Dataset Information

Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tubingen Schwannoma Cohort.

ABSTRACT: Most patients with vestibular schwannomas can be cured with microsurgical resection, or tumor growth can be stabilized by radiotherapy in certain cases. Recurrence is rare but usually difficult to treat. Treatment alternatives to local therapies are not established. There is growing evidence of the role of inflammatory processes in schwannomas, which may be exploitable by targeted innovative therapies. To further define the impact of inflammation with tumor growth in vestibular schwannoma, we performed immunohistochemical analyses of CD3, CD8, CD68 and CD163 to assess lymphocyte and macrophage infiltration in 923 tumor tissue samples of surgically resected vestibular schwannomas. An inflammatory score was compared with tumor size and volumetric growth. We observed a significantly larger preoperative tumor size with increased expression rates of CD3, CD8, CD68 and CD163 (p < 0.0001, p < 0.0001, p = 0.0015 and p < 0.0001, respectively), but no differences in percentual volumetric tumor growth. When all four markers were combined as an inflammatory score, tumors with high inflammatory infiltration showed slower percentual growth in a multivariate analysis, including MIB1 expression (p = 0.0249). We conclude that inflammatory cell infiltration increases with larger tumor size but is associated with slower percentual volumetric tumor growth.

SUBMITTER: Goncalves VM

PROVIDER: S-EPMC7865601 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tübingen Schwannoma Cohort.

Gonçalves Vítor Moura VM Suhm Elisa-Maria EM Ries Vanessa V Skardelly Marco M Tabatabai Ghazaleh G Tatagiba Marcos M Schittenhelm Jens J Behling Felix F

Cancers 20210126 3

Most patients with vestibular schwannomas can be cured with microsurgical resection, or tumor growth can be stabilized by radiotherapy in certain cases. Recurrence is rare but usually difficult to treat. Treatment alternatives to local therapies are not established. There is growing evidence of the role of inflammatory processes in schwannomas, which may be exploitable by targeted innovative therapies. To further define the impact of inflammation with tumor growth in vestibular schwannoma, we pe ...[more]

PMID: 33530441

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Project description:BACKGROUND: Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-?B. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. METHODS: Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-?) and low (TNF-?) expression in M2 macrophages, and molecules in NF-?B pathway (IKK? and I?-B) were evaluated by RT-qPCR or western blot. RESULTS: EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-? and increased TNF-?. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKK? suppression and concomitant I-?B accumulation; increase of IL-6 and TGF-?; and, decrease of TNF-?. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-?B pathway elicited by EGCG-treated exosomes. CONCLUSIONS: Our data demonstrate that EGCG up-regulates miR-16 in tumor cells, which can be transferred to TAM via exosomes and inhibits TAM infiltration and M2 polarization. We suggest a novel mechanism by which EGCG exerts anti-tumor activity via regulation of TAM in tumor microenvironment.

Project description:MicroRNAs are endogenous small noncoding RNAs that are functionally involved in numerous critical cellular processes including tumorigenesis. Data mining using a microRNA array database suggested that let-7d microRNA may be associated with renal cell carcinoma (RCC) malignant progression. Here, we performed further analyses to determine whether let-7d is functionally linked to RCC malignancy.Quantitative real-time PCR was used to determine the level of mature let-7d in RCC clinical specimens and its correlation with clinicopathological data. Immunohistochemical staining was conducted to characterize the stroma of RCC. Let-7d overexpressing RCC cell lines combined with mouse models bearing cell-derived xenografts and patient-derived xenografts were used to assess the functional role of let-7d in vitro and in vivo.Downregulation of let-7d in clinical RCC samples was associated with advanced tumor grade and T stage and increased vascular invasion. An inverse relationship between let-7d expression and macrophage infiltration was found in clinical RCC samples. Functional studies indicated that ectopic expression of let-7d significantly inhibited RCC cell proliferation, migration, and peripheral blood monocyte (PBMC) recruitment in vitro, as well as tumor growth, metastasis, and tumor macrophage infiltration in vivo. In silico analysis and subsequent experimental validation confirmed collagen, type III, alpha 1 (COL3A1) and C-C subfamily chemokine member CCL7 as direct let-7d target genes. The addition of COL3A1 and CCL7 counteracted the inhibitory effects of let-7d on RCC cell proliferation, migration, and PBMC recruitment. The inhibition of let-7d increased cell proliferation, migration, and PBMC recruitment by the enhanced expression of COL3A1 and CCL7 genes in vitro. The mRNA levels of COL3A1 and CCL7 were inversely correlated with let-7d level in RCC clinical specimens.These results suggest that let-7d may suppress RCC growth, metastasis, and tumor macrophage infiltration at least partially through targeting COL3A1 and CCL7.

Dataset Information

Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tubingen Schwannoma Cohort.

Publications

Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tübingen Schwannoma Cohort.

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