Interleukin (IL)-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumor microenvironment of cancer patients where it correlates with the grade of malignancy. The direct effect of IL-4 on cancer cells has been associated with increased cell survival; however, its role in cancer cell proliferation and related mechanisms is still unclear. Here it was shown that in a nutrient-depleted environment, IL-4 induces proliferation in prostate cancer PC3 cells. In these cells, under nutrient-depletion stress, IL-4 activates mitogen-activated protein kinases (MAPKs), including Erk, p38 and JNK. Using MAP-signaling-specific inhibitors, it was shown that IL-4-induced proliferation is mediated by JNK activation. In fact, JNK-inhibitor-V stunted IL-4-mediated cell proliferation. Furthermore, it was found that IL-4 induces survivin up-regulation in nutrient-depleted cancer cells. Using survivin-shRNAs, it was demonstrated that in this milieu survivin expression above a threshold limit is critical to the mechanism of IL-4-mediated proliferation. In addition, the significance of survivin up-regulation in a stressed environment was assessed in prostate cancer mouse xenografts. It was found that survivin knockdown decreases tumor progression in correlation with cancer cell proliferation. Furthermore, under nutrient depletion stress, IL-4 could induce proliferation in cancer cells from multiple origins: MDA-MB-231 (breast), A253 (head and neck), and SKOV-3 (ovarian). Overall, these findings suggest that in a tumor microenvironment under stress conditions, IL-4 triggers a simultaneous activation of the JNK-pathway and the up-regulation of survivin turning on a cancer proliferation mechanism.
Background: Recent evidence has demonstrated a high rate of return to running after hip arthroscopy for femoroacetabular impingement at short-term follow-up. The midterm outcomes and rates of continued running of these patients are unknown. Purpose: To evaluate midterm rates of return to running and outcomes after hip arthroscopy. Study Design: Case series; Level of evidence, 4. Methods: Data were prospectively collected for patients who underwent hip preservation surgery between July 2008 and November 2011. Patients were excluded for preoperative Tönnis osteoarthritis grade ≥2, previous ipsilateral hip conditions or hip surgery, or workers’ compensation status. All patients who participated in mid- to long-distance running before their surgery and intended on returning after their operation were considered for inclusion. Preoperative and minimum 5-year postoperative measures for the following patient-reported outcome scores (PROs) were necessary for inclusion in the final cohort: the modified Harris Hip Score, Non-arthritic Hip Score, Hip Outcome Score–Sports Specific Subscale, and visual analog scale (VAS) for pain. All patients were counseled about the risks of continued running after hip arthroscopy. Results: Sixty patients (62 hips) were eligible for inclusion, of which 50 (83.3%; 52 hips) had minimum 5-year follow-up. There were 10 male hips and 42 female hips. Mean ± SD age at surgery was 32.4 ± 12.4 years (range, 14.9-62.4), and mean body mass index was 22.9 ± 3.2 (range, 17.7-30.1). Latest follow-up was recorded at a mean 69.3 ± 8.5 months (range, 60.0-92.1 months). Level of competition included 39 recreational, 7 high school, 4 collegiate, and 2 professional athletes. There were significant improvements in all PROs and VAS scores preoperatively to latest follow-up. Mean modified Harris Hip Score improved from 67.5 to 88.2; mean Non-arthritic Hip Score, from 65.9 to 88.3; mean Hip Outcome Score–Sports Specific Subscale, from 49.5 to 81.0; and mean VAS, from 5.2 to 1.5. At latest follow-up, patient satisfaction was 8.4. Thirty-nine patients (78.0%, 41 hips) had returned to running postoperatively. When stratified by level of competition, 79% (31 of 39) of recreational, 100% (7 of 7) of high school, 50% (2 of 4) of collegiate, and 50% (1 of 2) of professional athletes returned to running. Conclusion: Hip arthroscopy for all levels of runners is associated with a significant increase in PROs and a low risk of complications. The rate of return to running is moderately high after hip arthroscopy at midterm follow-up. Hip arthroscopy may be considered for runners presenting with symptoms of femoroacetabular impingement that fail nonoperative treatments. Patients should be educated on the rate of return to running over time and the risks of continued running after hip arthroscopy.
Midterm results of hip arthroscopy in athletes are shown to be safe and favorable. Most athletes return to sports and continue to play after 5 years with the same or higher ability.
Patients with advanced prostate cancer often exhibit increased activation of the coagulation system. The key activator of the coagulation cascade is the serine protease thrombin which is capable of eliciting numerous cellular responses. We previously reported that the thrombin receptor PAR1 is overexpressed in prostate cancer. To investigate further the role of PAR1 in prostate cancer metastasis, we examined the effects of thrombin activation on cell adhesion and motility in PC-3 prostate cancer cells. Activation of PAR1-induced dynamic cytoskeletal reorganization and reduced PC-3 binding to collagen I, collagen IV, and laminin (P < 0.01) but not fibronectin. Expression of the cell surface integrin receptors did not change as assessed by flow cytometry. Immunofluorescence microscopy revealed that PAR1 stimulation caused reorganization of the focal adhesions, suggesting that PAR1 activation in PC-3 cells may be modulating cell adhesion through integrin function but not expression. Furthermore, RhoA was activated upon stimulation with thrombin with subsequent cell contraction, decreased cell adhesion, and induced migration towards monocyte chemoattractant protein 1 (MCP-1; CCL2). Thus, it appears that thrombin stimulation plays a role in prostate cancer metastasis by decreasing cell adhesion to the extracellular matrix and positioning the cell in a "ready state" for migration in response to a chemotactic signal. Further exploration is needed to determine whether PAR1 activation affects other signaling pathways involved in prostate cancer.
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