Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelialmesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.
Background: Decreased expression of the angiogenesis inhibitor ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif, 1) has previously been reported during prostate cancer progression. The aim of this study was to investigate the function of ADAMTS1 in prostate tumors.Methods: ADAMTS1 was downregulated by shRNA technology in the human prostate cancer cell line LNCaP (androgen-dependent), originally expressing ADAMTS1, and was upregulated by transfection in its subline , expressing low levels of ADAMTS1. Cells were implanted subcutaneously in nude mice and tumor growth, microvessel density (MVD), blood vessel morphology, pericyte coverage and thrombospondin 1 (TSP1) were studied in the tumor xenografts.Results: Modified expression of ADAMTS1 resulted in altered blood vessel morphology in the tumors. Low expression levels of ADAMTS1 were associated with small diameter blood vessels both in LNCaP and LNCaP-19 tumors, while high levels of ADAMTS1 were associated with larger vessels. In addition, TSP1 levels in the tumor xenografts were inversely related to ADAMTS1 expression. MVD and pericyte coverage were not affected. Moreover, upregulation of ADAMTS1 inhibited tumor growth of LNCaP-19, as evidenced by delayed tumor establishment. In contrast, downregulation of ADAMTS1 in LNCaP resulted in reduced tumor growth rate. Conclusions:The present study demonstrates that ADAMTS1 is an important regulatory factor of angiogenesis and tumor growth in prostate tumors, where modified ADAMTS1 expression resulted in markedly changed blood vessel morphology, possibly related to altered TSP1 levels. BackgroundExtracellular matrix (ECM) proteases are involved in several steps of cancer development and progression, including angiogenesis and metastasis. By cleavage of ECM components, proteases regulate endothelial cell migration and the selective release and modulation of pro-and anti-angiogenic factors [1].ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif, 1) is a widely expressed matrix metalloproteinase with documented roles in angiogenesis and tumor biology [2-6]. It has been described as a potent anti-angiogenic factor that effectively inhibits endothelial
The results show that the prostatic environment has a varying impact on AD and AI tumor xenografts. Data indicate that the androgen-stimulated prostatic environment limits growth of orthotopic AI tumors through induction of genes that inhibit tumor growth and suppression of genes that promote cell adhesion and metastasis.
Androgen-independent prostate cancer is an aggressive disease with high angiogenic and metastatic potential. Increased microvessel density and altered invasion properties have previously been described in LNCaP-19, an androgen-independent subline to LNCaP. To characterize the differences in angiogenesis and invasion, the vessels of these tumour xenografts were investigated with immunohistochemistry, and the influence of tumour cells on endothelial cell migration, proliferation and tube formation was studied in vitro. The blood vessels of LNCaP were found to be stabilized by pericytes more frequently than vessels in LNCaP-19. Further, tumour cell invasion was decreased in pericyte-covered blood vessels in both the tumour types. LNCaP-19 displayed an increased potential to induce endothelial cell migration in vitro. In conclusion, pericyte coverage seems to be important for the invasion of tumour cells into blood vessels. Further, LNCaP-19 has lower pericyte coverage and an increased potential to induce endothelial cell migration, which reflects its high microvessel density.
OBJECTIVE To investigate the relationship between microvessel density (MVD), blood vessel morphology and the expression of angiopoietin (Ang)‐1, Ang‐2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie)‐2, and vascular endothelial growth factor (VEGF) in androgen‐dependent (AD) and androgen‐independent (AI) prostate cancer models, to gain insight into the regulation of angiogenesis at different stages of prostate cancer. MATERIALS AND METHODS MVD and blood vessel morphology were evaluated by CD34 immunohistochemical staining. The mRNA and protein secretion of the Angs, Tie‐2 and VEGF were measured by real‐time polymerase chain reaction and enzyme‐linked immunosorbent assays, respectively, in LNCaP (AD) and LNCaP‐19, C4‐2, C4–2B4 and PC‐3 (AI) prostate cancer xenografts in mice. RESULTS LNCaP, C4‐2 and C4–2B4 xenografts had high expression of Ang‐2 and VEGF, similar MVD and blood vessel morphology. However, the most angiogenic cell line LNCaP‐19 expressed low levels of both factors and had different vessel morphology. PC‐3 xenografts had a similar MVD to LNCaP, C4‐2 and C4–2B4, but the Ang‐2 and VEGF expression as well as the vessel morphology were similar to LNCaP‐19. CONCLUSION The differences in MVD, blood vessel morphology and the expression of Ang‐2 and VEGF show that prostate cancer cells display angiogenic heterogeneity, which indicates different roles of these factors in the regulation of angiogenesis in different stages of prostate cancer.
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