ABSTRACT
Introduction: Prostate cancer (PCa) is one of the most common adult malignancies worldwide, and a major leading cause of cancer-related death in men in Western societies. In the last years, the prognosis of advanced PCa patients has been impressively improved thanks to the development of different therapeutic agents, including taxanes (docetaxel and cabazitaxel), second-generation anti-hormonal agents (abiraterone and enzalutamide), and the radiopharmaceutical Radium-223. However, great efforts are still needed to properly select the most appropriate treatment for each single patient.Areas covered: Several prognostic or predictive biomarkers have been studied, none of which has an established validated role in daily clinical practice. This paper analyzed the major biomarkers (including PSA, androgen receptor (AR) splice variants, ßIII-tubulin, ALP, circulating tumor cells, and DNA repair genes) with a potential prognostic and/or predictive role in advanced PCa patients.Expert commentary: Surrogate biomarkers - measurable, reproducible, closely associated with tumor behavior and linked to relevant clinical outcomes - are urgently needed to improve PCa patient management.
Subject(s)
Biomarkers, Tumor , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Clinical Decision-Making , Combined Modality Therapy , Disease Management , Drug Resistance, Neoplasm , Humans , Male , Neoplasm Staging , Neoplastic Cells, Circulating , Neoplastic Stem Cells , Precision Medicine/methods , Prostatic Neoplasms/etiology , Treatment OutcomeABSTRACT
RATIONALE: Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. AIMS: We examined whether poly(lactic-co-glycolic acid) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation, and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analysed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). METHODS AND RESULTS: We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve-month-old C57 mice underwent coronary artery ligation to induce AMI, and were randomized into five treatment groups: AMI control (saline 20 µL, n = 7), AMI followed by intramyocardial injection with AT-MSCs (2.5 × 10(5) cells/20 µL, n = 5), or concentrated medium (CM) from AT-MSCs (20 µL, n = 8), or AT-MSCs (2.5 × 10(5) cells/20 µL) conjugated with empty PAMs (n = 7), or VEGF-releasing PAMs (n = 8). Sham-operated mice (n = 7) were used as controls. VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. CONCLUSIONS: AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications.
Subject(s)
Adipose Tissue/cytology , Mesenchymal Stem Cell Transplantation , Myocardial Infarction/therapy , Vascular Endothelial Growth Factor A/metabolism , Animals , Cells, Cultured , Male , Mice , Mice, Inbred C57BL , MicrospheresABSTRACT
BACKGROUND: Adipose tissue-derived stromal cells (ADSCs) might help repair ischemic cardiovascular tissue. Their in vivo effects on the bioenergetics and microcirculation of ischemic muscle through a variety of non-invasive techniques was examined. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced in 42 rats. One day after femoral artery ligation, 6 rats per group were randomly injected with intramuscularly allogeneic ADSCs (10(6)-10(7)-10(8) cells/ml), conditioned media from ADSC cultures (conditioned media [CM], control), saline (control), allogeneic fibroblasts (10(7) cells/ml, control) or a non-conditioned medium (control). Rats underwent magnetic resonance angiography (MRA), short-time inversion recovery (STIR) edema-weighed imaging, proton MR spectroscopy ((1)H-MRS), thermal infrared imaging (IRI), immunoblotting and immunofluorescence analysis on both hindlimbs for 4 weeks. MRA and STIR documented arterial occlusion and ischemia, respectively. Muscle (1)H-MRS and IRI showed reductions of total creatine (tCr)/water and skin temperature in occluded hind limbs, respectively. At 4 weeks, the ADSC and CM groups had greater recovery of skin temperature and tCr/water in ischemic limbs compared with controls (P<0.01), with increased expression of α-sarcomeric actinin and vascular growth factors, such as hepatocyte growth factor (HGF), increased vessel density (capillaries, arterioles and venules) and less type III collagen. CONCLUSIONS: Allogeneic ADSCs improve ischemic muscle metabolism, increase neovasculogenesis and decrease fibrosis, largely through a paracrine mechanism. (1)H-MRS and IRI are useful tools to monitor attempts at salvaging the ischemic tissues with cell-derived novel therapies.
