Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition.
Ontology highlight
ABSTRACT:
SUBMITTER: Chiu WT
PROVIDER: S-EPMC4170798 | biostudies-literature | 2011 Jul
REPOSITORIES: biostudies-literature
Publications
Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition.
Chiu Wen-Tai WT Lee Hsueh-Te HT Huang Feng-Ju FJ Aldape Kenneth D KD Yao Jun J Steeg Patricia S PS Chou Cheng-Yang CY Lu Zhimin Z Xie Keping K Huang Suyun S
Cancer research 20110527 14
Stat3 activation has been implicated as an important driver of brain metastasis in breast cancer, but the critical targets of Stat3 in this process are yet to be fully defined. In this study, we identified the lipid raft organizing protein Caveolin-1 (Cav-1) as a critical genetic target of Stat3 in this process. In human breast cancers, we found that activated Stat3 correlated with attenuation of Cav-1 in brain metastases relative to primary tumors. Cav-1 promoter activity and gene expression we ...[more]
Similar Datasets
Project description:Human autoimmune diseases are characterized by systemic T cell dysfunction, resulting in chronically activated Th1 and Th17 cells that are inadequately suppressed by regulatory T cells (Tregs). IL-6, which is overexpressed in tissue and serum of patients with autoimmune diseases, inhibits human Treg function. We sought to determine the mechanism for the antitolerogenic properties of IL-6 by examining the signaling pathways downstream of IL-6R in primary human T cells. Inhibition of Stat3 signaling in MLCs containing IL-6 restores Treg-mediated suppression, demonstrating that IL-6-mediated loss of Treg suppression requires phosphorylation of Stat3. Cultures in which either effector T cells (Teffs) or Tregs were pretreated with Stat3 inhibitors indicate that phosphorylated (p)Stat3 is required in both T cell populations for IL-6-mediated reversal of Treg function. IL-21, which signals preferentially through pStat3, also reverses Treg suppression, in contrast to IL-27 and IFN-?, which signal preferentially through Stat1 and do not inhibit Treg function. Interestingly, both Teffs and Tregs respond to IL-6 stimulation through strong Stat3 phosphorylation with minimal MAPK/Erk activation and moderate Stat1 phosphorylation. Finally, Teffs stimulated strongly through the TCR are also resistant to suppression by Tregs and show concurrent Stat3 phosphorylation. In these cultures, inhibition of pStat3 restores functional suppression by Tregs. Taken together, our findings suggest that an early dominance of Stat3 signaling, prior to subsequent T cell activation, is required for the loss of functional Treg suppression and that kinase-specific inhibitors may hold therapeutic promise in the treatment of autoimmune and chronic inflammatory diseases.
| S-EPMC3133678 | biostudies-literature
Project description:PURPOSE:Prior reports on the location and sizes of brain metastases almost entirely focus on patients with primary breast and pulmonary cancer. This is the first study comparing multiple other types of cancer that metastasize to the brain. METHODS:This monocentric retrospective study includes 369 untreated patients with 3313 intraaxial brain metastases. Following semi-manual segmentation of metastases on post-contrast T1WI, cumulative spatial probability distribution maps of brain metastases were created for the whole group and for all primary tumors. Furthermore, mixed effects logistic regression model analysis was performed to determine if the primary tumor, patient age, and patient sex influence lesion location. RESULTS:The cerebellum as location of brain metastases was proportionally overrepresented. Breast and pulmonary cancer caused higher number of brain metastases to what would normally be expected. Multivariate analyses revealed a significant accumulation of brain metastases from skin cancer in a frontal and from breast and gastrointestinal cancer in a cerebellar location. CONCLUSION:Distribution of brain metastases is very heterogeneous for the distinct primaries, possibly reflecting the diversity of mechanisms involved in brain metastases formation. In daily clinical practice distribution patters may be beneficial to predict the primary cancer site, if unknown.
| S-EPMC7075842 | biostudies-literature
Project description:BackgroundBrain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary lung cancers and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary lung cancers and BMs, and the evolutionary process remains little known.MethodsTo deeply insight into the extent of inter-tumor heterogeneity at a single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 10 patients with matched primary lung cancers and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary lung cancers and BMs were evaluated by utilizing whole-exome sequencing (WESeq) and immunohistochemical analysis.ResultsIn addition to inheriting genomic phenotype and molecular phenotype from the primary lung cancers, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at a single-patient level. By analysis of a multi-metastases case (Case 3) of cancer cells' subclonal composition, we found similar multiple subclonal clusters in the four spatial and temporal isolated brain metastatic focus, with the characteristics of polyclonal dissemination. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0002) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary lung cancers. Additionally, tumor microvascular density (MVD) also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.ConclusionOur study revealed the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary lung cancers and BMs, which also provided novel insight for formulating individualized treatment strategies for BMs.
| S-EPMC10293929 | biostudies-literature
Project description:Randomized controlled trials have failed to report any survival advantage for WBRT combined with SRS in the management of brain metastases, despite the enhanced local and distant control in comparison to each treatment alone. Literature review have revealed important role of primary histology of the tumor when dealing with brain metastases. NSCLC responds better to combined approach even when there was only single brain metastasis present while breast cancer has registered better survival with SRS alone probably due to better response of primary tumor to advancement in surgical and chemotherapeutic agents. Furthermore, mutation status (EGFR/ALK) in lung cancer and receptor status (ER/PR/HER2) in breast cancer also exhibit diversity in their response to radiotherapy. Radioresistant tumors like renal cell carcinoma and melanoma brain metastases have achieved better results when treated with SRS alone. Secondly, single brain metastasis may benefit from local and distant brain control achieved with combined treatment. These diverse outcomes suggest a primary histology-based analysis of the radiotherapy regimens (WBRT, SRS, or their combination) would more ideally establish the role of radiotherapy in the management of brain metastases. Molecularly targeted therapeutic and immunotherapeutic agents have revealed synergism with radiation therapy particularly SRS in treating cancer patients with brain metastases. Clinical updates in this regard have also been reviewed.
| S-EPMC7358601 | biostudies-literature
Project description:BackgroundBrain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences.MethodsSeventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases.ResultsIn 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335-8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419-10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients.ConclusionsBoth temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.
| S-EPMC10809508 | biostudies-literature
Project description:BackgroundBrain metastases (BM) are a rare complication in colorectal cancer (CRC) patients and associated with an unfavorable survival prognosis. Primary tumor side (PTS) was shown to act as a prognostic and predictive biomarker in several trials including metastatic CRC (mCRC) patients. Here, we aim to investigate whether PTS is also associated with the outcome of CRC patients with BM.MethodsPatients treated for CRC BM between 1988 and 2017 at an academic care center were included. Right-sided CRC was defined as located in the appendix, cecum and ascending colon and left-sided CRC was defined as located in the descending colon, sigma and rectum.ResultsTwo hundred and eighty-one CRC BM patients were available for this analysis with 239/281 patients (85.1%) presenting with a left-sided and 42/281 patients (14.9%) with a right-sided primary CRC. BM-free survival (BMFS) was significantly longer in left-sided compared with right-sided CRC patients (33 versus 20 months, P = 0.009). Overall survival from CRC diagnosis as well as from diagnosis of BM was significantly longer in patients with a left-sided primary (42 versus 25 months, P = 0.002 and 5 versus 4 months, P = 0.005, respectively). In a multivariate analysis including graded prognostic assessment, PTS remained significantly associated with prognosis after BM (hazard ratio 0.65; 95% confidence interval: 0.46-0.92 months, P = 0.0016).ConclusionsPTS was associated with survival times after the rare event of BM development in CRC patients. Therefore, its prognostic value remains significant even thereafter.
| S-EPMC8190486 | biostudies-literature
Project description:IntroductionThis study investigates the immune profile of the primary lung tumors and the corresponding brain metastasis from patients with NSCLC using multiplex fluorescence immunohistochemistry.MethodsThe study evaluated 34 patients who underwent autopsy or surgical resection for brain metastasis and autopsy, surgical resection, or core biopsy for primary lung cancer. We compared the densities of various immune cells in the primary tumors and the brain metastases by multiplex fluorescence immunohistochemical analysis.ResultsThe density of CD4-positive (CD4+) T-cells, CD8-positive T-cells, and CD4+ Foxp3-positive T-cells were statistically higher in both tumor and stromal areas in primary lung cancer specimens when compared with brain metastases samples (p < 0.0001). Only CD204-positive cells were statistically higher in the tumor areas of the brain metastases (p = 0.0118). Tumor-infiltrating lymphocytes associated with brain metastases positively correlated with overall survival, but primary lung tumor-infiltrating lymphocytes did not. The density of CD4+ and CD4+ Foxp3-positive T-cells in brain metastases with radiation was statistically higher in the carcinoma and stromal areas compared with those without radiation (p = 0.0343, p = 0.0173).ConclusionsOur findings that CD204-positive cells were higher in brain metastases may have broader implications for treatment as these macrophages may be immunosuppressive and make the immune environment less reactive. Furthermore, the finding that the density of CD4+ T-cells was higher in cancer and stroma areas of brain metastases after radiotherapy supports the addition of immunotherapy to radiation therapy in the treatment of brain metastases in NSCLC.
| S-EPMC8501504 | biostudies-literature
Project description:Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.
| S-EPMC4226685 | biostudies-literature
Project description:BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.
| S-EPMC7860978 | biostudies-literature
Project description:E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.
| S-EPMC4966321 | biostudies-literature