An angiogenic response originating from peritumoral sinusoids and portal tracts that leads to the formation of metastases with sinusoidal-and portal-type angiogenic patterns, respectively, occurs during the course of liver colonization by murine 51b colon carcinoma (51b-CC) cells. We found a 5-fold increase in endogenous endostatin levels from hepatic blood over baseline (25 ؎ 6 ng/mL) when micrometastatic foci had a detectable size and a 14-fold increase when macrometastases were developed. Despite this endogenous endostatin production, subcutaneous administration of recombinant human endostatin (rh-E; 50 mg/kg) decreased metastasis number by 60% when dosed from days 1 to 20 after 51b-CC cell injection, by 40% when given from days 10 to 20, and by 30% when administered as a single dose 30 minutes before 51b-CC cell injection compared with controls. In addition, administration of rh-E from days 10 to 20 decreased overall metastasis volume by 90% compared with controls. rh-E increased the number of necrotic sinusoidal-type metastases by 7-fold and decreased their intrametastatic CD31 ؉ -microvessel density by 80% without affecting portal-type metastases. H epatic metastasis progression 1 involves 2 key microvascular events: (1) circulating cancer cell adhesion to endothelium, which facilitates metastatic cell implantation and growth along an angiogenesis-independent prevascular stage occurring when micrometastases are smaller than 400 m in diameter, and (2) cancer cell proliferation along an angiogenesisdependent stage, which leads to clinically relevant macrometastatic growth. 2 The transition from preangiogenic to angiogenic micrometastasis is critical in the progression of liver metastasis. However, its underlying mechanism is unclear. In fact, despite hepatic production of endogenous angiogenesis inhibitors, 3 a strong angiogenic response during metastasis development has been reported, which evolves in 2 metastasis subtypes 4 : (1) a sinusoidal type, in which the angiogenic process primarily depends on tumor-activated sinusoidal endothelium and stellate cell recruitment, 5 and (2) a portal type, in which the angiogenic process primarily depends on tumor-activated microvessels and fibroblasts from the perilobular stroma. These 2 angiogenic patterns are also observed in human hepatic metastases from colorectal cancer, 6 but the clinical significance is unknown.Antiangiogenic compounds such as recombinant human endostatin (rh-E) 7 can greatly decrease experimental metastatic growth in the lung. 8 However, because the liver is supposed to be a major source of antiangiogenic recombinant human endostatin; HSE, hepatic sinusoidal endothelium; FSC, forward scatter; SSC, side scatter. From the

Podocalyxin (PCLP1) is a CD34-related sialomucin expressed by some normal cells and a variety of malignant tumors, including leukemia, and associated with the most aggressive cancers and poor clinical outcome. PCLP1 increases breast tumor growth, migration and invasion; however, its role in hematologic malignancies still remains undetermined. The purpose of this study was to investigate the expression and function of PCLP1 in mature B-cell lymphoma cells. We found that overexpression of PCLP1 significantly increases proliferation, cell-to-cell interaction, clonogenicity, and migration of B-cell lymphoma cells. Furthermore, PCLP1 overexpression results in higher resistance to death induced by dexamethasone, reactive oxygen species and type II anti-CD20 monoclonal antibody obinutuzumab. Strikingly, enforced expression of PCLP1 enhances lipid droplet formation as well as pentose phosphate pathway and glutamine dependence, indicative of metabolic reprogramming necessary to support the abnormal proliferation rate of tumor cells. Flow cytometry analysis revealed augmented levels of PCLP1 in malignant cells from some patients with mature B-cell lymphoma compared to their normal B-cell counterparts. In summary, our results demonstrate that PCLP1 contributes to proliferation and survival of mature B-cell lymphoma cells, suggesting that PCLP1 may promote lymphomagenesis and represents a therapeutic target for the treatment of B-cell lymphomas.

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