The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells

Abstract

The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with agematched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL- 6 IntroductionSolid tumors can be viewed as abnormal organs composed of 3 general cell types: tumor cells, tumor-associated endothelium, and the stroma (reviewed by Liotta and Kohn 1 and Wernert 2 ). The latter serves to nourish and support the growing tumor cell mass, respectively. Similarly, the stroma of hematopoietic organs is known to support the processes of normal and malignant hematopoiesis (ie, "liquid" tumors or leukemias). 3,4 In both cases, support cells are essential for tumor growth and metastasis. However, the changes occurring in their associated endothelial and stromal cells that accelerate the disease process are poorly characterized.A number of hematologic malignancies including chronic lymphocytic leukemia (CLL), marginal zone non-Hodgkin lymphoma (NHL), hairy cell leukemia (HCL), and chronic myelogenous leukemia (CML) display varying propensities for pathological enlargement of the spleen (splenomegaly). 5-7 Thus, splenic involvement appears to be stage specific for each type of disease and is generally considered to take place during the mid to late stages. Particularly for CML, splenomegaly is evident during accelerated disease and blast crisis. 8 Surgical intervention (splenectomy) is typically reserved for patients who are experiencing extreme discomfort or who may benefit from a laparotomy if such a procedure is thought to be useful in governing the therapeutic strategy. 8 These clinical observations suggest mechanistic growth response elements contributed by the spleen, which remain rather enigmatic.Friend murine leukemia virus (F-MuLV)-induced erythroleukemia has been used for decades as a model for analyzing neoplastic transformation, leukemia progression, genetic susceptibility to cancer, and, more recently, erythroid differentiation. 9,10 It is well established that following inoculation of neonates of susceptible murine strains with F-MuLV, infected erythroblasts depart the bone marrow and sequester within the spleen, 11 followed by the development of foci over the following 2 weeks. 12 It has been previously reported that the spleen plays a role in the susceptibility and resistance of the host to Friend virus infection from the polycythe...

Alcohol, Signaling, and ECM Turnover

“…They showed that alcohol could induce erythroleukemia in a BALBc mouse model. The alcohol fed mice showed an accelerated progression of the preleukemic stage with enhanced proliferation of erythroblasts and splenic infiltration (Shaked et al, 2005). In this model, the TNF-a and IL-8 were greatly increased in the liver and spleen of mice exposed to alcohol.…”

“…Mechanisms include increased cell toxicity and immune modulation via TNF-a led signaling events during viral infection. Various strains of Friend virus can induce erythroleukemias through activation of erythropoietin (Epo) (Shaked et al, 2005), and Epo is also associated with enhanced tumorigenicity of erythroleukemias (Cocco et al, 1996). A link between the severity of leukemia and alcohol consumption has also been reported (Ido et al, 1996), and mice treated with alcohol had enhanced Epo-Rmediated signaling and acceleration of preleukemic stage, suggesting that Epo pathway is important in enhancing preleukemic stage, and that alcohol plays a role in this process.…”

“…In this model, chronic alcohol altered the course of the disease and in the noninfected mice, chronic alcohol feeding led to immune enhancement rather than suppression consistent with the hypothesis that chronic alcohol abuse depresses Th1 function and activates Th2 responses. The study of Friend erythroleukemia has made a contribution to the understanding of tumor progression events associated with human cancer (Ben-David and Bernstein, 1991;Shaked et al, 2005). Neuman et al have demonstrated that alcohol changes the splenic microenvironment promoting a hematologic malignancy via Epo ⁄ Epo-R pathway (Neuman et al, 2008), and paves the way to test possible pharmacological treatments for alcohol-induced tumor progression in human leukemia.…”

Drug resistance in mutant FLT3-positive AML

“…Bone marrow stroma has also been shown to prevent programmed cell death of AML and chronic lymphocytic leukemia cells (Lagneaux et al, 1998(Lagneaux et al, , 1999Konopleva et al, 2002). In addition, splenic stroma and splenocytes support the viability and proliferation of both normal and malignant hematopoiesis (Shaked et al, 2005;Despars and O'Neill, 2006). Furthermore, leukemic lymphoblasts that are coupled to bone marrow stroma through gap junction communication are believed to be held in a quiescent, nondividing state, which is thought to contribute to resistance to antimitotic agents (Paraguassu´-Braga et al, 2003).…”

Causative Factors Involved in Development of Resistance to Tyrosine Kinase Inhibition and Novel Strategies Designed to Override This Resistance

“…Specifically, bone marrow stroma provides signals, such as granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and terminal differentiation of hematopoietic stem cells or mediate/support their proliferation (Verfaillie et al, 1993;Liesveld et al, 1996;Harrison et al, 1997;Breems et al, 1997;O'Prey et al, 1998;Leslie et al, 1998;Shih et al, 1999). SSpenic stroma, as well, has been implicated in enhanced survival of both normal and leukemic cells (Shaked et al, 2005;Despars and O'Neill, 2006). Clinical trial data with tyrosine kinase inhibitors show that while the peripheral blood of patients responds well, bone marrow responds less well.…”