COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.

Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.

Hip Arthroscopic Microfracture Augmented With Platelet-Rich Plasma-Infused Micronized Cartilage Allograft Significantly Improves Functional Outcomes.

PURPOSE: To evaluate functional outcomes and survivorship in patients at 1 year after undergoing arthroscopic microfracture augmented with hyaline allograft for symptomatic chondral defects of the hip. METHODS: Consecutive patients with and without prior hip procedures presenting with Outerbridge grade IV chondral lesion of the acetabulum or femoral head were prospectively followed. Patients underwent hip microfracture augmented with hyaline allograft suspended in autologous platelet-rich plasma between October 2016 and April 2018. Extent of cartilage degeneration was quantified using the chondromalacia severity index (CMI). Patient functional scores, including Tegner, Hip Outcome Score-Activities of Daily Living (HOS-ADL), Sport-Specific Subscale (HOS-SSS), modified Harris Hip Score (mHHS), and Nonarthritic Hip Score (NAHS) were collected preoperatively and at minimum 1-year postoperatively. Minimal clinically important difference (MCID) was analyzed. Statistical significance was established at P < .05. Pearson's coefficient analysis was performed to identify preoperative variables correlated with clinical outcomes. RESULTS: Fifty-seven patients (86.4%) had minimum 1-year follow-up and were included in the final analysis, with a mean age and body mass index (BMI) of 38.3 ± 9.1 years and 27.7 ± 4.9 kg/m2, respectively. Comparison of baseline and postoperative score averages demonstrated significant improvements in Tegner scores (3.7 ± 2.9 vs 5.1 ± 2.6; P = .003), HOS-ADL (63.3 ± 16.4 vs 89.1 ± 14.5; P < .001), HOS-SSS (40.8 ± 20.4 vs 79.5 ± 21.6; P < .001), mHHS (61.5 ± 16.2 vs 87.0 ± 17.7; P < .001), and NAHS (56.6 ± 14.9 vs 78.7 ± 18.3; P < .001). The percentage of patients who achieved MCID for HOS-ADL, HOS-SSS, mHHS, and NAHS were 89.8%, 83.0%, 75.6%, and 81.6%, respectively. Overall, 91.8% of patients met the threshold for achieving MCID in at least one outcome score. Of the 57 patients, 5 (8.8%) failed clinically, with 1 (1.8%) undergoing revision surgery and 4 (6.9%) undergoing conversion to total hip arthroplasty. There was a direct correlation between preoperative alpha angle and postoperative HOS-ADL. Femoral chondral lesion size and CMI inversely correlated with postoperative HOS-ADL. CONCLUSIONS: Treatment of hip chondral defects with microfracture and hyaline allograft augmentation demonstrated excellent survivorship and significantly improved patient report outcomes at 1 year. LEVEL OF EVIDENCE: IV, retrospective case series.

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice.

BACKGROUND: Obesity and type 2 diabetes are major risk factors for peripheral arterial disease in humans, which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO). MATERIALS AND METHODS: DIO mice (n = 7) underwent unilateral femoral artery ligation and recovered for 2 wks followed by 4 wks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia (SI) group (n = 7) had femoral artery ligation without exercise. The contralateral limb muscles of SI served as control. Muscles were examined for capillary density, myofiber cross-sectional area, cytokine levels, and phosphorylation of STAT3 and ERK1/2. RESULTS: Exercise significantly enhanced capillary density (P < 0.01) and markedly lowered cross-sectional area (P < 0.001) in demand ischemia compared with SI. These findings coincided with a significant increase in granulocyte colony-stimulating factor (P < 0.001) and interleukin-7 (P < 0.01) levels. In addition, phosphorylation levels of STAT3 and ERK1/2 (P < 0.01) were increased, whereas UCP1 and monocyte chemoattractant protein-1 protein levels were lower (P < 0.05) without altering vascular endothelial growth factor and tumor necrosis factor alpha protein levels. Demand ischemia increased the PGC1α messenger RNA (P < 0.001) without augmenting PGC1α protein levels. CONCLUSIONS: Exercise-induced limb demand ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in tumor necrosis factor alpha, lower vascular endothelial growth factor, and failure to increase PGC1α protein may reflect a deficient adaption to demand ischemia in DIO.