Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1.

Advanced solid tumors are exposed to hypoxic conditions over longer periods of time as they grow. Tumor hypoxia is a major factor that induces malignant progression, but most previous studies on tumor hypoxia were performed under short-term hypoxia for up to 72 hours and few studies have focused on tumor response to chronic hypoxic conditions. Here we show a molecular mechanism by which chronic hypoxia promotes invasive behavior in prostate cancer cells. We found that an epithelial-mesenchymal transition (EMT)-driving transcription factor, slug, is specifically upregulated under chronic hypoxia and promotes tumor cell migration and invasion. Unexpectedly, processes associated with EMT, such as loss of E-cadherin, are not observed under chronic hypoxia. Instead, expression of ephrin-B1, a ligand of Eph-related receptor tyrosine kinases, is markedly induced by slug through E-box motifs and promotes cell migration and invasion. Furthermore, slug and ephrin-B1 are highly coexpressed in chronic hypoxic cells of human prostate adenocarcinoma tissues after androgen deprivation, which is known to cause tumor hypoxia. Taken together, these results indicate that chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating the expression of ephrin-B1. In addition, ephrin-B1 may be a novel therapeutic target in combination with androgen deprivation therapy for aggressive prostate cancer.

Mamushi bites in a kidney transplant recipient.

Introduction: Mamushi bites are the most common venomous snakebites in Japan. The clinical course of a common mamushi bite is known, and its alarming complication and cause of death are acute renal failure due to the venom. However, reports of mamushi bites in kidney transplant recipients are lacking, and the clinical course is unknown. Case presentation: A 66-year-old man who was bitten by a mamushi 3 years after kidney transplantation. Similar to the course of a typical mamushi bite, his severity gradually worsened to its peak 3 days after the bite, after which he turned lightly. A sufficient amount of infusion and continued immunosuppressive drugs were used to avoid acute renal failure. Conclusion: Even if the mamushi bite occurs in a kidney transplant recipient, the course and management may be the same as usual by continuing the immunosuppressive drugs and a sufficient amount of infusion.

Only three cycles of nivolumab showed remarkable durable response and reversible myeloradiculoneuropathy in a patient with metastatic papillary renal cell carcinoma type 2.

INTRODUCTION: The efficacy of nivolumab for non-clear cell renal cell carcinoma is still unclear. We present a rare case of metastatic papillary renal cell carcinoma remarkably responded to nivolumab but developed myeloradiculoneuropathy as immune-related adverse event. CASE PRESENTATION: The patient had previously undergone radical nephrectomy for right renal mass and was diagnosed as papillary renal cell carcinoma type 2, pT3bN0M0. Three years after the first surgery, he received 3 mg/kg of nivolumab as a second-line drug for mediastinum lymph nodes and lung metastases. With three cycles of nivolumab, the patient felt progressive weakness of the legs and received two cycles of steroid-pulse therapy based on the diagnosis of myeloradiculoneuropathy. Although nivolumab therapy has been discontinued, the metastases show radiographic complete response at 2 years after the last nivolumab administration without any additional therapy. CONCLUSION: Nivolumab may be a promising treatment option for non-clear cell renal cell carcinoma such as papillary renal cell carcinoma.

Hypoxia-induced angiopoietin-like protein 4 as a clinical biomarker and treatment target for human prostate cancer.

Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional protein, playing roles in glucose and lipid metabolism, inflammation, angiogenesis, and tumorigenesis. Recent research suggests that ANGPTL4 is induced by hypoxia and is a useful diagnostic or prognostic marker for various cancers. However, it remains unclear whether ANGPTL4 expression influences prostate cancer. Here we examined the biological and clinical relevance of ANGPTL4 expression in prostate cancer. Firstly we examined ANGPTL4 expression in the prostate cancer cell lines LNCaP and LNCaP/CH incubated at 1% O2 for at least 6 months. We compared cellular proliferation, migration, and ANGPTL4 secretion in a culture medium between these cell lines. In addition, we investigated the effect of various concentrations of recombinant ANGPTL4 protein (rANGPTL4) on cellular proliferation and intracellular signaling pathways. Moreover, we used ANGPTL4 knockdown by RNA interference to investigate the influence of ANGPTL4 expression on these cell lines. Finally, we investigated the correlation between ANGPTL4 expression in prostate cancer specimens and clinicopathological parameters using immunohistochemistry. Our data suggested that the expression of ANGPTL4 in hypoxic conditions was 14.4-fold higher than that in normoxic condition. ANGPTL4 secretion in the culture medium increased 7.0-fold. In addition, rANGPTL4 increased cellular proliferation 1.72-fold via Akt activation. Moreover, ANGPTL4 knockdown decreased cell growth and its secretion by 25.7 and 41.4%, respectively, compared with the control. A multivariate analysis showed that positive ANGPTL4 expression in the resected specimens was an independent prognostic indicator of biochemical recurrence (P=0.03, hazard ratio = 2.02). Our results show that ANGPTL4 is induced by hypoxia and promotes cancer progression via the activated PI3K/Akt pathway. Moreover, ANGPTL4 can be used as a prognostic marker for prostate cancer patients undergoing radical prostatectomy.

Efficacy and Safety of Enoxaparin for Preventing Venous Thromboembolic Events following Urologic Laparoscopic Surgery.

There is a paucity of definitive evidence that supports the use of enoxaparin to prevent venous thromboembolism (VTE) after urologic laparoscopic surgery. The purpose of this study was to evaluate the efficacy and safety of postoperative subcutaneous enoxaparin injection in patients who underwent urologic laparoscopic surgery. A total of 63 patients were evaluated from June 2010 to December 2012. All patients received postoperative prophylaxis with enoxaparin (2000 IU twice daily for 5 days). None of the patients treated with enoxaparin developed symptomatic VTE, but two cases (3.2%) of pulmonary embolism were noted before initial enoxaparin administration. Statistically significant differences were observed between the prothrombin time (PT) and activated partial thromboplastin time (APTT) values and D-dimer levels obtained at baseline and on day 7 after surgery; however, the PT and APTT values did not exceed the normal range. In addition, signs of any adverse events were not encountered in any of the patients treated with enoxaparin. The use of enoxaparin immediately after a surgery may confer valuable thromboprophylaxis benefits for urologic laparoscopic surgery.