Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA had less than half the abundance of type 1 insulin-like growth factor receptor (IGF-1R), less activity in the survival pathway mediated by PI3K-AKT signaling, and more activity in the proliferative pathway mediated by MAPK-ERK1/2 signaling. Biochemically, PSMA interacted with the scaffolding protein RACK1, disrupting signaling between the β1 integrin and IGF-1R complex to the MAPK pathway, enabling activation of the AKT pathway instead. Manipulation of PSMA abundance in PCa cell lines recapitulated this signaling pathway switch. Analysis of published databases indicated that IGF-1R abundance, cell proliferation, and expression of transcripts for antiapoptotic markers positively correlated with PSMA abundance in patients, suggesting that this switch may be relevant to human PCa. Our findings suggest that increase in PSMA in prostate tumors contributes to progression by altering normal signal transduction pathways to drive PCa progression and that enhanced signaling through the IGF-1R/β1 integrin axis may occur in other tumors.

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transcatheter aortic valve repair, open aneurysm repair, and endovascular aneurysm repair. The current study evaluated multiple variables including core muscle size, BMI, age, and Charlson comorbidity index (CCI) as predictors of all-cause mortality after EVAR. Materials: An IRB approved single-center retrospective study of patients with a history of EVAR between 2010 and 2016 was performed. After excluding patients without preprocedure crosssectional imaging and those incomplete medical records, a total of 407 patients were included. The total psoas muscle area (TPMA) was measured in cross-section at the superior endplate of L4. Kaplan-Meier curves were constructed for each of the candidate variables. Univariate and multivariate analyses were performed to determine which variables were significant predictors of mortality. Results: Mean follow-up time was 38.7 months (SD 33.5 months). Following endovascular repair, there was a significant difference (p<0.002) in mean survival time for patients with total psoas muscle area smaller than 1422 mm 2 (the lowest quartile); 63.7 months (SE 4.4 months) compared to 90.3 months (SE 4.0 months) for patients with TPMA greater than 1422 mm 2. The mean survival time for patients who were underweight was 38.1 months (SE 14.8 months); significantly different from normal, overweight, and obese patients, p<0.015. Multivariate analysis demonstrated that total psoas muscle area and BMI were significant predictors of mortality after EVAR (p<0.006 and p<0.012, respectively). Other variables such as age, gender, and CCI were not significant. Conclusions: Significant predictors of all-cause mortality after EVAR included BMI and TPMA. Age, gender, and Charlson comorbidity index were not significant predictors in the multivariate model. Therefore, inclusion of BMI and core muscle size in risk stratification tools may identify truly frail patients.

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