The role of activated protein C in cancer progression

Activated protein C (APC) is best known as a natural anticoagulant that also has direct cell signaling properties which (among others) enhance vascular barrier function. We recently established the relevance of APC-induced barrier enhancement by showing that endogenous APC limits cancer cell extravasation. In line with this concept, repeated administration of exogenous APC reduced the number of experimental metastasis. It is thus tempting to speculate that exogenous APC administration would be a novel therapeutic avenue to fight cancer metastasis. The current review summarizes recent data on the role of the protein C pathway in cancer metastasis. It discusses the APC pathway as a potential novel target to influence cancer progression, but it also points to several limitations of APC administration in the setting of cancer cell metastasis. (C) 2010 Elsevier Ltd. All rights reserve

Pulmonary tumor foci formation in syndencan-1 −/− versus wild type mice with and without treatment with LMWH.

<p>Syndecan-1 −/− and wild type mice were administered 2.0×10⁵ B16F10 melanoma cells into the lateral tail vein. One group of mice was treated with LMWH (15 mg/kg enoxaparin ) prior to the administration of B16F10 melanoma cells and LMWH treatment was repeated after 6, 12 and 24 h. Mice were sacrificed 14 days after cancer cell injection and the number of tumor foci at the surface of the lungs was determined. Error bars represent medians ± interquartile range (n = 8), * p<0.05; *** p<0.001.</p

A low molecular weight heparin inhibits experimental metastasis in mice independently of the endothelial glycocalyx

Contains fulltext : 88997.pdf (publisher's version ) (Open Access)BACKGROUND: Some low molecular weight heparins (LMWHs) prolong survival of cancer patients and inhibit experimental metastasis. The underlying mechanisms are still not clear but it has been suggested that LMWHs (at least in part) limit metastasis by preventing cancer cell-induced destruction of the endothelial glycocalyx. METHODOLOGY/PRINCIPAL FINDINGS: To prove or refute this hypothesis, we determined the net effects of the endothelial glycocalyx in cancer cell extravasation and we assessed the anti-metastatic effect of a clinically used LMWH in the presence and absence of an intact endothelial glycocalyx. We show that both exogenous enzymatic degradation as well as endogenous genetic modification of the endothelial glycocalyx decreased pulmonary tumor formation in a murine experimental metastasis model. Moreover, LMWH administration significantly reduced the number of pulmonary tumor foci and thus experimental metastasis both in the presence or absence of an intact endothelial glycocalyx. CONCLUSIONS: In summary, this paper shows that the net effect of the endothelial glycocalyx enhances experimental metastasis and that a LMWH does not limit experimental metastasis by a process involving the endothelial glycocalyx

Treatment patterns and clinical outcomes of asciminib in a real-world multi-resistant chronic myeloid leukemia patient population

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Treatment patterns and clinical outcomes of asciminib in a real-world multiresistant chronic myeloid leukemia patient population

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Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement

Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial barrier through sphingosine-1-phosphate receptor-1 (S1P1)activation, which may counteract cancer cell extravasation. Here, we provide evidence that endogenous APC limits cancer cell extravasation, with in vivo use of monoclonal antibodies against APC. The protective effect of endogenous APC depends on its signaling properties. The MAPC1591 antibody that only blocks anticoagulant activity of APC does not affect cancer cell extravasation as opposed to MPC1609 that blocks anticoagulant and signaling properties of APC. Combined administration of anti-APC antibodies and S1P1 agonist (SEW2871) resulted in a similar number of pulmonary foci in mice in presence and absence of APC, indicating that the protective effect of APC depends on the S1P1 pathway. Moreover, endogenous APC prevents cancer cell–induced vascular leakage as assessed by the Evans Blue Dye assay, and SEW2871 treatment reversed MPC1609-dependent vascular leakage. Finally, we show that cancer cells combined with MPC1609 treatment diminished endothelial VE-cadherin expression. In conclusion, endogenous APC limits cancer cell extravasation because of S1P1-mediated VE-cadherin–dependent vascular barrier enhancement

Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial

Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients #40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients .40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD2 after consolidation 1 in arm A vs 75/81 (93%) in arm B (P 5 .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity