thromboplastin and Carcinoma--Ductal--Breast

Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS).. In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival.. Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT.. This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Breast; Breast Neoplasms; Cancer-Associated Fibroblasts; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Disease-Free Survival; Female; Follow-Up Studies; Gene Expression Profiling; Humans; Mastectomy; Middle Aged; Neoplasm Invasiveness; Prognosis; Prospective Studies; Thrombin; Thromboplastin; Tissue Array Analysis; Tumor Microenvironment; Young Adult

Tissue factor (TF), the trigger of coagulation, not only initiates thrombus formation, but also elicits tumor growth and invasion in breast cancer. However, the characterization of TF expression in breast cancer tissue and its prognostic value remain unclear.. Three hundred and three primary breast cancer specimens from the local tumor tissue database were immunostained for TF expression and evaluated semiquantitatively. Tumor characteristics (size, grade, nodal status, and ER expression) as well as patient's survival were assessed.. Expression of TF was detected in 99% of specimens with higher expression in invasive lobular than ductal carcinoma (p=0.008). TF expression correlated with ER expression (p<0.0001) and inversely with tumor grade (p=0.006). Survival analysis did not reveal any prognostic impact of TF expression (p=0.966).. This study - by analyzing TF expression in the largest cohort of breast cancer patients so far - does not support a prognostic impact of TF expression.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lymphatic Metastasis; Middle Aged; Neoplasm Grading; Predictive Value of Tests; Receptors, Estrogen; Thromboplastin; Time Factors; Tumor Burden

The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown.. Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens.. Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01).. These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.

Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Cell Proliferation; Endothelial Cells; Female; Humans; Hyperplasia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Neovascularization, Pathologic; Precancerous Conditions; Prognosis; Thromboplastin; Vascular Endothelial Growth Factor A

The transmembrane cellular receptor tissue factor (TF) is the primary initiator of the coagulation cascade in man. Expression of TF was determined in 55 specimens of ductal adenocarcinoma of the pancreas and was found to correlate strongly with the degree of histological differentiation. A significant linear trend was observed with stronger immunoreactivity observed in poorly differentiated tumours (chi 2 = 6.69, P = 0.0098). No TF staining was seen in pancreatic samples from normal controls (n = 18). As expression of TF may be associated with tumour progression, its analysis could provide useful prognostic information in patients with pancreatic malignancy.

Topics: Adult; Aged; Carcinoma, Ductal, Breast; Humans; Immunohistochemistry; Middle Aged; Pancreatic Neoplasms; Thromboplastin