Karin Welén

N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

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 epithelial-mesenchymal 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.

Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050).

Tasquinimod (ABR‐215050) is an orally active quinoline‐3‐carboxamide analog that has completed phase II clinical trial in patients with castration resistant prostate cancer, showing promising inhibiting effects on the occurrence of metastasis and delayed disease progression. Its mechanism of action is not fully elucidated, but previous studies show anti‐angiogenic effects and strong interaction with the S100A9 protein.

Castration resistant prostate cancer is associated with increased blood vessel stabilization and elevated levels of VEGF and Ang‐2

Angiogenesis is important for the progression of prostate cancer and may be a target for treatment in castration resistant (CR) disease. This study was performed to investigate blood vessel stabilization and expression of the pro‐angiogenic factors vascular endothelial growth factor (VEGF) and Angiopoietin‐2 (Ang‐2) in CR and hormone naïve (HN) prostate cancer. The effect of androgen deprivation therapy (ADT) on these parameters was also studied.

The prostatic environment suppresses growth of androgen-independent prostate cancer xenografts: An effect influenced by testosterone

Interactions between prostate cancer cells and their surrounding stroma play an important role in the growth and maintenance of prostate tumors. To elucidate this further, we investigated how growth of androgen‐dependent (AD) LNCaP and androgen‐independent (AI) LNCaP‐19 prostate tumors was affected by different microenvironments and androgen levels.

ADAMTS1, a putative anti-angiogenic factor, is decreased in human prostate cancer.

To investigate the expression of ‘ADAM metallopeptidase with thrombospondin type I motif, 1’ (ADAMTS1) in human prostate cancer, and to study its relationship to microvessel density (MVD) and metastasis. ADAMTS1 has been described as an anti‐angiogenic and antitumour factor, but its function in prostate cancer is unknown.

ADAMTS1 alters blood vessel morphology and TSP1 levels in LNCaP and LNCaP-19 prostate tumors.

BackgroundDecreased 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.MethodsADAMTS1 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 LNCaP-19 (androgen-independent), 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.ResultsModified 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.ConclusionsThe 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.

O-glycosylation of MUC1 mucin in prostate cancer and the effects of its expression on tumor growth in a prostate cancer xenograft model.

MUC1 mucin is up-regulated and aberrantly glycosylated in many human epithelial carcinomas. Over-expression of MUC1 has also been implicated in prostate cancer, but neither the role of MUC1 in the cancer progression nor the mucin O-glycosylation has been fully elucidated. In this study, we characterized the O-glycans on MUC1 when over-expressed in the human prostate cancer cell line C4-2B4. We found that the main O-glycan consisted of the neutral core 2 oligosaccharide Galβ3(Galβ3/4GlcNAcβ6)GalNAc-ol, with minor components being fucosylated and sialylated variants of the same core 2 oligosaccharide. Small amounts of the shorter core 1 O-glycans were also detected.We then used the MUC1 over-expressing cell lines to study the effects of MUC1 on prostate cancer cell behavior. The results demonstrate that over-expression of MUC1 did not affect the cells’ proliferation, but led to a decreased adhesion to the extracellular matrix components fibronectin and collagen I in vitro. When inoculated in BALB/c nude mice, C4-2B4 cells expressing MUC1 showed a tendency to form fewer tumors than wt cells and the tumors also grew more slowly, but there was a large variation between different tumors. These findings suggest that MUC1 may not have the same cancer-promoting effect in prostate cancer cells that is commonly seen in other epithelial cancers such as breast, colon, and pancreatic cancer.

Differential expression of angiopoietin-2 and vascular endothelial growth factor in androgen-independent prostate cancer models

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.

Midkine is associated with neuroendocrine differentiation in castration-resistant prostate cancer.

Castration‐resistant prostate cancer (CRPC) is an incurable disease and both androgen‐deprivation therapy (ADT) and neuroendocrine differentiation (NED) are closely related to CRPC transition. More knowledge concerning neuroendocrine (NE)‐transformed PC cells, the NED process and its association with CRPC, is needed. Expression of growth factor midkine (MDK) is correlated with poor clinical outcomes in various human cancers, including PC. In the present study, we have evaluated MDK expression and NED in two separate tumor groups: early and advanced PC.

Circulating Tumor Cells as a Marker for Progression-free Survival in Metastatic Castration-naïve Prostate Cancer

Analysis of circulating tumor cells (CTC) is a promising prognostic marker in castration‐resistant prostate cancer (CRPC). The aim of this study was to investigate CTC detection and phenotyping as prognostic biomarkers for response to primary androgen deprivation therapy (ADT) of metastatic prostate cancer (PC).