Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhou M
PROVIDER: S-EPMC8134032 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundCLEC4E has been reported to promote lung cancer progression. Tumor-associated macrophages (TAMs) play an important role in tumorigenesis. Whether the expression of CLEC4E in TAMs is associated with gastric carcinogenesis remains unclear.MethodsThe TIMER, UALCAN, UCSC Xena, and KM plotter databases are used to examine the expression of CLEC4E and its prognostic significance in gastric cancer (GC). Additionally, GO, KEGG, and GSEA analysis were conducted, and single-cell RNA-seq (scRNA-seq) datasets were utilized. The Coremine medical database was used to predict therapeutic drugs, and molecular docking was performed. Human GC samples were obtained, and co-culture models were constructed to evaluate the effects of CLEC4E in TAMs on tumor growth, migration, and invasion in vitro.ResultsCLEC4E was significantly upregulated in GC, and high CLEC4E expression was associated with poor prognosis. Western blotting and immunostaining showed increased protein levels of CLEC4E in GC. GO, KEGG, and GSEA results indicated that CLEC4E is involved in immune response. Immune infiltration analysis demonstrated that CLEC4E expression positively correlated with multiple immune cell types. scRNA-seq analyses revealed that CLEC4E was predominantly expressed in myeloid cells specifically TAMs, in GC. In vitro experiments confirmed that MFC induced CLEC4E expression in TAMs to mediate tumor progression. Specifically targeting CLEC4E by si-CLEC4E or stigmasterol inhibited cancer cell migration and invasion.ConclusionCLEC4E is a potential prognostic biomarker and new therapeutic target for GC that can be specifically targeted by stigmasterol.
| S-EPMC10920739 | biostudies-literature
Project description:Macrophages, an important class of innate immune cells that maintain body homeostasis and ward off foreign pathogens, exhibit a high degree of plasticity and play a supportive role in different tissues and organs. Thus, dysfunction of macrophages may contribute to advancement of several diseases, including cancer. Macrophages within the tumor microenvironment are known as tumor-associated macrophages (TAMs), which typically promote cancer cell initiation and proliferation, accelerate angiogenesis, and tame anti-tumor immunity to promote tumor progression and metastasis. Massive infiltration of TAMs or enrichment of TAM-related markers usually indicates cancer progression and a poor prognosis, and consequently tumor immunotherapies targeting TAMs have gained significant attention. Here, we review the interaction between TAMs and cancer cells, discuss the origin, differentiation and phenotype of TAMs, and highlight the role of TAMs in pro-cancer functions such as tumor initiation and development, invasive metastasis, and immunosuppression. Finally, we review therapies targeting TAMs, which are very promising therapeutic strategies for malignant tumors.
| S-EPMC8222665 | biostudies-literature
Project description:Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.
| S-EPMC8728363 | biostudies-literature
Project description:This study investigated the exosomal circular RNAs (CircRNAs) produced by tumor-associated macrophages and delivered into the microenvironment of cholangiocarcinoma cells in order to use them as molecular targets for clinical therapy. Tumor-associated M2 macrophages (TAMs) were induced from THP-1 cells and identified by flow cytometry. The TAM-secreted exosomes were isolated from conditioned medium and a CircRNA microarray assay was performed to identify CircRNAs that were uniquely expressed in the isolated exosomes. Circ_0020256 was especially identified based on having the highest differential expression level among all of the CircRNA candidates. In vitro and in vivo experiments were performed to assess the effects of TAMs, exosomes, and Circ_0020256 on the growth and migration of cholangiocarcinoma (CCA) cells. The induced TAMs promoted the proliferation, migration, and invasion of CCA cells and those effects were mediated by exosomes secreted by the TAMs. In CCA cells (RBE and HCCC-9810), Circ_0020256 significantly promoted cellular activity by interacting with its intra-cellular microRNA target, miR-432-5p. In contrast, overexpression of transcription factor E2F3 in CCA cells restored the CCA cellular activities that were inhibited by miR-432-5p. On the other hand, treatment with small interference RNA (siRNA) for Circ_0020256 inhibited CCA cell proliferation, migration, and invasion both in vitro and in vivo. In conclusion, Circ_0020256 in TAM-secreted exosomes promoted the proliferation, migration, and invasion of CCA cells, and that promotional activity was regulated via a Circ_0020256/miR-432-5p/E2F3 axis.
| S-EPMC8799724 | biostudies-literature
Project description:In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail.
| S-EPMC5454892 | biostudies-other
Project description:Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders.
| S-EPMC7878118 | biostudies-literature
Project description:BackgroundM2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism.MethodsTwo progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system.ResultsWe found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p?<?0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC.ConclusionOur results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.
| S-EPMC7720384 | biostudies-literature
Project description:Metastasis the spread of cancer cells to distant organs, is the main cause of death for cancer patients. Metastasis is often mediated by lymphatic vessels that invade the primary tumor, and an early sign of metastasis is the presence of cancer cells in the regional lymph node (the first lymph node colonized by metastasizing cancer cells from a primary tumor). Understanding the interplay between tumorigenesis and lymphangiogenesis (the formation of lymphatic vessels associated with tumor growth) will provide us with new insights into mechanisms that modulate metastatic spread. In the long term, these insights will help to define new molecular targets that could be used to block lymphatic vessel-mediated metastasis and increase patient survival. Here, we review the molecular mechanisms of embryonic lymphangiogenesis and those that are recapitulated in tumor lymphangiogenesis, with a view to identifying potential targets for therapies designed to suppress tumor lymphangiogenesis and hence metastasis.
| S-EPMC3307004 | biostudies-literature
Project description:It is well known that the microenvironment of solid tumors is rich in inflammatory cells that influence tumor growth and development. Macrophages, called tumor-associated macrophages (TAMs), are the most abundant immune cell population present in tumor tissue. Several studies have demonstrated that the density of TAMs is associated with a poor prognosis and positively correlates with tumor growth. Several studies have proved that TAMs may activate and protect tumor stem cells, stimulate their proliferation as well as promote angiogenesis and metastasis. Furthermore, TAMs-derived cytokines and other proteins, such as CCL-17, CCL-22, TGF-?, IL-10, arginase 1, and galectin-3, make a significant contribution to immunosuppression. Since TAMs influence various aspects of cancer progression, there are many attempts to use them as a target for immunotherapy. The numerous studies have shown that the primary tumor growth and the number of metastatic sites can be significantly decreased by decreasing the population of macrophages in tumor tissue, for example, by blocking recruitment of monocytes or eliminating TAMs already present in the tumor tissue. Moreover, there are attempts at reprogramming TAMs into proinflammatory M1 macrophages or neutralizing the protumoral products of TAMs. Another approach uses TAMs for anticancer drug delivery into the tumor environment. In this review, we would like to summarize the clinical and preclinical trials that were focused on macrophages as a target for anticancer therapies.
| S-EPMC5851686 | biostudies-literature
Project description:BackgroundPatients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) have limited treatment options and poor prognosis. Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment and promote tumor stemness, proliferation, invasion and metastasis. Evidence suggested that transthyretin (TTR) influenced the prolifetation and invasion functions of different tumors and play an essential role in the tumor microenvironment.AimsTo investigate the involvement of TTR in TAMs affecting the invasion of cHCC-CCA.Methods and resultsData sets obtained from the Gene Expression Omnibus database were integrated. Differentially expressed genes (DEGs) were obtained using R software, and modules associated with cHCC-CCA were screened by weighted gene co-expression network analysis (WGCNA). Human THP-1 cells were induced to differentiate into macrophages and then co-cultured with HCCC9810 cells and tumor necrosis factor-α (TNF-α) to simulate the inflammatory microenvironment of cHCC-CAA. In addition, small interfering RNA against TTR was transfected into HCCC9810 cells, and recombinant TTR and ERK and AKT-specific inhibitors were added to HCCC9810 cells, respectively; after that, the levels of NF-κB protein and phosphorylated ERK and AKT were measured. The invasive abilities of HCCC9810 cells were also tested. One hundred forty-five DEGs were associated with cHCC-CCA, of which TTR was up-regulated. Turquoise modules containing TTR in WGCNA were most significantly associated with cHCC-CCA. TTR was highly expressed in HCCC9810 compared to Huh-28. HCCC9810 showed enhanced invasive capacity after co-culture with TNF-α + macrophages (p < .05). After interfering with TTR, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB, p-ERK1/2, and p-AKT (p < .05). After treating HCCC9810 with ERK and AKT-specific inhibitors, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB and TTR (p < .05).ConclusionTTR can promote the invasive ability of cHCC-CCA by regulating AKT/NF-κB and ERK pathways with the assistance of TAMs.
| S-EPMC10598247 | biostudies-literature