Glucocorticoid drugs are widely used to treat immune-related diseases, but their use is limited by side effects and by resistance, which especially occurs in macrophage-dominated diseases. In order to improve glucocorticoid therapies, more research is required into the mechanisms of glucocorticoid action. In the present study, we have used a zebrafish model for inflammation to study glucocorticoid effects on the innate immune response. In zebrafish larvae, the migration of neutrophils towards a site of injury is inhibited upon glucocorticoid treatment, whereas migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in the expression of genes that encode neutrophil-specific chemoattractants (Il8 and Cxcl18b) are attenuated by the synthetic glucocorticoid beclomethasone, but that beclomethasone does not attenuate the induction of the genes encoding Ccl2 and Cxcl11aa, which are required for macrophage recruitment. RNA sequencing on FACS-sorted macrophages shows that the vast majority of the wounding-induced transcriptional changes in these cells are inhibited by beclomethasone, whereas only a small subset is glucocorticoid-insensitive. As a result, beclomethasone decreases the number of macrophages that differentiate towards a pro-inflammatory (M1) phenotype, which we demonstrated using a tnfa:eGFP-F reporter line and analysis of macrophage morphology. We conclude that differentiation and migration of macrophages are regulated independently, and that glucocorticoids leave the chemotactic migration of macrophages unaffected, but exert their anti-inflammatory effect on these cells by inhibiting their differentiation to an M1 phenotype. The resistance of macrophage-dominated diseases to glucocorticoid therapy can therefore not be attributed to an intrinsic insensitivity of macrophages to glucocorticoids.

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Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration

Background: M2 macrophages are crucial components of tumor microenvironment that frequently associated with the resistance of therapeutic treatments in human cancers, but their role in the chemosensitivity of colorectal cancer (CRC) to 5-fluorouracil (5-FU) is still obscure. Methods: In our study, we clarified the biological functions of M2 macrophages and their mechanism on the chemosensitivity of CRC cells to 5-FU. Then, we analyzed the correlation between CCL22 and CD68+ and CD163+ tumor-associated macrophages (TAMs), and further elucidated the prognostic value of CCL22 and CD163+ M2 macrophages in clinical CRC samples. Results: M2 macrophages decreased the inhibitory effect of 5-FU on CRC cells migration and invasion by secreting CCL22, and declined the apoptosis induced by 5-FU. Treated with a neutralizing anti-CCL22 antibody destroyed these effects. We further illuminated that M2 macrophages regulated 5-FU resistance of CRC cells through epithelial-mesenchymal transition (EMT) program, PI3K/AKT pathway, and caspase-mediated apoptosis. Clinically, CCL22 was found to have elevated expression in CRC tissue samples, and was positively associated with CD163+ TAMs. Furthermore, the patients with higher CD163+ M2 macrophages and higher expression of CCL22 in CRC tissues had a lower overall survival (OS) rate compared with lower ones. Conclusion: Our findings indicate that M2 macrophage regulated 5-FU-mediated CRC chemoresistance via the EMT program, PI3K/AKT pathway, and caspase-mediated apoptosis by releasing CCL22.

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M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling.

Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.

The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment

Tumor microenvironment (TME) formation is a major cause of immunosuppression. The TME consists of a considerable number of macrophages and stromal cells that have been identified in multiple tumor types. CCL2 is the strongest chemoattractant involved in macrophage recruitment and a powerful initiator of inflammation. Evidence indicates that CCL2 can attract other host cells in the TME and direct their differentiation in cooperation with other cytokines. Overall, CCL2 has an unfavorable effect on prognosis in tumor patients because of the accumulation of immunosuppressive cell subtypes. However, there is also evidence demonstrating that CCL2 enhances the anti-tumor capability of specific cell types such as inflammatory monocytes and neutrophils. The inflammation state of the tumor seems to have a bi-lateral role in tumor progression. Here, we review works focusing on the interactions between cancer cells and host cells, and on the biological role of CCL2 in these processes.

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CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment.

Phosphodiesterase inhibitors say NO to Alzheimer's disease

Although the standard treatment for the patients with recurrent and metastatic prostate cancer (CaP) is androgen deprivation therapy, castration-resistant prostate cancer (CRPC) eventually emerges Our previous report indicated that bone morphogenetic protein 6 (BMP6) induced CRPC via tumour-infiltrating macrophages In a separate line of study, we have observed that the WNT5A/BMP6 loop in CaP bone metastasis mediates resistance to androgen deprivation in tissue culture Simultaneously, we have reported that BMP6 induced castration resistance in CaP cells via tumour-infiltrating macrophages Therefore, our present study aims to investigate the mechanism of WNT5A and its interaction with macrophages on CRPC Doxycycline inducible WNT5A overexpression prostate cancer cell line was used for detailed mechanical study WNT5A was associated with increased expression of chemokine ligand 2 (CCL2) in the human CaP cell line, LNCaP Mechanistically, this induction of CCL2 by WNT5A is likely to be mediated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway Our in vivo experiments demonstrated that the overexpression of WNT5A in LNCaP cells promoted castration resistance Conversely, this resistance was inhibited with the removal of macrophages via clodronate liposomes When patient-derived CaP LuCaP xenografts were analysed, high levels of WNT5A were correlated with increased levels of CCL2 and BMP6 In addition, higher levels of CCL2 and BMP6 were more commonly observed in intra-femoral transplanted tumours as compared to subcutaneous-transplanted tumours in the patient-derived PCSD1 bone-niche model These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively

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WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

Phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line drugs in the management of erectile dysfunction (ED). However, over the past two decades tremendous efforts have been made to identify new clinical uses of PDE5Is beyond their roles in ED. Areas covered: Basic science articles, clinical trials, reviews, and meta-analysis published between 1996 and 2015 were searched using MEDLINE (PubMed interface) to collect the most relevant and impactful studies from our perspectives as practicing urologists. This review mainly focuses on the level one evidence-based clinical efficacy and drug-related toxicity of oral PDE5Is. In addition, drug discovery, pharmacokinetics and pharmacodynamics, potential use in other diseases, and future directions are discussed. Expert opinion: On-demand PED5Is for the treatment of ED has shifted toward chronic administration in a broad spectrum of conditions that are thought to be associated with endovascular health. Several studies have shown that PDE5Is may play a cardioprotective or neuroprotective role. Further studies are under way to verify beneficial effects of PDE5I in non-urological conditions.

Pharmacodynamics, pharmacokinetics and clinical efficacy of phosphodiesterase-5 inhibitors.

Although androgen deprivation therapy (ADT) and immunotherapy are potential treatment options in men with metastatic prostate cancer (CaP), androgen has conventionally been proposed to be a suppressor of the immune response. However, we herein report that DHT activates macrophages. When the murine macrophage cell line (RAW 264.7), human monocyte cell line (THP-1), and human peripheral blood monocytes were cultured with androgen-resistant CaP cell lines, DHT increased cytotoxicity of macrophages in a concentration-dependent manner. Further studies revealed that DHT induced M1 polarization and increased the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) in macrophages and that this effect was abrogated when TRAIL was neutralized with a blocking antibody or small interfering RNA. Subsequent experiments demonstrated that induction of TRAIL expression was regulated by direct binding of androgen receptor to the TRAIL promoter region. Finally, an in vivo mouse study demonstrated that castration enhanced the growth of an androgen-resistant murine CaP tumor and that this protumorigenic effect of castration was blocked when macrophages were removed with clodronate liposomes. Collectively, these results demonstrate that DHT activates the cytotoxic activity of macrophages and suggest that immunotherapy may not be optimal when combined with ADT in CaP.

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Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL.

The aim of this study is to identify optimal patients for adjuvant radiation therapy (ART) in pT3 prostate cancer. The role of ART for patients with adverse pathologic features after radical prostatectomy (RP) has been demonstrated, but over- or under-treatment remains a significant concern. Two-hundred and five patients with pT3N0M0 who underwent robot-assisted RP without ART were analyzed. Multivariate Cox proportional regression analyses were used to identify predictors of biochemical recurrence (BCR) and clinical progression (CP). The estimated 5-year BCR-free survival (BCRFS) and CP-free survival (CPFS) were 52.8% and 85.6%, respectively. Preoperative prostate-specifc antigen (PSA) ≥10 ng ml−1 (hazard ratio [HR]: 3.288-6.027; P = 0.003), pathologic Gleason score (pGS) ≥8 (HR: 4.146; P = 0.014), and lymphovascular invasion (LVI) (HR: 2.167; P = 0.026) were associated with BCR. Based on these factors, a risk stratification tool was developed. Patients with no risk factors (PSA <10 ng ml−1 , pGS 6, and absent LVI) showed excellent BCRFS and CPFS at 5 years (91.9% and 100.0%, respectively), but those with two or more risk factors (PSA ≥10 ng ml−1 , pGS ≥8, or present LVI) had poor BCRFS and CPFS (12.1% and 54.6%, respectively). In addition, the multivariate analysis revealed that pathologic stage pT3b (HR: 5.393; P = 0.025) was the only predictor of CP. Our study demonstrated the heterogeneity of oncologic outcomes in patients with pT3 prostate cancer. The proposed risk stratification can be used to identify patients who are at risk for disease progression and may aid in identifying the best patients for ART.

Jeong Hee Hong

Papers

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

Pharmacodynamics, pharmacokinetics and clinical efficacy of phosphodiesterase-5 inhibitors.

Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL.

Risk stratification for disease progression in pT3 prostate cancer after robot-assisted radical prostatectomy.