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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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 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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

Androgen-Independent Prostate Cancer - studies on angiogenesis and ADAMTS1

Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer since prostate tumors initially are dependent on androgens for growth. However, most tumors will eventually relapse and grow in a highly aggressive and androgen-independent (AI) manner. AI prostate cancer is associated with poor prognosis and new treatment modalities are therefore urgently needed. Anti-angiogenic therapy could be one strategy to suppress tumor growth, but this requires an increased understanding about the regulation of angiogenesis in AI prostate cancer. The aim of this thesis was therefore to increase the knowledge about AI prostate cancer, with special focus on angiogenesis. First, an experimental model system that allows comparative studies of androgen-dependent (AD) and AI prostate cancer was established. An AD human prostate cancer cell line was cultured under selective pressure in androgen depleted medium, which resulted in an AI subline. Characterization of the newly established AI cell line revealed that transition into androgen-independency was associated with a more rapid tumor take, decreased PSA levels, increased microvessel density (MVD) and altered blood vessel morphology. To identify factors that could be of importance for the increased angiogenesis observed in AI tumors, a gene expression analysis was performed. The results demonstrated that transition into androgen-independency was accompanied with altered expression of a number of genes associated with angiogenesis, including ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). ADAMTS1 is a potent anti-angiogenic factor that was found to be significantly downregulated in AI cancer cells and its expression correlated negatively with MVD in the tumor xenografts. Furthermore, immunohistochemical studies of tumor tissue from prostate cancer patients demonstrated significantly lower levels of ADAMTS1 in cancer areas than in benign glands. In addition, low levels of ADAMTS1 were associated with metastatic disease and higher MVD in AI tumors. In order to further elucidate the role of ADAMTS1 in prostate cancer progression and tumor angiogenesis, the expression of ADAMTS1 was modified by transfection in the experimental model system. The results revealed that altered expression of ADAMTS1 markedly affected the blood vessel morphology but not the number of blood vessels in the tumor xenografts. Modified expression of ADAMTS1 also affected the levels of the anti-angiogenic protein TSP1, whose expression was inversely related to ADAMTS1. Moreover, upregulation of ADAMTS1 resulted in a markedly delayed growth of AI tumors, while the opposite was observed in AD tumors. In summary, the results show that transition into androgen-independency is associated with increased angiogenesis and altogether the data from this thesis suggest that ADAMTS1 is an important factor in prostate cancer biology that is lost during disease progression and that is associated with decreased angiogenesis, tumor growth and metastasis in AI prostate cancer

Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial

International audienceAbstract Background Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO 2 ) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO 2 with patients’ outcome. Methods Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO 2  300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. Results 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO 2 -AUC), for hyperoxemia was significantly associated with mortality ( p = 0.003). Conclusions In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. Trial registration : clinicaltrials.gov NCT02908308 , Registered September 20, 2016