer, poorly differentiated stomach cancer, small cell and nonsmall cell lung cancers, endometrial cancer, and prostate cancer (1, 2). Reduced expression of cell surface peptidases such as neprilysin results in the accumulation of higher peptide concentrations that mediate neoplastic progression (3).Using prostate cancer as a model to study the involvement of neprilysin in malignancy, we have demonstrated the following. 1) Neprilysin protein expression is absent in nearly 50% of primary prostate cancers (2). 2) Neprilysin inhibits neuropeptidemediated cell growth, cell migration, and ligand-independent activation of the insulin-like growth factor-1 receptor leading to Akt phosphorylation (1, 4). 3) Neprilysin can inhibit cell migration independentl...

show abstract

“…A small number of studies have compared vascularization in normal prostate, BPH/LUTS, and cancer specimens. These studies have demonstrated increased microvessel density (MVD) in BPH/LUTS compared to normal prostate tissue (Deering et al, 1995) and even in BPH/LUTS compared to malignant tissue (Shih et al, 2003). These studies provide some rationale for exploring chemokine-mediated angiogenesis as a contributing factor to BPH/LUTS development and progression (Figure 1).…”

Section: Chemokines As Cytokines In Bph/lutsmentioning

confidence: 99%

Chemokines and BPH/LUTS

Macoska

2011

Differentiation

View full text Add to dashboard Cite

A wealth of published studies indicate that a variety of chemokines are actively secreted by the prostatic microenvironment consequent to disruptions in normal tissue homeostasis due to the aging process or inflammatory responses. The accumulation of senescent stromal fibroblasts, and, possibly, epithelial cells, may serve as potential driving forces behind chemokine secretion in the aging and enlarged human prostate. Chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) and histological inflammation may also potentially serve as rich sources of chemokine secretion in the prostate. Once bound to their cognate receptors, chemokines can stimulate powerful pro-proliferation signal transduction pathways and thus function as potent growth factors in the development and progression of Benign Prostatic Hyperplasia (BPH) and Lower Urinary Tract Symptoms (LUTS). These functions have been amply demonstrated experimentally and particularly point to robust Mitogen Activated Protein Kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) signaling, as well as global transcriptional responses, which mediate chemokine-stimulated cellular proliferative responses. A small body of literature also suggests that chemokine-mediated angiogenesis may comprise a contributing factor to BPH/LUTS development and progression. Thus, the observed low-level secretion of multiple chemokines within the aging prostatic microenvironment may promote a concomitant low-level, but cumulative, over-proliferation of both stromal fibroblastic and epithelial cell types associated with increased prostatic volume. Though the accumulated evidence is far from complete and suffers from some rather extensive gaps in knowledge, it argues favorably for the conclusion that chemokines can, and likely do, promote prostatic enlargement and the associated lower urinary tract symptoms, and justifies further investigations examining chemokines as potential therapeutic targets to delay or ablate BPH/LUTS initiation and progression.

show abstract

Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue

Cited by 19 publications

References 27 publications

Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics

Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics

Neprilysin Inhibits Angiogenesis via Proteolysis of Fibroblast Growth Factor-2

Chemokines and BPH/LUTS

Contact Info

Product

Resources

About