Radiotherapy and surgery are curative treatment options for localized prostate cancer (PCa) with a 5-year survival rate of nearly 100%. Once PCa cells spread into distant organs, such as bone, the overall survival rate of patients drops dramatically. The metastatic cascade and organotropism of PCa cells are regulated by different cellular subtypes, organ microenvironment, and their interactions. This cross-talk leads to pre-metastatic niche formation that releases chemo-attractive factors enforcing the formation of distant metastasis. Biological characteristics of PCa metastasis impacting on metastatic sites, burden, and latency is of clinical relevance. Therefore, the implementation of modern hybrid imaging technologies into clinical routine increased the sensitivity to detect metastases at earlier stages. This enlarged the number of PCa patients diagnosed with a limited number of metastases, summarized as oligometastatic disease. These patients can be treated with androgen deprivation in combination with local-ablative radiotherapy or radiopharmaceuticals directed to metastatic sites. Unfortunately, the number of patients with disease recurrence is high due to the enormous heterogeneity within the oligometastatic patient population and the lack of available biomarkers with predictive potential for metastasis-directed radiotherapy. Another, so far unmet clinical need is the diagnosis of minimal residual disease before onset of clinical manifestation and/or early relapse after initial therapy. Here, monitoring of circulating and disseminating tumor cells in PCa patients during the course of radiotherapy may give us novel insight into how metastatic spread is influenced by radiotherapy and vice versa. In summary, this review critically compares current clinical concepts for metastatic PCa patients and discuss the implementation of recent preclinical findings improving our understanding of metastatic dissemination and radiotherapy resistance into standard of care.
Graphene oxide complexed with calcium phosphate nanoparticles enhances bone regeneration through signalling between monocytes and mesenchymal stem cells.
Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa.
Silica nanosheets (SiO NS) are considered to be a promising material in clinical practice for diagnosis and therapy applications. However, an appropriate surface functionalization is essential to guarantee high biocompatibility and molecule loading ability. Although SiO NS are chemically stable, its effects on immune systems are still being explored. In this work, we successfully synthesized a novel 2D multilayer SiO NS and SiO NS coated with carbon (C/SiO NS), and evaluated their impact on human Peripheral Blood Mononuclear Cells (PBMCs) and some immune cell subpopulations. We demonstrated that the immune response is strongly dependent on the surface functionalities of the SiO NS. Ex vivo experiments showed an increase in biocompatibility of C/SiO NS compared to SiO NS, resulting in a lowering of hemoglobin release together with a reduction in cellular toxicity and cellular activation. However, none of them are directly involved in the activation of the acute inflammation process with a consequent release of pro-inflammatory cytokines. The obtained results provide an important direction towards the biomedical applications of silica nanosheets, rendering them an attractive material for the development of future immunological therapies.
Background Semaphorin 4D (Sema4D) is a glycoprotein that inhibits bone formation and has been associated with cancer progression and the occurrence of bone metastases. Recently, Sema4D expression has been linked to estrogen signaling in breast cancer. Endocrine therapies like tamoxifen and aromatase inhibitors (AI) are a standard therapeutic approach in hormone receptor positive breast cancers. Tamoxifen exerts ER-agonistic effects on bone, whereas AI negatively affect bone health by increasing resorption and fracture risk. The effect of endocrine therapies on circulating Sema4D levels in breast cancer patients has not been investigated yet. Methods We measured circulating Sema4D plasma levels at primary diagnosis and in a follow-up sample 12 months after surgery in a cohort of 46 pre- and postmenopausal women with primary estrogen receptor positive breast cancer receiving adjuvant tamoxifen or AI. Results The mean baseline levels ± SD for Sema4D were 441.6 ± 143.4 pmol/l. No significant differences in total plasma Sema4D were observed when stratifying the patients according to age, menopausal status, tumor subtype, nodal and hormone receptor status, or tumor size. However, Sema4D levels were significantly reduced by 28% ( p <0.001) in tamoxifen treated patients 12 months after surgery, whereas no alteration was observed in patients treated with AI. Conclusion This finding potentially represents an additional mechanism of the bone-protective properties of tamoxifen and further emphasizes a link between Sema4D and estrogen receptor signaling.
Prostate cancer (PCa) is a major cause of cancer-related death in men. Tumor-derived WNT5A plays an important role in primary and metastatic PCa. Surrounding stroma cells also produce WNT5A, which may modulate the biology of PCa. Here we assessed the role of stroma-derived WNT5A (stWNT5A) in primary PCa. A tissue microarray of samples obtained from 400 patients who underwent radical prostatectomy and control samples from 41 patients with benign prostate hyperplasia (BPH) was immunohistochemically assessed for expression of stWNT5A. The cores were scored for staining intensity: 0 (no staining), 1 (weak), 2 (moderate), or 3 (strong) and the stained stromal surface area: 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%). Gleason Score (GS) and TNM-stage were assessed by stratifying the cohort into high-risk (≥ pT3, pN1, GS ≥ 8) and non-high-risk patients. Ki67 and TUNEL assays were performed to assess proliferation and apoptosis. Expression of stWNT5A in BPH and tumor free control samples was 1.2-fold higher compared to tumor samples (p<0.001). Non-high-risk patients had a higher stWNT5A score than high-risk patients (p<0.05). stWNT5A expression was not correlated with overall and cancer-specific survival. Proliferation (r2=0.038, p<0.001) and apoptosis (r2=0.277, p<0.001) negatively correlated with stWNT5A expression. In summary, we show that expression of stWNT5A is higher in benign tissue and non-high-risk PCa. Stroma-derived Wnt signaling and tumor-derived Wnt may differentially impact on tumor behavior. Future studies are warranted to dissect the Wnt profile in tumor vs. surrounding stroma tissues.
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