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Sylvester, United States

Mesri E.A.,Sylvester Cancer Center | Mesri E.A.,Developmental Center for Research | Mesri E.A.,University of Miami | Cesarman E.,New York Medical College
Cell Host and Microbe | Year: 2011

Culture of KSHV-infected lymphatic endothelial cells in 3D increases viral gene expression, leading to Notch-induced MT1-MMP-dependent endothelial-to- mesenchymal transition. This reproduces patterns of KSHV gene expression and presence of mesenchymal KSHV-infected cells found in KS lesions, narrowing the gap between in vitro systems of infection and KSHV tumorigenesis. © 2011 Elsevier Inc. Source

Perry G.,University of Miami | Iragavarapu-Charyulu V.,Florida Atlantic University | Harhaj E.W.,University of Miami | Harhaj E.W.,Sylvester Cancer Center | And 2 more authors.
Oncology Reports | Year: 2010

Macrophages from mice bearing advanced mammary tumors are critically impaired in their immune functions, exhibiting reduced expression at the mRNA and protein levels of the crucial transcription factors, nuclear factor κB (NFκB) and CCAAT enhancer binding protein (C/EBP). We have previously shown that tumor-derived factors such as transforming growth factor ß (TGFß) and prostaglandin E2 (PGE2) modulate NFκB and C/EBP expression in macrophages. Transcriptional, post-transcriptional, translational and/or post-translational mechanisms may also play a role in altered levels of NFκB and C/EBP in macrophages from tumor hosts, contributing to impaired inflammatory response. One of the post-translational mechanisms that may tune down or recycle proteins in cells is the proteasomal pathway. Since upregulation of ubiquitin/proteasomal pathways has been described under cancer-induced cachexia, we examined the possible role of this proteolytic machinery in the decrease of NFκB and C/EBP proteins in macrophages from tumor hosts. Using MG-132 proteasome inhibitor to block the proteasome machinery in macrophages from normal and tumor-bearing animals we found that macrophages from tumor hosts display higher ubiquitination and proteolysis compared to those from normal mice and also that NFκB and C/EBP downregulation is reversed in these treated cells. Thus, proteasome degradation may contribute, at least in part, to NFκB and C/EBP impairment in macrophages from tumor-bearers. Source

Caso R.,University of Miami | Silvera R.,Sylvester Cancer Center | Carrio R.,Sylvester Cancer Center | Iragavarapu-Charyulu V.,Florida Atlantic University | And 3 more authors.
International Journal of Oncology | Year: 2010

We have previously shown that peritoneal macrophages from mice bearing advanced D1-DMBA3 mammary tumors are impaired in their inflammatory functions but are not alternatively activated either and are less differentiated than the ones from normal mice. However, little is known about whether similar defects exist in their precursor stages as blood monocytes. We examined if blood monocytes from mammary tumor-bearing mice are already altered in their activation profiles before becoming macrophages and whether they correspond to inflammatory or resident monocyte subtypes. Much effort is currently devoted to reversing macrophage adverse traits in tumor hosts; as these cells reside within tissues, access is limited. Blood monocytes could be better targeted and manipulated by less invasive means. In the present study, mononuclear cells were isolated from whole blood of D1-DMBA-3 mammary tumor-bearing and normal BALB/c mice and CD115+ monocytes were analyzed. Our results show that there is an increase in circulating monocytes in tumor hosts; these monocytes exhibit a reduced expression of several myeloid differentiation markers such as CD115, F4/80, CD68 and CD11b. Moreover, downregulation of MHC II, CD62L and the proangiogenic marker Tie-2 are observed in these cells, whereas Gr-1 and Ly6C are upregulated. Furthermore, gene microarray analysis performed for the first time in blood monocytes from tumor hosts indicates that they express a mixture of pro-inflammatory and anti-inflammatory cytokines and chemokines. Interestingly, CCR2 and CX3CR1, which are crucial in monocyte definition as inflammatory or resident, respectively, are both upregulated. Importantly, complement proteins are enhanced whereas nitric oxide production is decreased and there is no measurable arginase activity detected in these cells. Collectively, our study represents the first comprehensive analysis of blood monocytes from tumor-bearing mice; we conclude that these cells are neither completely inflammatory nor suppressive and are less differentiated, similar to the macrophages they later become. Source

Hatzistergos K.E.,Interdisciplinary Stem Cell Institute | Blum A.,Interdisciplinary Stem Cell Institute | Ince T.,Interdisciplinary Stem Cell Institute | Ince T.,Sylvester Cancer Center | And 4 more authors.
Circulation Research | Year: 2011

Accumulating clinical and preclinical trials are adding to the database, supporting the idea that human cell therapy with MSC transplantation is a safe and a reliable procedure for treating heart disease. Long-term rigorous patient monitoring demonstrates the durability and safety of cell-based therapies for heart disease, with no incidence of tumorigenesis. As with any new therapy, extreme vigilance is required to monitor for, manage, and understand the risk of unwanted and desirable side effects. The specter of neoplasia raises major concerns. However, we conclude that the observations in rodent animal models used to study human diseases should be interpreted with caution when assessing safety and efficacy of any new therapeutic modality and that the risk- benefit profile of MSC cell therapy in the rodent is substantially different from that in large mammals. We believe that ongoing trials of MSCs in humans are of acceptable risk, but strongly argue for ongoing vigilance, particularly over the long term. © 2011 American Heart Association, Inc. Source

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