Although KIF4A has been found to play an important role in a variety of tumors and is closely associated with the activation of immunocytes, its role in bladder cancer (BC) remains unclear. Here, we report increased expression of KIF4A in both lymph node-positive and high grade BC tissues. High expression of KIF4A has been significantly correlated with fewer CD8+ tumor-infiltrating lymphocytes (TILs) and a much worse prognosis in patients with BC. With respect to promoting tumor growth, the expression of KIF4A in promoting tumor growth was more pronounced in immune-competent mice (C57BL/6) than in immunodeficient mice (BALB/C). In addition, the more increased accumulation of myeloid-derived suppressor cells (MDSCs) was observed in tumor-bearing mice with KIF4A overexpression than in the control group. Transwell chemotaxis assays revealed that KIF4A overexpression in T24 cells increased MDSC recruitment. Furthermore, according to ELISA results, CXCL5 was the most noticeably increased cytokine in the KIF4A-transduced BC cells. Additional studies in vitro and in vivo showed that the capability of KIF4A to promote BC cells to recruit MDSCs could be significantly inhibited by anti-CXCL5 antibody. Therefore, our results demonstrated that KIF4A-mediated BC production of CXCL5 led to an increase in MDSC recruitment, which contributed to tumor progression.
© 2022. The Author(s).

Cancer cell-intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non-cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1+CD11b+ myeloid-derived suppressor cells (MDSC) or Foxp3+ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2-CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2-CCR2 axis could be an effective therapeutic target in RB-deficient tumors. SIGNIFICANCE: These findings demonstrate the cell-nonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.
©2019 American Association for Cancer Research.

Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 (LNMAT1), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that LNMAT1 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, LNMAT1 epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore, LNMAT1-induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for LNMAT1-modulated tumor microenvironment in lymphatic metastasis and suggest that LNMAT1 may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer.

Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.

Exudative pleural effusions affect over 1500 patients per million population each year. The pathobiology of pleural exudate formation remains unclear. Our recent study revealed monocyte chemotactic protein-1 (MCP-1) as a key driver of fibrinolytic-induced exudate effusion while another study found a role for MCP-1 in malignant effusion formation. In the present study, we further evaluated the role of MCP-1 in the development of pleural effusion in a mouse model of acute pleural inflammation.
λ-Carrageenan (CAR) was injected into the pleural cavity of CD1 mice and pleural effusion volume measured up to 16 h post-injection. Pleural effusion and serum protein and MCP-1 concentrations were measured and differential cell counts performed in fluids. Mice were also treated with either intraperitoneal (i) anti-MCP-1 antibody or isotype control or (ii) an MCP-1 receptor (CCR2) antagonist or vehicle control 12 h prior to and at the time of CAR injection.
Intrapleural CAR induced significant pleural fluid accumulation (300.0 ± 49.9 μL) in mice after 4 h. Pleural fluid MCP-1 concentrations were significantly higher than corresponding serum MCP-1 (144 603 ± 23 204 pg/mL vs 3703 ± 801 pg/mL, P < 0.0001). A significant decrease in pleural fluid formation was seen both with anti-MCP-1 antibody (median (interquartile range, IQR): 36 (0-168) μL vs controls 290 (70-436) μL; P = 0.02) or CCR2 antagonist (153 (30-222) μL vs controls 240 (151-331) μL, P = 0.0049).
Blockade of MCP-1 activity significantly reduced inflammatory pleural effusion formation in a CAR model. Together with recent successes in MCP-1 blockade in other effusion formation models, our data strongly support clinical evaluation of MCP-1 antagonists as a novel approach to pleural fluid management.
© 2016 Asian Pacific Society of Respirology.