UPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils.
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ABSTRACT:
SUBMITTER: Uhl B
PROVIDER: S-EPMC8185543 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease involved in cancer invasion and metastasis, interacting with plasminogen activator inhibitor-1 (PAI-1), which was originally identified as a blood-derived endogenous fast-acting inhibitor of uPA. At concentrations found in tumor tissue, however, both PAI-1 and uPA promote tumor progression and metastasis. Consistent with the causative role of uPA and PAI-1 in cancer dissemination, several retrospective and prospective studies have shown that elevated levels of uPA and PAI-1 in breast tumor tissue are statistically independent and potent predictors of poor patient outcome, including adverse outcome in the subset of breast cancer patients with lymph node-negative disease. In addition to being prognostic, high levels of uPA and PAI-1 have been shown to predict benefit from adjuvant chemotherapy in patients with early breast cancer. The unique clinical utility of uPA/PAI-1 as prognostic biomarkers in lymph node-negative breast cancer has been confirmed in two independent level-of-evidence-1 studies (that is, in a randomized prospective clinical trial in which the biomarker evaluation was the primary purpose of the trial and in a pooled analysis of individual data from retrospective and prospective studies). Thus, uPA and PAI-1 are among the best validated prognostic biomarkers currently available for lymph node-negative breast cancer, their main utility being the identification of lymph node-negative patients who have HER-2-negative tumors and who can be safely spared the toxicity and costs of adjuvant chemotherapy. Recently, a phase II clinical trial using the low-molecular-weight uPA inhibitor WX-671 reported activity in metastatic breast cancer.
| S-EPMC4423643 | biostudies-literature
Project description:The supporting role of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor 1 (PAI-1) in migration and invasion is well known. In addition, both factors are key components in cancer cell-related signaling. However, little information is available for uPA and PAI-1-associated signaling pathways in primary cancers and corresponding lymph node metastases. The aim of this study was to compare the expression of uPA and PAI-1-associated signaling proteins in 52 primary breast cancers and corresponding metastases. Proteins were extracted from formalin-fixed paraffin-embedded tissue samples of the primary tumors and metastases. Protein lysates were subsequently analyzed by reverse phase protein array for the expression of members of the PI3K/AKT (FAK, GSK3-β, ILK, pGSK3-β, PI3K, and ROCK) and the MAPK pathways (pp38, pSTAT3, and p38). A solid correlation of uPA expression existed between primary tumors and metastases, whereas PAI-1 expression did not significantly correlate between them. The correlations of uPA and PAI-1 with signaling pathways found in primary tumors did not persist in metastases. Analysis of single molecules revealed that some correlated well between tumors and metastases (FAK, pGSK3-β, ILK, Met, PI3K, ROCK, uPA, p38, and pp38), whereas others did not (PAI-1 and GSK3-β). Whether the expression of a protein correlated between tumor and metastasis or not was independent of the pathway the protein is related to. These findings hint at a complete deregulation of uPA and PAI-1-related signaling in metastases, which might be the reason why uPA and PAI-1 reached clinical relevance only for lymph node-negative breast cancer tissues.
| S-EPMC3323931 | biostudies-literature
Project description:The interactions of cancer cells with neighboring non-malignant cells in the microenvironment play an important role for progressive neoplastic development and metastasis. Long-term direct co-culture of human MDA-MB-231cherry breast cancer cells with benign human mesenchymal stroma/stem-like cells (MSC) MSC544GFP stably expressing mCherry and eGFP fluorescence proteins, respectively, was associated with the formation of three-dimensional (3D) tumor spheroids in vitro. The quantification of the breast tumor marker urokinase plasminogen activator (uPA) in mono-cultured MDA-MB-231 cells revealed an approximately 14-fold enhanced expression when compared to five different normal human MSC mono-cultures. Moreover, uPA levels in 3D tumor spheroids remained elevated 9.4-fold above the average of five different human MSC cultures. In contrast, the expression of the corresponding plasminogen activator inhibitor type-1 (PAI-1) declined by 2.6-fold in the breast cancer cells and was even further reduced by 3.2-fold in the MDA-MB-231cherry/MSC544GFP 3D co-culture spheroids when compared to the various MSC populations. The supportive data were obtained for the production of TGF-β1, which is an important growth factor in the regulation of tumor growth and metastasis formation. Whereas, TGF-β1 release in MDA-MB-231cherry/MSC544GFP co-cultures was elevated by 1.56-fold as compared to MSC544 mono-cultures after 24 h; this ratio further increased to 2.19-fold after 72 h. Quantitative PCR analyses in MSC544 and MDA-MB-231 cells revealed that MSC, rather than the breast cancer cells, are responsible for TGF-β1 synthesis and that TGF-β1 contributes to its own synthesis in these cells. These findings suggested potential synergistic effects in the expression/secretion of uPA, PAI-1, and TGF-β during the co-culture of breast cancer cells with MSC.
| S-EPMC6600334 | biostudies-literature
Project description:Inflammatory bowel disease confers an increased risk of developing colitis-associated colon cancer (CAC). During the active colitis or developing tumor stage, commensal bacteria show dynamic translocation. However, whether alteration of the bacterial composition in the gut causes CAC is still unclear. To clarify the effect of commensal bacteria on CAC development, we employed an azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine CAC model treated with or without antibiotics. In addition, we analyzed the effects of antibiotics on infiltration of myeloid cells, colonic inflammatory responses, and colorectal cancer formation. We found that vancomycin treatment dramatically suppressed tumor development. In addition, AOM/DSS treatment greatly induced the infiltration of Gr-1(high)/CD11b(high) neutrophils to the colon, which led to the production of tumor necrosis factor ? and inducible nitric oxide synthase. Vancomycin treatment suppressed the infiltration of neutrophils induced by AOM/DSS. Moreover, vancomycin treatment greatly reduced the colon injury and DNA damage caused by AOM/DSS-induced NO radicals. Our results indicate that vancomycin-sensitive bacteria induced colon inflammation and DNA damage by attracting neutrophils into damaged colon tissue, thus promoting tumor formation.
| S-EPMC4822119 | biostudies-literature
Project description:Purpose. Our physiopathological assumption is that u-PA, t-PA, and PAI-1 are released by calcified aortic valves and play a role in the calcification of these valves. Methods. Sixty-five calcified aortic valves were collected from patients suffering from aortic stenosis. Each valve was incubated for 24 hours in culture medium. The supernatants were used to measure u-PA, t-PA, and PAI-1 concentrations; the valve calcification was evaluated using biphotonic absorptiometry. Results. Aortic stenosis valves expressed normal plasminogen activators concentrations and overexpressed PAI-1 (u-PA, t-PA, and PAI-1 mean concentrations were, resp., 1.69 ng/mL ± 0.80, 2.76 ng/mL ± 1.33, and 53.27 ng/mL ± 36.39). There was no correlation between u-PA and PAI-1 (r = 0.3) but t-PA and PAI-1 were strongly correlated with each other (r = 0.6). Overexpression of PAI-1 was proportional to the calcium content of the AS valves. Conclusions. Our results demonstrate a consistent increase of PAI-1 proportional to the calcification. The overexpression of PAI-1 may be useful as a predictive indicator in patients with aortic stenosis.
| S-EPMC3947876 | biostudies-literature
Project description:Here, we report that lipocalin 2 (Lcn2) promotes breast cancer progression, and we identify the mechanisms underlying this function. We first found that Lcn2 levels were consistently associated with invasive breast cancer in human tissue and urine samples. To investigate the function of Lcn2 in breast cancer progression, Lcn2 was overexpressed in human breast cancer cells and was found to up-regulate mesenchymal markers, including vimentin and fibronectin, down-regulate the epithelial marker E-cadherin, and significantly increase cell motility and invasiveness. These changes in marker expression and cell motility are hallmarks of an epithelial to mesenchymal transition (EMT). In contrast, Lcn2 silencing in aggressive breast cancer cells inhibited cell migration and the mesenchymal phenotype. Furthermore, reduced expression of estrogen receptor (ER) alpha and increased expression of the key EMT transcription factor Slug were observed with Lcn2 expression. Overexpression of ERalpha in Lcn2-expressing cells reversed the EMT and reduced Slug expression, suggesting that ERalpha negatively regulates Lcn2-induced EMT. Finally, orthotopic studies demonstrated that Lcn2-expressing breast tumors displayed a poorly differentiated phenotype and showed increased local tumor invasion and lymph node metastasis. Taken together, these in vitro, in vivo, and human studies demonstrate that Lcn2 promotes breast cancer progression by inducing EMT through the ERalpha/Slug axis and may be a useful biomarker of breast cancer.
| S-EPMC2656179 | biostudies-literature
Project description:The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL-17 levels. In this study, we investigated the role of IL-17 in invasive breast tumor pathogenesis. We found that metastatic tumor-infiltrating T lymphocytes produced elevated levels of IL-17, whereas IL-17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, and their depletion suppressed tumor growth. Moreover, IL-17 induced IL-6 and CXCL1 production in tumor cells, and IL-6 depletion reduced metastatic tumor growth and infiltration by Th17 cells and neutrophils. In addition, inoculation of a non-metastatic mammary tumor cell line pre-incubated with IL-17 promoted tumor growth, confirming the pro-tumor role of IL-17. Furthermore, high IL-17 expression was associated with lower disease-free survival (DFS) and worse prognosis in IDC patients. Thus, IL-17 blockade represents an attractive approach for the control of invasive breast tumors. Biopsies of patients with breast tumors
| S-ECPF-GEOD-56822 | biostudies-other
Project description:Both urokinase-like plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor (PAI-1), as well as uPA-PAI-1 complexes, have been identified as important prognostic factors in breast cancer. We have recently reported that the latter are identifiable inside breast cancer cells by means of immunohistochemistry. Using this technique, we have studied a series of 212 early (pT1) unifocal breast cancers and have correlated the expression of uPA-PAI-1 complexes, together with other clinical and biological features (histologic variety, histologic and nuclear grade, hormone receptors, Ki67 labelling index, c-erb-B2-, p53- and CD44std-expression) with or without the occurrence of axillary node invasion. In a logistic regression model, looking for associations with axillary metastasis, we found a statistically significant interaction between the presence of uPA-PAI-1 complexes and progesterone receptor positivity (P=0.04). A final model showed that the presence of uPA-PAI-1 complexes was a determinant factor for axillary metastasis among women carrying tumours expressing progesterone receptors. In these cases, the presence of uPA-PAI-1 complexes carried with it a nearly 14-fold risk of axillary node invasion (P=0.009). These results may indicate that small, hormone-receptor-positive breast cancers (with a theoretical good prognosis) may carry an elevated risk of nodal involvement if accumulation of uPA-PAI-1 complexes is shown inside their tumour cells by means of immunohistochemistry.
| S-EPMC2376772 | biostudies-other
Project description:Tumor biomarkers assist in the early detection of cancer, act as therapeutic targets for intervention, and function as diagnostic indicators for the evaluation of therapeutic responses. To identify novel human breast cancer biomarkers, we have analyzed the protein content of lipid rafts isolated from a series of human mammary epithelial cell lines with increasing tumorigenic potential. Since lipid rafts function as platforms for protein interaction critical to several biological processes, we hypothesized that the abundance of proteins associated with proliferation, invasion and metastasis would be dysregulated in highly transformed cells. For this purpose, the MCF10A epithelial lineage, which include benign MCF10A cells, premalignant AT and TG3B cells, and malignant CA1a tumor cells, was utilized. Detergent-resistant membranes were isolated from each line and proteins were identified and relatively quantitated using iTRAQ™ reagents and tandem mass spectrometry. 57 proteins were identified, and 1667 peptide identifications, mapping to 49 proteins, contained sufficient information for semi-quantitative analysis. When comparing malignant to benign cells, we observed consistent alterations in groups of proteins, such as a 5.7-fold average decrease in G protein content (n = 5), 2.7-fold decrease in glycosylphosphatidylinositol-linked proteins (n = 7) and 3.3-fold increase in intermediate filaments (n = 9). Several of the identified proteins, including caveolin-1, filamin A, keratins 5, 6 and 17, and vimentin, are bona fide or candidate biomarkers in clinical studies, underscoring the usefulness of the MCF10A series as a model to better understand the biological mechanisms underlying cancer progression.
| S-EPMC3827680 | biostudies-literature
Project description:BackgroundBreast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear.MethodsAdipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co- implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes.ResultsIt was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer.ConclusionIn summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.
| S-EPMC6554964 | biostudies-literature