Endothelial progenitor cells are increasingly being studied in various diseases ranging from ischemia, diabetic retinopathy, and in cancer. The discovery that these cells can be mobilized from their bone marrow niche to sites of inflammation and tumor to induce neovasculogenesis has afforded a novel opportunity to understand the tissue microenvironment and specific cell-cell interactive pathways. This review provides a comprehensive up-to-date understanding of the physiological function and therapeutic utility of these cells. The emphasis is on the systemic factors that modulate their differentiation/mobilization and survival and presents the challenges of its potential therapeutic clinical utility as a diagnostic and prognostic reagent.

Key Points• Expression of the Epstein-Barr virusencoded oncoprotein LMP1 leads to sequestration of TRAF3 in B-lymphoma cells.• This sequestration inhibits TRAF3-negative regulation of prosurvival membrane, cytoplasmic, and nuclear signaling events in the B cell.Loss-of-function mutations in genes encoding the signaling protein tumor necrosis factor receptor-associated factor 3 (TRAF3) are commonly found in human B-cell malignancies, can render B cells functionally TRAF3 deficient without TRAF3 gene mutations, a finding of significant relevance to selecting pathway-targeted therapies for B-cell malignancies.

The human TRAF3 gene is frequently mutated in multiple myeloma and lymphoma. TRAF3 restrains homeostatic B cell survival. B cell TRAF3 deficiency promotes enhanced viability and over-expression of the anti-apoptotic molecules NIK, Mcl1 and Pim2, enhanced nuclear CREB, and increased pSTAT3 in response to IL6 signaling. We assessed TRAF3 protein expression in human lymphoma samples. The number of TRAF3low DLBCL was higher than predicted based on genetic loss, so we speculated that cellular TRAF3 can be depleted through other means. The oncogenic Epstein Barr virus protein LMP1 binds TRAF3 with much higher avidity than do CD40 or BAFF receptors, so we hypothesized that LMP1-sequesters TRAF3, causing functional depletion. We found evidence of induction of survival pathways in TRAF3 sufficient B cells expressing LMP1 consistent with those in B cells genetically lacking TRAF3. B lymphoma cell lines stably transfected with inducible LMP1 were stimulated via CD40 or BAFFR. TRAF3 binding was studied via CD40/BAFFR immunoprecipitation and Western blotting. We also examined levels of cellular NIK, and used confocal fluorescence microscopy to assess nuclear CREB expression. We found LMP1 expression sequesters cellular and nuclear TRAF3, decreasing its availability to CD40 and BAFFR, and increases survival-promoting NIK, CREB and pSTAT3. LMP1 mutated at the major TRAF binding site only marginally induced TRAF3 sequestration and NIK. Thus, B cell LMP1 expression can enhance survival by functionally reducing TRAF3 availability.