Hi-C and DNA methylation analyses reveal novel chromatin loops between distant sites implicated in stem and progenitor cell function.

Cancer progression and metastasis involves interactions between tumor cells and the tumor microenvironment (TME). We reported that mice deficient for cytosolic phospholipase A 2 (cPLA 2 -KO) are protected against the development of lung tumors. The goal of this study was to examine the role of cPLA 2 in the TME. Mouse lung cancer cells (CMT167 and Lewis lung carcinoma cells) injected directly into lungs of syngeneic mice formed a primary tumor, and then metastasized to other lobes of the lung and to the mediastinal lymph nodes. Identical cells injected into cPLA 2 -KO mice showed a dramatic decrease in the numbers of secondary metastatic tumors. This was associated with decreased macrophage staining surrounding the tumor. Wild-type mice transplanted with cPLA 2 -KO bone marrow had a marked survival advantage after inoculation with tumor cells compared with mice receiving wild-type (WT) bone marrow. In vitro, coculturing CMT167 cells with bone marrow-derived macrophages from WT mice increased production of interleukin 6 (IL-6) by cancer cells. This increase was blocked in cocultures using cPLA 2 -KO macrophages. Correspondingly, IL-6 staining was decreased in tumors grown in cPLA 2 -KO mice. These data suggest that stromal cPLA 2 plays a critical role in tumor progression by altering tumor-macrophage interactions and cytokine production.

Expression of oncogenic K-Ras is frequently observed in non-

Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen activator (uPA). Although the roles of uPA and PAI-1 in plasmin generation and the degradation of fibrin are well known, recent evidence also suggests that they can participate in acute inflammatory conditions that involve neutrophil activation. In the present experiments, we found that the addition of PAI-1 to LPS- stimulated neutrophils resulted in enhanced nuclear translocation of NF-kappaB and increased production of the proinflammatory cytokines IL-1beta, Tnf-alpha, and Mip-2. uPA and the kringle domain (KD) of uPA potentiated cytokine expression and NF-kappaB activation by neutrophils cultured with LPS, and had additive effects when combined with PAI-1. The c-Jun N-terminal kinase (JNK) was activated after exposure of resting neutrophils to PAI-1 or the uPA KD. Enhanced JNK activation, but not that of other kinases induced by LPS, was present in neutrophils cocultured with PAI-1 or uPA KD. Inhibition of JNK activation prevented the potentiation of expression of proinflammatory cytokines induced by PAI-1 or uPA KD in LPS stimulated neutrophils. These results demonstrate that PAI-1 and uPA KD enhance LPS-induced neutrophil responses through their effects on JNK mediated pathways.

The metastasis of tumor cells is one of the major obstacles to successful clinical chemotherapy, surgery, and radiotherapy. Accordingly, new therapeutic strategies are needed for overcoming the occurrence of invasion and metastasis of tumor to improve patients' prognosis and survival.The anticoagulants low-molecular weight heparin (LMWH) and recombinant hirudin have shown anti-invasion and antimetastasis effects in experimental models.1,2) However, recombinant hirudin was found ineffective at preventing metastasis of HT168-M1 human melanoma cells in preclinical study, 1) suggesting that the anti-invasion and anti-metastasis effects of anticoagulants may vary by tumor cells. Most likely, each anticoagulant agent has its own mechanisms for application.The association of thrombosis and cancers as evidenced by platelet and fibrin deposition is well established.3-6) Previous studies indicate that exogenous thrombin (1 U/ml) acting through its protease-activated receptor (PAR-1) is capable of enhancing tumor adhesion to platelets, 7-9) endothelial cells, 10) fibronectin, and von Willebrand factor 8) in vitro. Studies have also revealed that exogenous thrombin promotes tumor growth in vitro 11) and in vivo 7,8,12) as well as metastasis in experimental animals (via tail-vein injection of cancer cells). 9,13) The endogenous generation of host thrombin plays a significant role during tumor growth and spontaneous metastasis.2) Recent investigation demonstrated that advanced cancer is associated with a hypercoagulable state triggered by tissue factor (TF).14) TF-initiated thrombin generation is a critical step for metastasis through fibrin, platelet deposition, and PAR-1 signaling responses. In addition, PAR-2, which was not cleaved by thrombin, appears to be a cosignal with PAR-1 to elicit thrombin effects in metastatic tumor cells. 14)Hirudin is a highly potent and specific inhibitor of thrombin. It has shown an inhibitory effects against tumor growth and metastasis in experimental tumor models. [15][16][17] Hirudin induced a pronounced lag time in the appearance of tumor growth, as compared with phosphate-buffered saline (PBS) as control, but had no effect on existing tumor cells. We postulated that hirudin may have different effects on tumor growth depending on its administrations, because hirudin resulted in central necrosis of the tumor nodule, and inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs following administration at early stage of tumor cell inoculation in experimental animals. 2)Heparins are negatively charged polysaccharides that are able to bind to a number of proteins and molecules, thus probably influencing their biological activity. LMWH is composed of low-molecular weight fragments of heparin manufactured by controlled enzymatic or chemical depolymerization. LMWH may affect the progression of tumor in many ways. For example, it may potentially inhibit intravascular arrest and metastasis due to its anticoagulant role. [18][19][20] I...