Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 145
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Commun Signal ; 20(1): 92, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715860

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC. METHODS: Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells. RESULTS: Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C-C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of ß-catenin. Furthermore, ß-catenin knockdown reversed TAM-induced EMT and CSC properties. CONCLUSIONS: This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/ß-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC. Video Abstract.


Assuntos
Quimiocina CCL2 , Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-akt , Neoplasias de Mama Triplo Negativas , Macrófagos Associados a Tumor , beta Catenina , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CCL2/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , beta Catenina/metabolismo
2.
Carbohydr Polym ; 292: 119683, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35725176

RESUMO

Promoting M1 polarization of tumor-associated macrophages (TAMs) is an effective pathway for malignant tumor therapy. In this study, we aimed to demonstrate whether homogeneous Dendrobium officinale polysaccharide (DOP) could promote M1 polarization of TAMs to inhibit tumor growth, and how it promoted. Results exhibited that DOP could inhibit the tumor growth and promote the M1 polarization of TAMs in tumor-bearing mice. Macrophage depletion and replenishment experiment clearly proved that the inhibitory effect of DOP on tumor growth is dependent on promoting M1 polarization of TAMs. Moreover, we found that DOP could reach tumor microenvironment (TME) and directly bind to TAMs to promote its M1 polarization via targeting toll-like receptor 2 (TLR2) after oral administration. These results clarified that DOP could remarkably inhibit the tumor growth of tumor-bearing mice via directly targeting the TLR2 of TAMs to promote its M1 polarization.


Assuntos
Dendrobium , Neoplasias , Animais , Camundongos , Neoplasias/patologia , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Receptor 2 Toll-Like , Microambiente Tumoral , Macrófagos Associados a Tumor
3.
Int J Pharm ; 622: 121860, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35654378

RESUMO

Chemotherapy is an effective anti-tumor treatment. Some anticancer chemotherapeutic drugs can not only induce cell death, but can also elicit antitumor immune responses. Here, the stability of cisplatin-loaded polymeric micelles (CDDP-PMs), pharmacokinetic drug-drug interactions of CDDP and anti-PD-L1 antibody (aPD-L1) in vivo and the alteration of the tumor microenvironment by combination of CDDP-PMs and aPD-L1 were evaluated. CDDP-PMs were fabricated by coordinated complexation and self-assembly method for tumor targeting. CDDP-PMs with higher mass ratio of copolymer have higher thermodynamic stability. The pharmacokinetic study showed that the CDDP and aPD-L1 were metabolized and cleared by two different pathways, suggesting that there is almost no risk of potential drug interactions between CDDP and aPD-L1 and the combination of aPD-L1 and CDDP- PMs may not alter the tissue distribution of CDDP. In vivo antitumor test showed that the tumor growth inhibition rates of CDDP-PMs combined with medium-dose aPD-L1 and CDDP-PMs combined with high-dose PD-L1 were 89.41% and 93.16%, respectively and therapeutic efficacy can be further increased by increasing the dose of aPD-L1 in co-administration group. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between them and holds great potential to offer better safety and antitumor efficacy profiles.


Assuntos
Antineoplásicos , Cisplatino , Antígeno B7-H1 , Linhagem Celular Tumoral , Micelas , Polímeros , Termodinâmica , Macrófagos Associados a Tumor
4.
Biomolecules ; 12(6)2022 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-35740975

RESUMO

Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC-TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk.


Assuntos
Neoplasias , Macrófagos Associados a Tumor , Humanos , Macrófagos/metabolismo , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Microambiente Tumoral
5.
ACS Appl Mater Interfaces ; 14(24): 27651-27665, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35675569

RESUMO

Rapid glycolysis of tumor cells produces excessive lactate to trigger acidification of the tumor microenvironment (TME), leading to the formation of immunosuppressive TME and tumor-associated macrophage (TAM) dysfunction. Therefore, reprogramming TAMs by depleting lactate with nanodrugs is expected to serve as an effective means of tumor-targeted immunotherapy. Herein, we report the use of lactic acid dehydrogenase (LDH)-mimicking SnSe nanosheets (SnSe NSs) loaded with a carbonic anhydrase IX (CAIX) inhibitor to reconstruct an acidic and immunosuppressive TME. As expected, this nanosystem could reprogram the TAM to achieve M1 macrophage activation and could also restore the potent tumor-killing activity of macrophages while switching their metabolic mode from mitochondrial oxidative phosphorylation to glycolysis. In addition, the repolarizing effect of SnSe NSs on macrophages was validated in a coculture model of bone marrow-derived macrophages, in three patient-derived malignant pleural effusion and in vivo mouse model. This study proposes a feasible therapeutic strategy for depleting lactate and thus ameliorating acidic TME employing Se-containing nanosheets, which could further amply the effects of TAM-based antitumor immunotherapy.


Assuntos
Neoplasias , Macrófagos Associados a Tumor , Animais , Humanos , Imunoterapia , L-Lactato Desidrogenase , Ácido Láctico/metabolismo , Camundongos , Neoplasias/patologia , Microambiente Tumoral
6.
Front Immunol ; 13: 830169, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35651620

RESUMO

Tumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis. Neuropilin-2 (NRP2), consisting of the NRP2a and NRP2b isoforms, is a co-receptor for heparin-binding growth factors including VEGF-C and Class 3 Semaphorins. Selective upregulation in response to environmental stimuli and independent signaling pathways endow the NRP2 isoforms with unique functionality, with NRP2b promoting increased Akt signaling via receptor tyrosine kinases including VEGFRs, MET, and PDGFR. Although NRP2 has been shown to regulate macrophage/TAM biology, the role of the individual NRP2a/NRP2b isoforms in TAMs has yet to be evaluated. Using transcriptional profiling and spectral flow cytometry, we show that NRP2 isoform expression was significantly higher in TAMs from murine mammary tumors. NRP2a/NRP2b levels in human breast cancer metastasis were dependent upon the anatomic location of the tumor and significantly correlated with TAM infiltration in both primary and metastatic breast cancers. We define distinct phenotypes of NRP2 isoform-expressing TAMs in mouse models of breast cancer and within malignant pleural effusions from breast cancer patients which were exclusive of neuropilin-1 expression. Genetic depletion of either NRP2 isoform in macrophages resulted in a dramatic reduction of LPS-induced IL-10 production, defects in phagosomal processing of apoptotic breast cancer cells, and increase in cancer cell migration following co-culture. By contrast, depletion of NRP2b, but not NRP2a, inhibited production of IL-6. These results suggest that NRP2 isoforms regulate both shared and unique functionality in macrophages and are associated with distinct TAM subsets in breast cancer.


Assuntos
Neoplasias da Mama , Neuropilina-2 , Animais , Neoplasias da Mama/patologia , Feminino , Humanos , Camundongos , Neuropilina-1/genética , Neuropilina-2/genética , Neuropilina-2/metabolismo , Isoformas de Proteínas , Macrófagos Associados a Tumor
7.
J Extracell Vesicles ; 11(6): e12228, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35656866

RESUMO

Tumour-derived extracellular vesicles (EVs) participate in tumour progression by deregulating various physiological processes including angiogenesis and inflammation. Here we report that EVs released by endothelial cells in a mammary tumour environment participate in the recruitment of macrophages within the tumour, leading to an immunomodulatory phenotype permissive for tumour growth. Using RNA-Seq approaches, we identified several microRNAs (miRNAs) found in endothelial EVs sharing common targets involved in the regulation of the immune system. To further study the impact of these miRNAs in a mouse tumour model, we focused on three miRNAs that are conserved between humans and mouse, that is, miR-142-5p, miR-183-5p and miR-222-3p. These miRNAs are released from endothelial cells in a tumour microenvironment and are transferred via EVs to macrophages. In mouse mammary tumour models, treatment with EVs enriched in these miRNAs leads to a polarization of macrophages toward an M2-like phenotype, which in turn promotes tumour growth.


Assuntos
Vesículas Extracelulares , MicroRNAs , Neoplasias , Animais , Modelos Animais de Doenças , Células Endoteliais , Vesículas Extracelulares/genética , Camundongos , MicroRNAs/genética , Microambiente Tumoral , Macrófagos Associados a Tumor
8.
Theranostics ; 12(8): 3584-3600, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35664073

RESUMO

Molecular mechanisms that regulate tumor-associated macrophage (TAM) phenotype and function are incompletely understood. The pseudokinase TRIB1 has been reported as a regulator of macrophage phenotypes, both in mouse and human systems. Methods: Bioinformatic analysis was used to investigate the link between TRIB1 expression in breast cancer and therapeutic response to chemotherapy. In vivo models of breast cancer included immune-competent mice to characterize the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumor growth and composition of stromal immune cell populations. Results: TRIB1 was highly expressed by TAMs in breast cancer and high TRIB1 expression correlated with response to chemotherapy and patient survival. Both overexpression and knockout of myeloid Trib1 promote mouse breast tumor growth, albeit through different molecular mechanisms. Myeloid Trib1 deficiency led to an early acceleration of tumor growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increased late-stage mammary tumor volume, coupled with a reduction of NOS2 expressing macrophages and an overall reduction of macrophages in hypoxic tumor regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumor cytokine IL-15, and that increased myeloid Trib1 expression leads to reduced IL-15 levels in mammary tumors, with a consequent reduction in the number of T-cells that are key to anti-tumor immune responses. Conclusions: Together, these results define a key role for TRIB1 in chemotherapy responses for human breast cancer and provide a mechanistic understanding for the importance of the control of myeloid TRIB1 expression in the development of this disease.


Assuntos
Neoplasias da Mama , Macrófagos Associados a Tumor , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocinas/metabolismo , Feminino , Humanos , Interleucina-15/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Fenótipo , /genética
9.
Theranostics ; 12(9): 4221-4236, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35673564

RESUMO

Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored. Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo. Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvß5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection. Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvß5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Receptores de Vitronectina , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(5): 658-664, 2022 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-35673908

RESUMO

OBJECTIVE: To investigate the effect of interference of P2X4 receptor expression in tumor-associated macrophages (TAMs) on invasion and migration of glioma cells. METHODS: C57BL/6 mouse models bearing gliomas in the caudate nucleus were examined for glioma pathology with HE staining and expressions of Iba-1 and P2X4 receptor with immunofluorescence assay. RAW264.7 cells were induced into TAMs using conditioned medium from GL261 cells, and the changes in mRNA expressions of macrophage polarization-related markers and the mRNA and protein expressions of P2X4 receptor were detected with RT-qPCR and Western blotting. The effect of siRNA-mediated P2X4 interference on IL-1ß and IL-18 mRNA and protein expressions in the TAMs was detected with RT-qPCR and Western blotting. GL261 cells were cultured in the conditioned medium from the transfected TAMs, and the invasion and migration abilities of the cells were assessed with Transwell invasion and migration experiment. RESULTS: The glioma tissues from the tumor-bearing mice showed a significantly greater number of Iba-1-positive cells, where an obviously increased P2X4 receptor expression was detected (P=0.001), than the brain tissues of the control mice (P < 0.001). The M2 macrophage markers (Arg-1 and IL-10) and M1 macrophage markers (iNOS and TNF-α) were both significantly up-regulated in the TAMs derived from RAW264.7 cells (all P < 0.01), but the up-regulation of the M2 macrophage markers was more prominent; the expression levels of P2X4 receptor protein and mRNA were both increased in the TAMs (P < 0.05). Interference of P2X4 receptor expression significantly lowered the mRNA(P < 0.01)and protein (P < 0.01, P < 0.05)expression levels of IL-1ß and IL-18 in the TAMs and obviously inhibited the ability of the TAMs to promote invasion and migration of the glioma cells (P < 0.05). CONCLUSION: Interference of P2X4 receptor in the TAMs suppresses the migration and invasion of glioma cells possibly by lowering the expressions of IL-1ß and IL-18.


Assuntos
Glioma , Receptores Purinérgicos P2X4/metabolismo , Macrófagos Associados a Tumor , Animais , Meios de Cultivo Condicionados , Interleucina-18 , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro
11.
Cell Death Dis ; 13(6): 540, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680853

RESUMO

Collective detachment of cancer cells at the invading front could generate efficient metastatic spread. However, how cancer cell clusters shed from the leading front remains unknown. We previously reported that the dynamic expression of CD44 in breast cancers (BrCas) at collectively invading edges was associated with tumor-associated macrophages (TAMs). In this study, we first observed that the highly expressed CD44 (CD44high) cancer cell clusters were located in the BrCa circulating vessels, accompanied by CD206+ TAMs. Next, we identified that the cancer cell clusters can be converted to an invasive CD44high state which was induced by TAMs, thus giving rise to CD44-associated signaling mediated cohesive detachment. Then, we showed that disrupting CD44-signaling inhibited the TAMs triggered cohesive detaching using 3D organotypic culture and mouse models. Furthermore, our mechanistic study showed that the acquisition of CD44high state was mediated by the MDM2/p53 pathway activation which was induced by CCL8 released from TAMs. Blocking of CCL8 could inhibit the signaling cascade which decreased the CD44-mediated cohesive detachment and spread. Our findings uncover a novel mechanism underlying collective metastasis in BrCas that may be helpful to seek for potential targets.


Assuntos
Neoplasias da Mama , Macrófagos Associados a Tumor , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Macrófagos/metabolismo , Camundongos , Transdução de Sinais
12.
Breast J ; 2022: 5169405, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711892

RESUMO

Discoidin domain receptor 2 (DDR2) is arising as a promising therapeutic target in breast carcinoma (BC). The ability of DDR2 to bind to collagen promotes protumoral responses in cancer cells that influence the tumor microenvironment (TME). Nonetheless, the interrelation between DDR2 expression and TME modulation during BC progression remains poorly known. For this reason, we aim to evaluate the correlation between intratumoral expression of DDR2 and the infiltration of the main TME cell populations, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs). First, collagen and DDR2 expression levels were analyzed in human invasive BC samples. Then, DDR2 status correlation with tumor aggressiveness and patient survival were retrieved from different databases. Subsequently, the main pathways, cell types, and tissues correlated with DDR2 expression in BC were obtained through bioinformatics approach. Finally, we studied the association of DDR2 expression with the recruitment of CAFs and TAMs. Our findings showed that, together with the expected overexpression of TME markers, DDR2 was upregulated in tumor samples. Besides, we uncovered that altered TME markers were linked to DDR2 expression in invasive BC patients. Consequently, DDR2 modulates the stromal reaction through CAFs and TAMs infiltration and could be used as a potential worse prognostic factor in the treatment response of invasive BC.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Receptor com Domínio Discoidina 2 , Macrófagos Associados a Tumor , Neoplasias da Mama/patologia , Colágeno/metabolismo , Receptor com Domínio Discoidina 2/genética , Receptor com Domínio Discoidina 2/metabolismo , Feminino , Humanos , Prognóstico , Microambiente Tumoral
13.
Front Immunol ; 13: 839460, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603205

RESUMO

Bladder cancer(BC)is one of the most common urinary system tumors, which characterized by a high incidence. Polyporus polysaccharide is the main active component of polyporus, which is clinically used in the treatment of bladder cancer, but the mechanism is not clear. In previous study, we isolated homogeneous polyporus polysaccharide(HPP) with high purity from polyporus. The goal of this study was to assess the polarization of macrophages induced by HPP in the bladder tumor microenvironment and explored its anti-bladder cancer mechanism through BBN bladder cancer rat model and Tumor associated macrophages(TAM). The results suggested that HPP regulates TAM polarization to improve the tumor inflammatory microenvironment, possibly through the NF-κB/NLRP3 signaling pathway. Our results suggested that HPP may be a potential therapeutic agent for bladder tumors.


Assuntos
Polyporus , Neoplasias da Bexiga Urinária , Animais , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Polyporus/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Ratos , Transdução de Sinais , Microambiente Tumoral , Macrófagos Associados a Tumor , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
14.
Int Rev Cell Mol Biol ; 368: 61-108, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35636930

RESUMO

Tumor-associated macrophages (TAMs) are one of the most abundant immune components in the tumor microenvironment and play a plethora of roles in regulating tumorigenesis. Therefore, the therapeutic targeting of TAMs has emerged as a new paradigm for immunotherapy of cancer. Herein, the review summarizes the origin, polarization, and function of TAMs in the progression of malignant diseases. The understanding of such knowledge leads to several distinct therapeutic strategies to manipulate TAMs to battle cancer, which include those to reduce TAM abundance, such as depleting TAMs or inhibiting their recruitment and differentiation, and those to harness or boost the anti-tumor activities of TAMs such as blocking phagocytosis checkpoints, inducing antibody-dependent cellular phagocytosis, and reprogramming TAM polarization. In addition, modulation of TAMs may reshape the tumor microenvironment and therefore synergize with other cancer therapeutics. Therefore, the rational combination of TAM-targeting therapeutics with conventional therapies including radiotherapy, chemotherapy, and other immunotherapies is also reviewed. Overall, targeting TAMs presents itself as a promising strategy to add to the growing repertoire of treatment approaches in the fight against cancer, and it is hopeful that these approaches currently being pioneered will serve to vastly improve patient outcomes and quality of life.


Assuntos
Neoplasias , Macrófagos Associados a Tumor , Humanos , Imunoterapia , Macrófagos , Neoplasias/patologia , Qualidade de Vida , Microambiente Tumoral
15.
Nat Commun ; 13(1): 3022, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641483

RESUMO

PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.


Assuntos
Neoplasias da Mama , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Proteína BRCA1/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linfócitos T CD8-Positivos , Feminino , Humanos , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Mutações Sintéticas Letais , Macrófagos Associados a Tumor
16.
Bioengineered ; 13(5): 12435-12445, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35587159

RESUMO

Colorectal cancer (CRC) is one of the most common malignant tumors. Tumor-associated macrophages (TAMs) promote the progression of CRC, but the mechanism is not completely clear. The present study aimed to reveal the expression and function of FAM198B in TAMs, and the role of FAM198B in mediating macrophage polarization in CRC. The role of FAM198B in macrophage activity, cell cycle, and angiogenesis was evaluated by CCK-8 assay, flow cytometry, and vasculogenic mimicry assay. The effects of FAM198B on macrophage polarization were determined by flow cytometry. The function of FAM198B-mediated macrophage polarization on CRC progression was evaluated by transwell assays. Bioinformatic analyses and rescue assays were performed to identify biological functions and signaling pathways involved in FAM198B regulation of macrophage polarization. Increased FAM198B expression in TAMs is negatively associated with poor CRC prognosis. Functional assays showed that FAM198B promotes M2 macrophage polarization, which leads to CRC cell proliferation, migration, and invasion. Mechanistically, FAM198B regulates the M2 polarization of macrophages by targeting SMAD2, identifying the SMAD2 pathway as a mechanism by which FAM198B promotes CRC progression through regulating macrophage polarization. These findings provide a possible molecular mechanism for FAM198B in TAMs in CRC and suggest that FAM198B may be a novel therapeutic target in CRC.


Assuntos
Neoplasias Colorretais , Macrófagos Associados a Tumor , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/metabolismo , Humanos , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Microambiente Tumoral
17.
Nano Lett ; 22(11): 4410-4420, 2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35575719

RESUMO

Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancers, but achieving multitarget therapy of TAMs is still challenging. Here, we develop a protein-crowned micelle system for targeted and synergistic TAM reprogramming to enhance cancer treatment. The doxorubicin-loaded micelles with a hemoglobin crown (Hb-DOXM) can bind with endogenous plasma haptoglobin to realize specific M2-type TAM targeting. Under the tumor hypoxic and acidic environments, Hb-DOXM can responsively release O2 and DOX to reduce the recruitment of TAMs by hypoxia remission and release DOX to kill M2-type TAMs and cancer cells. To reprogram TAMs adequately, the TAM-modulating drug celecoxib is further encapsulated (Hb-DOXM@Cel) to repolarize M2-type TAMs. The targeted and synergistic TAM reprogramming by Hb-DOXM@Cel can remodel the tumor microenvironment (TME) to an immunostimulatory microenvironment and augment the antitumor effect of cytotoxic T lymphocyte, thus strongly enhancing the DOX-based chemotherapy. The protein-crowned micelle strategy presents a targeted and synergistic TAM therapy tool for enhanced cancer treatment.


Assuntos
Neoplasias , Macrófagos Associados a Tumor , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Imunoterapia , Micelas , Neoplasias/tratamento farmacológico , Microambiente Tumoral
18.
Int Immunopharmacol ; 109: 108799, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35525232

RESUMO

The type III interferon family (IFN-III), including IFN-λ3 [interleukin (IL)-28B], has antiviral, anti-tumor, and immunomodulatory activities. Although the IL-28B anti-tumor effect has been extensively explored, its underlying mechanism remains unclear. Here, we explored IL-28B effects on colon cancer. Our results show that IL-28B significantly inhibits colon cancer progression in a mouse MC38 tumor cell colonization model and colitis-associated colorectal tumor model. Interestingly, IL-28B does not directly promote apoptosis or inhibit MC38 tumor cell proliferation in vitro. Rather, IL-28B treatment has indirect anti-tumor activity by downregulating tumor-associated macrophages. Furthermore, IL-28B inhibits M2 macrophage polarization in vitro, while also halting M2 macrophage differentiation predominantly via inhibition of the signal transducer and activator of transcription (STAT)3 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings revealed that IL-28B inhibits M2 macrophages in the tumor microenvironment to delay colon cancer progression. These findings provide novel evidence of IL-28B anti-tumor and immunomodulatory activities.


Assuntos
Neoplasias do Colo , Macrófagos Associados a Tumor , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Macrófagos , Camundongos , Transdução de Sinais , Microambiente Tumoral
19.
Cancer Commun (Lond) ; 42(6): 536-557, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35615815

RESUMO

BACKGROUND: Interleukin-15 (IL-15) is a promising immunotherapeutic agent owing to its powerful immune-activating effects. However, the clinical benefits of these treatments are limited. Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance. Herein, this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression. METHODS: T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15. Western blotting, histological analysis, CRISPR-Cas9 knockout, multi-parameter flow cytometry, and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα+ tumor-associated macrophages (TAMs) regulate breast cancer cell resistance to IL-15. RESULTS: We found that macrophages contributed to the resistance of tumor cells to IL-15, and tumor cells induced macrophages to express high levels of the α subunit of the IL-15 receptor (IL-15Rα). Further investigation showed that IL-15Rα+ TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1 (CX3CL1) in tumor cells to inhibit the recruitment of CD8+ T cells by releasing the IL-15/IL-15Rα complex (IL-15Rc). Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti- programmed cell death protein 1 (PD-1) antibody immunotherapy. Interestingly, Granulocyte-macrophage colony-stimulating factor (GMCSF) induced γ chain (γc) expression to promote tumor cell-macrophage crosstalk, which facilitated tumor resistance to IL-15. Additionally, we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha (HIF-1α) was essential for IL-15Rc to regulate CX3CL1 expression in tumor cells. CONCLUSIONS: The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumor microenvironment of breast cancer. Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.


Assuntos
Neoplasias da Mama , Interleucina-15 , Animais , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Interleucina-15/metabolismo , Interleucina-15/farmacologia , Camundongos , Receptores de Interleucina-15/imunologia , Microambiente Tumoral , Macrófagos Associados a Tumor
20.
Int J Oncol ; 61(1)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35616129

RESUMO

The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post­translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation­mediated tumor formation, and the function of cancer­associated fibroblasts and infiltrating immune cells (tumor­associated macrophages, T­cells, myeloid­derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.


Assuntos
Neoplasias , Microambiente Tumoral , Carcinogênese , Humanos , Neoplasias/patologia , Macrófagos Associados a Tumor , Ubiquitinação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...