The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer.
- 作者列表："Larsson P","Syed Khaja AS","Semenas J","Wang T","Sarwar M","Dizeyi N","Simoulis A","Hedblom A","Wai SN","Ødum N","Persson JL
:Currently, no effective targeted therapeutics exists for treatment of metastatic prostate cancer (PCa). Given that matrix metalloproteinases 9 (MMP9) and its associated vascular endothelial growth factor (VEGF) are critical for tumor vascularization and invasion under castration-resistant condition, it is therefore of great importance to define the functional association and interplay between androgen receptor (AR) and MMP9 and their associated key survival and invasion pathways in PCa cells. Here, we found that there was a significant correlation between MMP9 and AR protein expression in primary and metastatic PCa tissues, and a trend that high level of MMP9 expression was associated with poor prognosis. We demonstrated that constitutive activation of AR increased expression of MMP9 and VEGF/VEGF receptors. We further showed that AR exerts its effect on MMP9/VEGF signaling axis through PIP5K1α/AKT. We showed that MMP9 physically interacted with PIP5K1α via formation of protein-protein complexes. Furthermore, elevated expression of MMP9 enhanced ability of AR to activate its target gene cyclin A1. The elevated sequential activation of AR/PIP5K1α/AKT/MMP9/VEGF signaling axis contributed to increased invasiveness and growth of metastatic tumors. Conversely, treatment with PIP5K1α inhibitor significantly suppressed invasiveness of PCa cells expressing constitutively activated AR, this was coincident with its inhibitory effect of this inhibitor on AR/MMP9/VEGF pathways. Our results suggest that AR and MMP9-associated network proteins may be effectively targeted by blocking PIP5K1α/AKT pathways using PIP5K1α inhibitor in metastatic PCa.
: 目前，尚无有效的靶向治疗方法用于治疗转移性前列腺癌 (PCa)。鉴于基质金属蛋白酶 9 (MMP9) 及其相关的血管内皮生长因子 (VEGF) 在去势抵抗条件下对肿瘤血管化和侵袭至关重要，因此，确定雄激素受体 (AR) 之间的功能关联和相互作用非常重要。和MMP9 及其相关的关键生存和侵袭途径在PCa细胞中。在此，我们发现在原发性和转移性PCa组织中MMP9 和AR蛋白表达之间存在显著相关性，并且MMP9 高水平表达与不良预后相关。我们证明AR的组成性激活增加了MMP9 和VEGF/VEGF受体的表达。我们进一步发现AR通过pip5k1 α/AKT对MMP9/VEGF信号轴发挥作用。我们发现MMP9 通过形成蛋白-蛋白复合物与pip5k1 α 发生物理相互作用。此外，MMP9 的表达升高增强了AR激活其靶基因cyclin a1 的能力。AR/pip5k1 α/AKT/MMP9/VEGF信号轴的顺序激活升高有助于转移性肿瘤的侵袭性和生长。相反，pip5k1 α 抑制剂治疗可显著抑制表达组成性激活AR的PCa细胞的侵袭力，这与其抑制AR/MMP9/VEGF通路的作用一致。我们的结果表明，在转移性PCa中，AR和MMP9-associated网络蛋白可能通过使用pip5k1 α 抑制剂阻断pip5k1 α/AKT通路而有效靶向。
METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.
METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.