Tumor-associated macrophages (TAM) are prominent components of tumor microenvironment (TME) and capable of promoting cancer progression. However, the mechanisms for the formation of M2-like TAMs remain enigmatic. Here, we show that lactate is a pivotal oncometabolite in the TME that drives macrophage M2-polarization to promote breast cancer proliferation, migration, and angiogenesis. In addition, we identified that the activation of ERK/STAT3, major signaling molecules in the lactate signaling pathway, deepens our molecular understanding of how lactate educates TAMs. Moreover, suppression of ERK/STAT3 signaling diminished tumor growth and angiogenesis by abolishing lactate-induced M2 macrophage polarization. Finally, research data of the natural compound withanolide D provide evidence for ERK/STAT3 signaling as a potential therapeutic strategy for the prevention and treatment of breast cancer. These findings suggest that the lactate-ERK/STAT3 signaling pathway is a driver of breast cancer progression by stimulating macrophage M2-like polarization and reveal potential new therapeutic targets for breast cancer treatment.

Altered cellular metabolism is now generally acknowledged as a hallmark of cancer cells, the resultant abnormal oncometabolites cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy. A subset of cancers have been found to be associated with mutations in succinate dehydrogenase genes which result in the accumulation of succinate. However, the function of succinate in tumorigenesis remains unclear. In the present study, we aim to investigate the role of oncometabolite succinate in tumor angiogenesis. Our data demonstrated the accumulation of markedly elevated succinate in gastric cancer tissues compared with that in paracancerous tissues. Moreover, succinate was able to increase the chemotactic motility, tube-like structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) in vitro, as well as promoting the blood vessel formation in transgenic zebrafish. Our mechanistic studies reveal that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor GPR91 in a HIF-1α independent mechanism. Taken together, these data indicate an important role of the succinate-GPR91 axis in tumor angiogenesis, which may enable development of a novel therapeutic strategy that targets cancer metabolism.

Gastric cancer (GC) is a malignancy of the lining of the stomach and is prone to distant metastasis, which involves a variety of complex molecules. The S100 proteins are a family of calcium‐binding cytosolic proteins that possess a wide range of intracellular and extracellular functions and play pivotal roles in the invasion and migration of tumour cells. Among these, S100A10 is known to be overexpressed in GC. Lysine succinylation, a recently identified form of protein post‐translational modification, is an important regulator of cellular processes. Here, we demonstrated that S100A10 was succinylated at lysine residue 47 (K47), and levels of succinylated S100A10 were increased in human GC. Moreover, K47 succinylation of S100A10 was stabilized by suppression of ubiquitylation and subsequent proteasomal degradation. Furthermore, carnitine palmitoyltransferase 1A (CPT1A) was found to function as a lysine succinyltransferase that interacts with S100A10. Succinylation of S100A10 is regulated by CPT1A, while desuccinylation is regulated by SIRT5. Overexpression of a succinylation mimetic mutant, K47E S100A10, increased cell invasion and migration. Taken together, this study reveals a novel mechanism of S100A10 accumulation mediated by succinylation in GC, which promotes GC progression and is regulated by the succinyltransferase CPT1A and SIRT5‐mediated desuccinylation.

BackgroundEnzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis.MethodsCHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function.ResultsCHI3L1 upregulation occurred during GC development, and positively correlated with GC invasion depth, lymph node status, and tumor staging. Mechanically, CHI3L1 binding to CD44 activated Erk and Akt, along with β-catenin signaling by phosphorylating β-catenin at Ser552 and Ser675. CD44 also interacted with IL-13Rα2 to form a complex. Notably, CD44v3 peptide and protein, but not CD44v6 peptide or CD44s protein, bound to both CHI3L1 and IL-13Rα2. Our in vivo and in vitro data further demonstrated that CHI3L1 promoted GC cell proliferation, migration, and metastasis.ConclusionsCHI3L1 binding to CD44v3 activates Erk, Akt, and β-catenin signaling, therefore enhances GC metastasis. CHI3L1 expression is a novel biomarker for the prognosis of GC, and these findings have thus identified CHI3L1/CD44 axis as a vital pathway and potential therapeutic target in GC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0876-2) contains supplementary material, which is available to authorized users.

Background:Osteoporotic vertebral compression fractures (OVCFs) commonly afflicts most aged people resulting back pain, substantial vertebral deformity, functional disability, decreased quality of life, and increased adjacent spinal fractures and mortality. Percutaneous vertebral augmentation (PVA) included percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP), nerve block (NB), and conservative treatment (CT) are used for the nonsurgery treatment strategy of OVCFs, however, current evaluation of their efficacy remains controversial.Methods and analysis:A systematic literature search was carried out in PubMed, EMBASE, Web of Knowledge, and the Cochrane Central Register of Controlled Trials up to October 31, 2017. Randomized controlled trials (RCTs) were compared PVP, PKP, NB, or CT for treating OVCFs. The risk of bias for each trial was rated according to the Cochrane Handbook. Mean differences (MDs) with 95% confidence intervals (CIs) were utilized to express VAS (visual analog scale) outcomes. The network meta-analysis (NMA) of the comparative efficacy measured by change of VAS on acute/subacute and chronic OVCFs was conducted for a short-term (<4 weeks) and long-term (≥6–12months) follow-up with the ADDIS software.Results:A total of 18 trials among 1994 patients were included in the NMA. The PVA (PVP and PKP) had better efficacy than CT. PKP was first option in alleviating pain in the case of the acute/subacute OVCFs for long term, and chronic OVCFs for short term and long term, while PVP had the most superiority in the case of the acute/subacute OVCFs for short term. NB ranks higher probability than PKP and PVP on acute/subacute OVCFs in short and long-term, respectively.Conclusions:The present results suggest that PVA (PVP/PKP) had better performance than CT in alleviating acute/subacute and chronic OVCFs pain for short and long-term. NB may be used as an alternative or before PVA, as far as pain relief is concerned. Various nonsurgery treatments including CT, PVA (PVP/PKP), NB, or a combination of these treatments are performed with the goal of reducing pain, stabilizing the vertebrae, and restoring mobility.