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1.
Am J Pathol ; 194(5): 828-848, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38320632

RESUMO

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells, one of CAF origins, with ESCC cells. Periostin (POSTN) was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes, such as survival, growth, and migration, as well as increased phosphorylation of Akt and extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin ß4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Periostina , Proteínas Proto-Oncogênicas c-akt/metabolismo , Microambiente Tumoral
2.
J Pathol ; 261(1): 55-70, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37436683

RESUMO

M2 macrophages contribute to the progression of oesophageal squamous cell carcinoma (ESCC); however, the roles of M2 macrophages in early ESCC remain unclear. To clarify the biological mechanisms underlying the interaction between M2 macrophages and oesophageal epithelial cells in early-stage ESCC, in vitro co-culture assays between the immortalised oesophageal epithelial cell line Het-1A and cytokine-defined M2 macrophages were established. Co-culture with M2 macrophages promoted the proliferation and migration of Het-1A cells via the mTOR-p70S6K signalling pathway activated by YKL-40, also known as chitinase 3-like 1, and osteopontin (OPN) that were hypersecreted in the co-culture supernatants. YKL-40 and OPN promoted the above phenotypes of Het-1A by making a complex with integrin ß4 (ß4). Furthermore, YKL-40 and OPN promoted M2 polarisation, proliferation, and migration of macrophages. To validate the pathological and clinical significances of in vitro experimental results, immunohistochemistry of human early ESCC tissues obtained by endoscopic submucosal dissection (ESD) was performed, confirming the activation of the YKL-40/OPN-ß4-p70S6K axis in the tumour area. Moreover, epithelial expression of ß4 and the number of epithelial and stromal infiltrating YKL-40- and OPN-positive cells correlated with the Lugol-voiding lesions (LVLs), a well-known predictor of the incidence of metachronous ESCC. Furthermore, the combination of high expression of ß4 and LVLs or high numbers of epithelial and stromal infiltrating YKL-40- and OPN-positive immune cells could more clearly detect the incidence of metachronous ESCC than each of the parameters alone. Our results demonstrated that the YKL-40/OPN-ß4-p70S6K axis played important roles in early-stage ESCC, and the high expression levels of ß4 and high numbers of infiltrating YKL-40- and OPN-positive immune cells could be useful predictive parameters for the incidence of metachronous ESCC after ESD. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/metabolismo , Integrina beta4/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Neoplasias Esofágicas/patologia , Proteína 1 Semelhante à Quitinase-3/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Relevância Clínica , Macrófagos/patologia , Linhagem Celular Tumoral
3.
Pathol Int ; 74(3): 139-145, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38258897

RESUMO

Immunohistochemistry is primarily employed to visualize the localization of specific molecules in tissue samples. However, there is an increasing need for software-assisted quantitative assessment. In the present study, we performed inverted blue channel-based pseudoimmunofluorescence image analysis using original immunohistochemistry images. In human esophageal squamous cell carcinoma tissues, various humoral factors promote the phosphorylation of signaling proteins, including protein kinase B (Akt) and/or extracellular signal-regulated kinase 1/2 (ERK1/2), leading to tumor progression. Our method demonstrated applicability in the analysis of localized signaling proteins in histological sections. Relatively high phosphorylated Akt (p-Akt) intensity was observed in the cancer-stroma adjacent (Adj) and noncancerous regions of the superficial layer (SL). Furthermore, localized phosphorylated ERK1/2 (Thr202/Tyr204) was observed in the Adj of the SL and invasive front, distinct from the pattern of p-Akt (Ser473) and p-Akt (Thr308). In conclusion, pseudoimmunofluorescent immunohistochemistry image analysis is useful for the quantitative assessment and objective interpretation of localized signaling proteins in esophageal squamous cell carcinoma. The method can also be applied to analyze various immunohistochemistry images from diverse tissues.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Proteínas Proto-Oncogênicas c-akt , Neoplasias Esofágicas/patologia , Imuno-Histoquímica , Fosforilação , Linhagem Celular Tumoral
4.
Pathol Int ; 74(1): 33-38, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38131501

RESUMO

Herein, we report a rare case of a carcinoma with primitive phenotype (enteroblastic and/or hepatoid differentiation) occurring at a colostomy site. The patient was an elderly male who underwent neoadjuvant chemoradiotherapy for rectal cancer, followed by abdominoperineal resection. A biopsy specimen for the rectal carcinoma before neoadjuvant chemoradiotherapy was conventional tubular adenocarcinoma. Moreover, a pathological complete response was confirmed in the proctectomy specimen. However, a colostomy-site tumor appeared 6 months after the proctectomy, and it was resected 1 year after the initial proctectomy. The colostomy-site tumor comprised solid to focal glandular growth of atypical polygonal cells with clear to pale eosinophilic cytoplasm and was immunohistochemically positive for cytokeratin, spalt-like transcription factor 4, glypican-3, caudal type homeobox 2, and special AT-rich sequence-binding protein 2. Thus, the tumor was diagnosed as poorly differentiated adenocarcinoma with primitive phenotype, with suggested origin from the colorectal epithelium. Additionally, a multilocular cystic lesion comprising various types of epithelia was found adjacent to the tumor, suggestive of metaplasia or heterotopia. Changes in the histology and immunophenotype, and the findings of an adjacent cystic lesion suggest a metachronous tumor rather than a recurrence of the primary tumor.


Assuntos
Adenocarcinoma , Neoplasias Retais , Humanos , Masculino , Idoso , Terapia Neoadjuvante , Colostomia , Neoplasias Retais/patologia , Reto/patologia , Adenocarcinoma/patologia , Quimiorradioterapia
5.
Int J Mol Sci ; 25(16)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39201509

RESUMO

Causal networks are important for understanding disease signaling alterations. To reveal the network pathways affected in the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to the poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) were analyzed. The network pathways in GC were analyzed using Ingenuity Pathway Analysis (IPA). The analysis of the probe sets in which the gene expression had significant differences between diffuse- and intestinal-type GC in RNA sequencing of the publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of EMT regulation via the growth factors pathway, the coronavirus pathogenesis pathway, and vorinostat. The network had RNA-RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-223, mir-25, mir-27, mir-29, and mir-34. The molecular networks revealed in the study may lead to identifying drug targets for GC.


Assuntos
Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/virologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Transição Epitelial-Mesenquimal/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Histona Desacetilase 1/metabolismo , Histona Desacetilase 1/genética , Perfilação da Expressão Gênica
6.
Int J Mol Sci ; 25(19)2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39408927

RESUMO

Macrophages in the tumor microenvironment, termed tumor-associated macrophages (TAMs), promote the progression of various cancer types. However, many mechanisms related to tumor-stromal interactions in epithelial ovarian cancer (EOC) progression remain unclear. High-grade serous ovarian carcinoma (HGSOC) is the most malignant EOC subtype. Herein, immunohistochemistry was performed on 65 HGSOC tissue samples, revealing that patients with a higher infiltration of CD68+, CD163+, and CD204+ macrophages had a poorer prognosis. We subsequently established an indirect co-culture system between macrophages and EOC cells, including HGSOC cells. The co-cultured macrophages showed increased expression of the TAM markers CD163 and CD204, and the co-cultured EOC cells exhibited enhanced proliferation, migration, and invasion. Cytokine array analysis revealed higher YKL40 secretion in the indirect co-culture system. The addition of YKL40 increased proliferation, migration, and invasion via extracellular signal-regulated kinase (Erk) signaling in EOC cells. The knockdown of integrin ß4, one of the YKL40 receptors, suppressed YKL40-induced proliferation, migration, and invasion, as well as Erk phosphorylation in some EOC cells. Database analysis showed that high-level expression of YKL40 and integrin ß4 correlated with a poor prognosis in patients with serous ovarian carcinoma. Therefore, the YKL40/integrin ß4 axis may play a role in ovarian cancer progression.


Assuntos
Proliferação de Células , Proteína 1 Semelhante à Quitinase-3 , Cistadenocarcinoma Seroso , Progressão da Doença , Integrina beta4 , Neoplasias Ovarianas , Macrófagos Associados a Tumor , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular , Proteína 1 Semelhante à Quitinase-3/metabolismo , Proteína 1 Semelhante à Quitinase-3/genética , Técnicas de Cocultura , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Integrina beta4/metabolismo , Integrina beta4/genética , Gradação de Tumores , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Transdução de Sinais , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
7.
Am J Pathol ; 192(3): 536-552, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34954212

RESUMO

Tumor-associated macrophages are associated with more malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. Previously, an indirect co-culture assay of ESCC cells and macrophages was used to identify several factors associated with ESCC progression. Herein, a direct co-culture assay of ESCC cells and macrophages was established, which more closely simulated the actual cancer microenvironment. Direct co-cultured ESCC cells had significantly increased migration and invasion abilities, and phosphorylation levels of Akt and p38 mitogen-activated protein kinase (MAPK) compared with monocultured ESCC cells. According to a cDNA microarray analysis between monocultured and co-cultured ESCC cells, both the expression and release of S100 calcium binding protein A8 and A9 (S100A8 and S100A9), which commonly exist and function as a heterodimer (herein, S100A8/A9), were significantly enhanced in co-cultured ESCC cells. The addition of recombinant human S100A8/A9 protein induced migration and invasion of ESCC cells via Akt and p38 MAPK signaling. Both S100A8 and S100A9 silencing suppressed migration, invasion, and phosphorylation of Akt and p38 MAPK in co-cultured ESCC cells. Moreover, ESCC patients with high S100A8/A9 expression exhibited significantly shorter disease-free survival (P = 0.005) and cause-specific survival (P = 0.038). These results suggest that S100A8/A9 expression and release in ESCC cells are enhanced by direct co-culture with macrophages and that S100A8/A9 promotes ESCC progression via Akt and p38 MAPK signaling pathways.


Assuntos
Calgranulina A , Calgranulina B , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteína Quinase 14 Ativada por Mitógeno , Calgranulina A/genética , Calgranulina B/genética , Calgranulina B/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Macrófagos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Am J Pathol ; 191(4): 686-703, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33460563

RESUMO

Tumor-associated macrophages (TAMs) promote tumor progression. The number of infiltrating TAMs is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) patients; however, the mechanism underlying this phenomenon is unclear. cDNA microarray analysis indicates that the expression of chemokine (C-C motif) ligand 1 (CCL1) is up-regulated in peripheral blood monocyte-derived macrophages stimulated using conditioned media from ESCC cells (TAM-like macrophages). Here, we evaluated the role of CCL1 in ESCC progression. CCL1 was overexpressed in TAM-like macrophages, and CCR8, a CCL1 receptor, was expressed on ESCC cell surface. TAM-like macrophages significantly enhanced the motility of ESCC cells, and neutralizing antibodies against CCL1 or CCR8 suppressed this increased motility. Recombinant human CCL1 promoted ESCC cell motility via the Akt/proline-rich Akt substrate of 40 kDa/mammalian target of rapamycin pathway. Phosphatidylinositol 3-kinase or Akt inhibitors, CCR8 silencing, and neutralizing antibody against CCR8 could significantly suppress these effects. The overexpression of CCL1 in stromal cells or CCR8 in ESCC cells was significantly associated with poor overall survival (P = 0.002 or P = 0.009, respectively) and disease-free survival (P = 0.009 or P = 0.047, respectively) in patients with ESCC. These results indicate that the interaction between stromal CCL1 and CCR8 on cancer cells promotes ESCC progression via the Akt/proline-rich Akt substrate of 40 kDa/mammalian target of rapamycin pathway, thereby providing novel therapeutic targets.


Assuntos
Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CCR8/metabolismo , Sirolimo/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular/fisiologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Ligantes , Macrófagos/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
9.
Pathobiology ; 89(4): 222-232, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35272288

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is associated with very poor prognoses. Therefore, new therapies and preclinical models are urgently needed. In the present study, we sought to develop more realistic experimental models for use in PDA research. METHODS: We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), which we integrated to create 13 matched "trios" - i.e., patient-derived tumor models of PDA. We then compared and contrasted histological and molecular alterations between these three model systems. RESULTS: Orthotopic implantation (OI) of the PDCLs resulted in tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDXs and OI-PDXs with passaged tumors revealed that the histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. When gene expression levels in the PDCLs, ectopic tumors, and OI tumors were compared, the distant metastasis-promoting gene CXCR4 was specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. CONCLUSION: These patient-derived tumor models provide useful tools for monitoring responses to antineoplastic agents and for studying PDA biology.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Humanos , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Pancreáticas
10.
Lab Invest ; 101(3): 353-368, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33311557

RESUMO

Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs' function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Movimento Celular/efeitos dos fármacos , Carcinoma de Células Escamosas do Esôfago/metabolismo , Macrófagos/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Idoso , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Macrófagos/fisiologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Inibidor 1 de Ativador de Plasminogênio/metabolismo
11.
Pathobiology ; 88(5): 327-337, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33965948

RESUMO

BACKGROUND: The mortality of oral squamous cell carcinoma (OSCC) has remained high for decades; therefore, methods for early detection of OSCC are warranted. However, in the oral cavity, various mucosal diseases may be encountered, including reactive lesions and oral potentially malignant disorders, and it is difficult to differentiate OSCC from these lesions based on both clinical and histopathological findings. It is well known that chronic inflammation contributes to oral cancer development. Macrophages are among the most common inflammatory cells in cancer stromal tissue and have various roles in cancer aggressiveness. Although the roles of macrophages in cancer development have attracted attention, only a few studies have linked macrophages to carcinogenesis, particularly, oral precancerous lesions. SUMMARY: This review article consists of 3 parts: first, we summarize current knowledge on macrophages in human various epithelial precancerous lesions, excluding the oral cavity, to show the importance and gaps in knowledge regarding macrophages in carcinogenesis; second, we review published data related to the role of macrophages in oral carcinogenesis; finally, we present a novel view on oral carcinogenesis, focusing on crosstalk between epithelial cells and macrophages. Key Messages: The biological features of macrophages in oral carcinogenesis differ drastically depending on the anatomical compartment that they infiltrate. Focusing on the alteration of macrophage infiltrating compartment may serve as a useful novel approach for studying the role of the macrophages in oral carcinogenesis and for gaining further insight into cancer prevention and early detection.


Assuntos
Carcinogênese/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias Bucais/imunologia , Humanos , Inflamação/complicações , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Microambiente Tumoral
12.
Lab Invest ; 100(9): 1140-1157, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32457351

RESUMO

Tumor-associated macrophages (TAMs) contribute to the progression and mortality of various malignancies. We reported that high numbers of infiltrating TAMs were significantly associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma (ESCC). In our previous investigation of TAMs' actions in ESCC, we compared gene expression profiles between peripheral blood monocyte (PBMo)-derived macrophages and TAM-like macrophages stimulated with conditioned media of ESCC cell lines. Among the upregulated genes in the TAM-like macrophages, we focused on CC chemokine ligand 3 (CCL3), which was reported to contribute to tumor progression in several malignancies. Herein, we observed that not only TAMs but also ESCC cell lines expressed CCL3. A CCL3 receptor, CC chemokine receptor 5 (CCR5) was expressed in the ESCC cell lines. Treating the ESCC cell lines with recombinant human (rh)CCL3 induced the phosphorylations of Akt and ERK, which were suppressed by CCR5 knockdown. Migration and invasion of ESCC cells were promoted by treatment with rhCCL3 and co-culture with TAMs. TAMs/rhCCL3-promoted cell migration and invasion were suppressed by inhibition of the CCL3-CCR5 axis, PI3K/Akt, and MEK/ERK pathways. Treatment with rhCCL3 upregulated MMP2 and VEGFA expressions in ESCC cell lines. Our immunohistochemical analysis of 68 resected ESCC cases showed that high expression of CCL3 and/or CCR5 in ESCC tissues was associated with poor prognosis. High CCR5 expression was associated with deeper invasion, presence of vascular invasion, higher pathological stage, higher numbers of infiltrating CD204+ TAMs, and higher microvascular density. High expression of both CCL3 and CCR5 was an independent prognostic factor for disease-free survival. These results suggest that CCL3 derived from both TAMs and cancer cells contributes to the progression and poor prognosis of ESCC by promoting cell migration and invasion via the binding of CCR5 and the phosphorylations of Akt and ERK. The CCL3-CCR5 axis could become the target of new therapies against ESCC.


Assuntos
Carcinoma de Células Escamosas/genética , Quimiocina CCL3/genética , Neoplasias Esofágicas/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores CCR5/genética , Idoso , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Quimiocina CCL3/metabolismo , Progressão da Doença , Neoplasias Esofágicas/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CCR5/metabolismo
13.
Pathobiology ; 87(2): 100-113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31896114

RESUMO

OBJECTIVES: Growth differentiation factor 15 (GDF15), which is derived from tumor-associated macrophages (TAM) and cancer cells, promotes progression of esophageal squamous cell carcinomas (ESCC). However, its role in the ESCC microenvironment remains unclear. Here, we examined the effects of GDF15 on ESCC cell lines and tissues. METHODS: Western blotting, MTS, and Transwell migration/invasion assays were used to evaluate cell signaling, proliferation, and migration/invasion, respectively, in ESCC cell lines treated with recombinant human GDF15 (rhGDF15). ESCC cell lines were administered a TGF-ßRI/II inhibitor (LY2109761), small interfering RNA against TGF-ß type II receptor (TGF-ßRII), or neutralizing antibody against TGF-ßRII to study the role of TGF-ßRII in mediating the effects of rhGDF15. The localization of GDF15 and TGF-ßRII in ESCC cell lines was observed by immunofluorescence. TGF-ßRII expression in ESCC tissues was analyzed by immunohistochemistry, and the relationship between clinicopathological factors and prognosis in ESCC patients was evaluated. RESULTS: rhGDF15 increased levels of phosphorylated Akt, Erk1/2, and TGF-ßRII in ESCC cell lines. Inhibition/knockdown of TGF-ßRII suppressed rhGDF15-induced activation of Akt and Erk1/2 and enhancement of cellular proliferation, migration, and invasion. Immunofluorescence revealed that TGF-ßRII and GDF15 were colocalized in ESCC cell lines. High TGF-ßRII expression in ESCC tissues, as determined by immunohistochemistry, correlated with depth of invasion and increased number of infiltrating TAMs. ESCC patients with high TGF-ßRII expression showed a tendency toward poor prognosis. CONCLUSIONS: GDF15 promotes ESCC progression by increasing cellular proliferation, migration, and invasion via TGF-ßRII signaling.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais/genética , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Inclusão em Parafina , Fosforilação , Proteínas Recombinantes/farmacologia
14.
Oral Dis ; 26(3): 527-536, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31886947

RESUMO

OBJECTIVE: Oral leukoplakia has mixed and differing histopathological features, and it is thus difficult to reach an accurate histological diagnosis of oral leukoplakia based on a local biopsy alone. We recently demonstrated the significance of CD163+ macrophages in oral carcinogenesis. Herein we sought to determine whether CD163+ macrophages in biopsy specimens of oral leukoplakia help identify the overall histological nature of the lesion. PATIENTS AND METHODS: Twenty-six patients with tongue leukoplakia who underwent a histological examination by both a preoperative local biopsy and consecutive total excision were enrolled. We evaluated clinicopathological factors and the expression of CD163+ macrophages based on a retrospective comparison of the histological diagnostic concordance between the biopsies and excisions. RESULTS: Seventeen patients (diagnostic-agreement group) were diagnosed with squamous intraepithelial lesion based on both the biopsy and the excision. Nine patients (diagnostic-discrepancy group) were diagnosed with invasive cancer by excision, although invasive cancer was not observed in their biopsy specimens. Compared to the diagnostic-agreement group, the diagnostic-discrepancy group had more tongue leukoplakia with non-homogenous or high numbers of intraepithelial CD163+ macrophages. CONCLUSION: The evaluation of intraepithelial CD163+ macrophages in local biopsy specimens from tongue leukoplakia patients is a promising tool for cancer screening.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Detecção Precoce de Câncer , Leucoplasia Oral/diagnóstico , Macrófagos/metabolismo , Receptores de Superfície Celular/metabolismo , Neoplasias da Língua/diagnóstico , Biópsia , Humanos , Estudos Retrospectivos
15.
Lab Invest ; 99(6): 777-792, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30683902

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with frequent recurrence even after curative resection. The tumor microenvironment, which consists of non-cancer cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), was recently reported to promote several cancers, including ESCC. However, the role of CAF as a coordinator for tumor progression in ESCC remains to be elucidated. In our immunohistochemical investigation of ESCC tissues, we observed that the intensity of expression of two CAF markers-alpha smooth muscle actin (αSMA) and fibroblast activation protein (FAP)-in the tumor stroma was significantly correlated with the depth of tumor invasion, lymph node metastasis, advanced pathological stage, and poor prognosis. We co-cultured human bone marrow-derived mesenchymal stem cells (MSCs) with ESCC cells and confirmed the induction of FAP expression in the co-cultured MSCs. These FAP-positive MSCs (which we defined as CAF-like cells) promoted the cell growth and migration of ESCC cells and peripheral blood mononuclear cell-derived macrophage-like cells. CAF-like cells induced the M2 polarization of macrophage-like cells. A cytokine array and ELISA revealed that CAF-like cells secreted significantly more CCL2, Interleukin-6, and CXCL8 than MSCs. These cytokines promoted the migration of tumor cells and macrophage-like cells. The silencing of FAP in CAF-like cells attenuated cytokine secretion. We compared cell signaling of MSCs, CAF-like cells, and FAP-silenced CAF-like cells; PTEN/Akt and MEK/Erk signaling were upregulated and their downstream targets, NF-κB and ß-catenin, were also activated with FAP expression. Silencing of FAP attenuated these effects. Cytokine secretion from CAF-like cells were attenuated by inhibitors against these signaling pathways. These findings indicate that the collaboration of CAFs with tumor cells and macrophages plays a pivotal role in tumor progression, and that FAP expression is responsible for the tumor promotive and immunosuppressive phenotypes of CAFs.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/metabolismo , Quimiocina CCL2/metabolismo , Neoplasias Esofágicas/metabolismo , Gelatinases/metabolismo , Interleucina-6/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Actinas/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Endopeptidases , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Esôfago/patologia , Humanos , Interleucina-8/metabolismo , Japão/epidemiologia , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/metabolismo , Microambiente Tumoral
16.
Pathol Int ; 69(3): 135-147, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30758105

RESUMO

Tumor-associated macrophages (TAMs) have important roles in the growth, angiogenesis and progression of various tumors. Although we have demonstrated the association of an increased number of infiltrating CD204+ TAMs with poor prognosis in esophageal squamous cell carcinomas (ESCCs), the roles of TAMs in ESCC remain unclear. Here, to study the effects of TAMs on the tumor microenvironment of ESCCs, we established a co-culture assay using a human ESCC cell line and TAM-like peripheral blood monocyte-derived macrophages and performed a cDNA microarray analysis between monocultured and co-cultured ESCC cell lines. Our qRT-PCR confirmed that in the co-cultured ESCC cell lines, CYP1A1, DHRS3, ANXA10, KLK6 and CYP1B1 mRNA were highly up-regulated; AMTN and IGFL1 mRNA were down-regulated. We observed that the high expression of a calcium-dependent phospholipid-binding protein ANXA10 was closely associated with the depth of invasion and high numbers of infiltrating CD68+ and CD204+ TAMs and poor disease-free survival (P = 0.0216). We also found ANXA10 promoted the cell growth of ESCC cell lines via the phosphorylation of Akt and Erk1/2 pathways in vitro. These results suggest that ANXA10 induced by the interaction with TAMs in the tumor microenvironment is associated with cell growth and poor prognosis in human ESCC tissues.


Assuntos
Anexinas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Macrófagos/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Macrófagos/patologia , Neovascularização Patológica/patologia , Microambiente Tumoral/fisiologia
17.
Surg Endosc ; 32(4): 2123-2130, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29098429

RESUMO

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a reliable method that can replace surgery under certain conditions. However, limited information is available on the clinical course of T1b colorectal cancer (CRC) after ESD. The aim of the study was to clarify the feasibility of ESD for T1b CRC. PATIENTS AND METHODS: Three hundred and two patients with 312 T1 CRC were identified in this retrospective cohort study. All patients were treated with ESD, other endoscopic treatments, or surgery. In this study, we (I) investigated the en bloc resection rate of ESD and (II) compared the overall survival (OS) rate for patients who underwent ESD with additional surgery (Group A) and surgery without upfront endoscopic resection (Group B) for T1b CRC. RESULTS: No significant differences were observed in the en bloc resection rates between T1b and T1a CRC (100 vs. 98.7%), but the en bloc R0 resection rate was significantly lower in T1b CRC than in T1a CRC (64.7 vs. 97.4%). Regarding complications, perforations occurred in 2.9% of patients with T1b CRC, which was not significantly different from the rate of 5.3% in patients with T1a CRC. No significant differences were observed in the OS or recurrence-free survival (RFS) curves between Groups A and B (OS rates at 5 years: 92.3 vs. 88.9%, RFS rates at 5 years: 81.4 vs. 85.3%). Similarly, the 5-year disease-specific survival (DSS) rate of Group A was identical to that of Group B (both 100%). CONCLUSIONS: ESD for T1b CRC before surgery is a possible strategy because of the low rate of complications and favorable long-term outcomes.


Assuntos
Adenocarcinoma/cirurgia , Neoplasias Colorretais/cirurgia , Ressecção Endoscópica de Mucosa , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Auditoria Clínica , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
18.
Pathol Int ; 68(6): 334-352, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29671926

RESUMO

We review the significance of cancer-stromal interactions (CSIs) in the development, morphogenesis and progression of human gastric and esophageal cancer based on the data obtained from co-culture experiments. Orthotopic fibroblasts in the gastric cancer stroma not only promoted their growth by cancer cells but were also responsible for the mobility, morphogenesis and epithelial-to-mesenchymal transition (EMT) of the cancer cells through CSI. Bone marrow-derived mesenchymal stem cells could be part of the origin of cancer-associated fibroblasts (CAFs) of the gastric cancer providing an advantageous microenvironment for the restoration of cancer stem cells with the induction of the EMT. Tumor-associated macrophages (TAMs) may differentiate from bone marrow-derived monocytes/macrophages within the tumor microenvironment of esophageal cancer and participate in the growth and the progression of esophageal squamous cell carcinomas (ESCCs). Macrophages infiltrated into the intraepithelial neoplastic lesions of the esophagus may function as a biological promoter by promoting the growth and motility of squamous epithelia. Tumor cells build up "cancer as a tissue" by taking advantage of the existing network of growth factors, cytokines and chemokines through the interactions of TAMs, CAFs and cancer cells themselves.


Assuntos
Neoplasias Esofágicas/patologia , Neoplasias Gástricas/patologia , Microambiente Tumoral , Progressão da Doença , Humanos
20.
J Pathol ; 240(2): 211-23, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27425378

RESUMO

Neuroblastoma is the most common extracranial solid tumour in children and is histologically classified by its Schwannian stromal cells. Although having fewer Schwannian stromal cells is generally associated with more aggressive phenotypes, the exact roles of other stromal cells (mainly macrophages and fibroblasts) are unclear. Here, we examined 41 cases of neuroblastoma using immunohistochemistry for the tumour-associated macrophage (TAM) markers CD68, CD163, and CD204, and a cancer-associated fibroblast (CAF) marker, alpha smooth muscle actin (αSMA). Each case was assigned to low/high groups on the basis of the number of TAMs or three groups on the basis of the αSMA-staining area for CAFs. Both the number of TAMs and the area of CAFs were significantly correlated with clinical stage, MYCN amplification, bone marrow metastasis, histological classification, histological type, and risk classification. Furthermore, TAM settled in the vicinity of the CAF area, suggesting their close interaction within the tumour microenvironment. We next determined the effects of conditioned medium of a neuroblastoma cell line (NBCM) on bone marrow-derived mesenchymal stem cells (BM-MSCs) and peripheral blood mononuclear cell (PBMC)-derived macrophages in vitro. The TAM markers CD163 and CD204 were significantly up-regulated in PBMC-derived macrophages treated with NBCM. The expression of αSMA by BM-MSCs was increased in NBCM-treated cells. Co-culturing with CAF-like BM-MSCs did not enhance the invasive ability but supported the proliferation of tumour cells, whereas tumour cells co-cultured with TAM-like macrophages had the opposite effect. Intriguingly, TAM-like macrophages enhanced not only the invasive abilities of tumour cells and BM-MSCs but also the proliferation of BM-MSCs. CXCL2 secreted from TAM-like macrophages plays an important role in tumour invasiveness. Taken together, these results indicate that PBMC-derived macrophages and BM-MSCs are recruited to a tumour site and activated into TAMs and CAFs, respectively, followed by the formation of favourable environments for neuroblastoma progression. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinogênese/patologia , Macrófagos/patologia , Neuroblastoma/patologia , Antígenos CD/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Ganglioneuroblastoma/metabolismo , Ganglioneuroblastoma/patologia , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/metabolismo
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