Combined Dynamic Alterations in Urinary VEGF Levels and Tissue ADAM9 Expression as Markers for Lethal Phenotypic Progression of Prostate Cancer

Abstract

Recent evidence has demonstrated that detection of changes in the levels of urinary vascular endothelial growth factor (VEGF) and tissue a distintegrin and metalloproteinase 9 (ADAM9) is effective in determining prostate cancer progression. To evaluate the combined application of VEGF and ADAM9 as early progression markers of lethal phenotypic cancer, quantification of urinary VEGF and tissue ADAM9 expression was studied in patients with late stage prostate cancer. Tissue biopsies were collected during palliative transurethral resection of prostate (TURP) surgery, and urine samples were collected before hormone therapy and 3, 6 and 12 months post-TURP. We observed a nearly 100% correlation between increasing urinary VEGF levels over time and prostate cancer progression, but no correlation was observed when comparing urinary VEGF concentrations at a single time point and cancer progression. In addition, we also observed correlation of increasing ADAM9 nuclear positive staining and lethal phenotypic transition. Statistical analysis revealed that both the increase in urinary VEGF level and the presence of the tissue ADAM9 nuclear staining were significantly correlated with the risk of patients with relapse prostate cancer (P<0.05). Thus, we suggest that combination of detection of changes in urinary VEGF and tissue staining of ADAM9 may be accurate for predicting the mortality of patients with prostate cancer during hormone therapy.

The Role of the Metzincin Superfamily in Prostate Cancer Progression: A Systematic-Like Review

“…Thus, many metzincins have been demonstrated to be regulated by androgens [ 107 , 213 , 217 , 223 , 227 , 228 ], which can clearly be a complicating factor given the environment in which these cancers develop. In addition, expression is also impacted by oncogenes [ 85 , 147 ], inflammation and inflammatory cytokines [ 99 , 229 ], as well as angiogenic factors such as vascular endothelial factor [ 216 ], which are intrinsic features of any cancer. The cellular environment can further influence both expression [ 127 ] and activation [ 143 ].…”

“…Clearly, more research is required to understand this important aspect of metzincin pathobiology. Moreover, other roles should also be considered, especially given reports suggesting that nuclear localization may be important in some situations [ 204 , 213 , 216 ], with both ADAMs and ADAMTSs known to have nonenzymatic roles.…”

“…ADAM-28 expression was similarly demonstrated to be higher in PrCa, with enforced expression enhancing the proliferation and migration [203]. The results regarding ADAM-9 were more complex, with one study showing no change in expression in PrCa [189] and others showing an increased expression that correlates with malignancy and reduced survival [207,216] but another reporting a decrease in expression in castrate-resistant compared to androgen-sensitive PrCa [210]. However, the ablation of ADAM-9 reduced the proliferation and tumor growth and increased the differentiation, decreasing the metastatic ability while increasing the sensitivity to chemotherapeutic drugs [209].…”

Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer

“…In PCa, ADAM9 was reported to be significantly associated with shortened PSA relapse-free survival 31 . Moreover, ADAM9 in combination with urinary vascular endothelial growth factor (VEGF) may be correlated with the risk of PCa recurrence and death in patients who underwent ADT 35 . In mAIPC cell lines and an in vivo xenograft model, depletion of ADAM9 enhanced radiosensitivity and chemosensitivity of mAIPC cells, and suppressed tumor bone metastasis in vivo 28 , 29 .…”

The Clinical Significance and Mechanisms of REG4 in Human Cancers

“…A disintegrin and metalloproteinase 9 (ADAM9) encoded protein regulates prostate cancer proliferation and invasion by interacting with a variety of cell surface proteins in prostate cancer (73)(74)(75). Expression of ADAM9 correlates with poor prognosis, recurrence risk and therapy-resistance (75,76).…”