In the last several years, multiple lines of evidence have suggested that the COP9 signalosome (CSN) plays a significant role in the regulation of multiple cancers and could be an attractive target for therapeutic intervention. First, the CSN plays a key role in the regulation of Cullin-containing ubiquitin E3 ligases that are central mediators of a variety of cellular functions essential during cancer progression. Second, several studies suggest that the individual subunits of the CSN, particularly CSN5, might regulate oncogenic and tumor suppressive functions independently of, or coordinately with, the CSN holocomplex. Thus, deregulation of CSN subunit function can have a dramatic effect on diverse cellular functions, including the maintenance of DNA fidelity, cell cycle control, DNA repair, angiogenesis, and microenvironmental homeostasis that are critical for tumor development. Additionally, clinical studies have suggested that the expression or localization of some CSN subunits correlate to disease progression or clinical outcome in a variety of tumor types. Although the study of CSN function in relation to tumor progression is in its infancy, this review will address current studies in relation to cancer initiation, progression, and potential for therapeutic intervention. (Mol Cancer Res 2005;3(12):645 -53)

It has been shown that the renin-angiotensin system (RAS) plays key roles in the development of fibrosis in numerous organs, including the liver. Other studies have suggested that the RAS also may play roles in diseases of chronic inflammation. However, whether the RAS also can mediate acute inflammation in liver is unclear. The purpose of this study therefore was to determine the effect of the RAS inhibitors captopril and losartan on acute liver damage and inflammation caused by hepatic ischemia and subsequent reperfusion. Accordingly, male rats were subjected to 1 hour of hepatic ischemia (70%) followed by reperfusion; animals were killed 3, 8, or 24 hours after reperfusion. The effect of captopril or losartan (100 or 5 mg/kg intragastrically, respectively) was compared with that of vehicle (saline). The expression of angiotensinogen in liver increased fivefold 3 hours after reperfusion. Indices of liver damage and inflammation (e.g., alanine aminotransferase levels, pathological features, tumor necrosis factor-␣ levels, and intercellular adhesion molecule-1 expression) all were significantly elevated in vehicle-treated animals after hepatic ischemia and subsequent reperfusion. Ischemia and reperfusion also caused an increase in the accumulation of protein adducts of 4-hydroxynonenal, an index of oxidative stress. Captopril or losartan treatment showed profound protective effects under these conditions, significantly blunting the increase in all these parameters caused by ischemia and reperfusion. In conclusion, RAS inhibitors prevent acute liver injury in a model of inflammation caused by ischemia and reperfusion. These data further suggest that the RAS may play a key role in mediating such responses in the liver and suggest a novel role for this system. (HEPATOLOGY 2004;40:583-589.)

This study reveals that the IL-15 rapidly released into serum upon IL-12 injection into tumor-bearing mice is critical for the subsequent leukocytic infiltration of the tumor and tumor-bearing tissue. The increase in serum IL-15 occurs within 2 h after IL-12 injection concomitantly with a decrease in cytoplasmic IL-15 in tumor-associated M/ (TAM). Injection of anti-IL-15 one hour prior to IL-12 abrogates subsequent leukocytic infiltration into the tumor and prevents the IL-12-induced reduction of primary tumor mass and the clearance of metastases. Administration of anti-IL-15 18 h after IL-12 did not have a detectable impact on IL-12-induced leukocytic infiltration of the tumor. Deletion of NK cells had no impact on the IL-12-induced change in the functional phenotype of TAM or on the subsequent initiation of leukocytic infiltration of the tumor. In concert with our previous studies demonstrating that IL-12 reduces tumor-supportive activities of TAM, the current study supports the hypothesis that functional re-programming of TAM not only undermines M/ support for tumor growth but also contributes to a critical step in the initiation of anti-tumor immune responses. In this context, the functional plasticity and pro-immunogenic potential of TAM may constitute a significant and unappreciated target in existing cytokine therapies.

Macrophages are now known to play multiple roles in the progression and metastasis of many solid tumors. Although tumor-derived cytokines play a role in stimulating cytokine production by the macrophages, the extent of tumor-macrophage cross-talk remains to be explored. We have previously demonstrated that CD154:CD40 interactions are a dominant mechanism of contact-dependent communication between a variety of cell types. We therefore initiated a study of the role of CD154:CD40 interactions in tumor-macrophage interactions. Flow cytometric analysis reveals CD154 expression on 3LLC carcinoma cells. In corroboration of previous studies, co-culture of supernatants of tumor cell cultured with normal macrophages stimulated moderate cytokine production and this was equally effective with both CD40+/+ and CD40-/- macrophages. Co-culture of paraformaldehyde-fixed tumor cells with normal macrophages stimulated cytokine production by the macrophages, indicating that a cell contact dependent mechanism was also involved in the stimulation of macrophages by the tumor cells. Implantation of 3LLC tumors subcutaneously in CD40+/+ and CD40-/- mice resulted in similar growth of the primary tumor mass. However, no lung metastases were detectable in the CD40-/- mice. Bone marrow chimeric mice were generated by reconstituting irradiated CD40+/+ mice with either CD40+/+ or CD40-/- bone marrow. Nine weeks later, the splenic and peripheral blood leukocytes were >94% donor derived. Both recipients of CD40+/+ and CD40-/- bone marrow displayed similar growth of the primary tumor and similar frequency of lung metastases, indicating that CD40 expression by bone marrow derived macrophages was not critical for tumor metastasis. The study demonstrates that ligation of CD40 on hematopoietic and non-hematopoietic cells may play critical roles in tumor progression and metastasis. This research was supported by grants from the Kentucky Lung Cancer Foundation (J.S.) and the Susan G. Komen Race for the Cure (R.S.) and by an NRSA T32 Postdoctoral Training Grant (K.R.) and a Ruth Kirschstein T31 Predoctoral Fellowship (C.G.). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1342.