thromboplastin and Small-Cell-Lung-Carcinoma

Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.

Topics: Aged; Biomarkers, Tumor; Disease-Free Survival; Extracellular Vesicles; Female; Heparin, Low-Molecular-Weight; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Phospholipids; Small Cell Lung Carcinoma; Survival Rate; Thromboplastin; Venous Thromboembolism

Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease.. CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested.. In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection.

Topics: Aged; Animals; Biomarkers, Tumor; Blood Vessels; CD13 Antigens; Cell Line, Tumor; Female; Humans; Infarction; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mice, Nude; Middle Aged; Molecular Targeted Therapy; Peptides; Recombinant Fusion Proteins; Small Cell Lung Carcinoma; Thromboplastin; Xenograft Model Antitumor Assays

Tissue factor (TF), the transmembrane receptor for factor VIIa (FVIIa), has key regulatory functions in coagulation as well as in tumour progression and metastasis. Small-cell lung cancer (SCLC) metastasises more aggressively than non-small-cell lung cancer (NSCLC). Previously, we described the transition of SCLC cell line H69 to adherent growth and TF expression. Here, we explored the differential expression of TF and its functional impact on morphology and matrix metalloproteinase (MMP) secretion.. The constitutional TF expression was evaluated in a panel of established NSCLC and SCLC cell lines. Furthermore, in three stress-selected adherent SCLC H69 cells, TF and MMP expressions were determined by mRNA, protein, and activity measurements. RNA interference-mediated TF down-regulation and FVIIa stimulation were used to study the impact of TF on cellular functions.. NSCLC cells expressed high TF antigen (median 3.75 ng/mg; range 0.31-65.2 ng/mg protein, n = 8), while SCLC expressed none or low TF (median 0.07 ng/mg; range 0-0.39 ng/mg protein, n = 6). However, selected H69 adherent cells markedly expressed TF (range: 4.8-44.3 ng/mg protein, n = 3) and secreted MMP-2 and MMP-9. FVIIa stimulated MMP-2 and MMP-9 secretion in H69adh cells, whereas TF down-regulation diminished MMP-2 and MMP-9 expression and promoted reversion to suspension growth.. Our data show the significance of TF expression in the reversible growth phenotype of H69. Because TF, MMP expression, and adherence are highly relevant to cancer metastasis, this study suggests a novel mechanism of adaptation, thereby adding to the understanding of SCLC biology and its aggressiveness.

Topics: Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Factor VIIa; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Small Cell Lung Carcinoma; Thromboplastin