Inhibition of tissue factor-factor VIIa proteolytic activity blunts hepatic metastasis in colorectal cancer.

BACKGROUND: Expression of the principal initiator of coagulation, tissue factor (TF), by colorectal cancer (CRC) cells is involved in tumoral angiogenesis and metastasis progression, after binding of factor VIIa (FVIIa) to TF and generation of TF-FVIIa activity. We thus hypothesized that inhibition of the TF pathway by active site-blocked FVIIa (FFR-FVIIa) may prevent the development of hepatic metastasis in CRC. METHODS: Rat tumoral cells (DHDK12 proB cells) expressing high levels of TF were injected in the portal vein in syngenic BDIX rats. Rats received intraperitoneal injection of either FFR-FVIIa, from d 3 to d 7 (adjuvant treatment) (n = 19), or solvent buffer (n = 18) (control group). Additionally, cancer cells were infused subcutaneously in 20 other rats, which were assigned to FFR-FVIIa adjuvant treatment (n = 10), or buffer treatment (n = 10). Macroscopic and histological analysis was performed at d 14. RESULTS: In the control group, infusion of cancer cells resulted in development of macroscopic hepatic tumors in 17/18 rats. In the adjuvant FFR-FVIIa group, macroscopic hepatic tumors were visible on the liver surface in 3/19 rats (P = 0.002 versus control). All rats with subcutaneous injection of proB cells exhibited macroscopic tumors, with no significant difference between the control and the treated ones. CONCLUSION: Inhibition of the proteolytic activity of TF-FVIIa complex blunted hematogenous hepatic metastasis, suggesting that TF-FVIIa is a relevant target for the prevention of hepatic metastasis in CRC. TF-blocking agents should be investigated as adjuvant treatment in this setting.

In vivo and in vitro effect of sirolimus on insulin secretion.

BACKGROUND: The effects of sirolimus on insulin secretion are still debated. Our aim was to investigate the effects of sirolimus, both (1) in vivo in healthy minipigs; and (2) in vitro on human islets. METHODS: (1) Ten minipigs were evaluated during three successive stages: (a) basal; (b) at the end of a 4-week period of treatment with sirolimus; and (c) after a 4-week period of wash-out. We evaluated insulin secretion with the acute insulin response (AIR), and glucose tolerance with the glucose disposal rate (GDR). (2) Insulin content, stimulation index, adenosine triphosphate (ATP), and apoptosis were measured in human islets treated in vitro with sirolimus at therapeutic and supratherapeutic concentrations. RESULTS: (1) Basal and stimulated insulin levels and GDR increased during sirolimus administration and returned to baseline after a wash-out period; (2) regardless of culture duration, sirolimus dose-dependently decreased apoptosis and increased insulin content. Stimulation indexes and ATP were also significantly enhanced but only at therapeutic concentrations. CONCLUSIONS: This study suggests that sirolimus, at plasma-drug concentrations usually targeted in clinical practice, (1) increases basal and stimulated insulin levels in vivo and insulin content in vitro regardless of culture duration; (2) is able to reduce apoptosis. These findings may partly underlie the improved results of islet transplantation.

Structural Characterization of Mucin O-Glycosylation May Provide Important Information to Help Prevent Colorectal Tumor Recurrence.

Although colorectal cancer is a preventable and curable disease if early stage tumors are removed, it still represents the second cause of cancer-related death worldwide. Surgical resection is the only curative treatment but once operated the patient is either subjected to adjuvant chemotherapy or not, depending on the invasiveness of the cancer and risks of recurrence. In this context, we investigated, by mass spectrometry (MS), alterations in the repertoire of glycosylation of mucins from colorectal tumors of various stages, grades, and recurrence status. Tumors were also compared with their counterparts in resection margins from the same patients and with healthy controls. The obtained data showed an important decrease in the level of expression of sialylated core 3-based O-glycans in tumors correlated with an increase in sialylated core 1 structures. No correlation was established between stages of the tumor samples and mucin O-glycosylation. However, with the notable exception of sialyl Tn antigens, tumors with recurrence presented a milder alteration of glycosylation profile than tumors without recurrence. These results suggest that mucin O-glycans from tumors with recurrence might mimic a healthier physiological situation, hence deceiving the immune defense system.

Celiac axis and superior mesenteric artery: danger zone for left nephrectomy.

We report two cases of iatrogenic occlusion of the superior mesenteric artery (SMA) and celiac axis (CA) during left nephrectomy. A patient with a urothelial carcinoma (open surgery) and one with coralliform calculi (laparoscopy) experienced injury to both the SMA and/or CA due to bulky perihilar adenopathy and kidney adherence to surrounding tissue. The cancer patient survived after fast repair. Repair was delayed in the second patient who subsequently died. It is essential to identify each arterial branch carefully on the preoperative CT-scan to identify any duplicate renal arteries and avoid mistaking the SMA and/or CA for the renal artery.