Role Of Colony-stimulating Factor Research Articles

Role of colony-stimulating factor 1 in the neoplastic process of tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TGCTs) are rare, locally aggressive, mesenchymal neoplasms, most often arising from the synovium of joints, bursae, or tendon sheaths. Surgical resection is the first-line treatment, but recurrence is common, with resulting impairments in patients' mobility and quality of life. Developing and optimizing the role of systemic pharmacologic therapies in TGCT management requires an understanding of the underlying disease mechanisms. The colony-stimulating factor 1 receptor (CSF1R) has emerged as having an important role in the neoplastic processes underlying TGCT. Lesions appear to contain CSF1-expressing neoplastic cells derived from the synovial lining surrounded by non-neoplastic macrophages that express the CSF1R, with lesion growth stimulated by both autocrine effects causing proliferation of the neoplastic cells themselves and by paracrine effects resulting in recruitment of CSF1 R-bearing macrophages. Other signaling pathways with evidence for involvement in TGCT pathogenesis include programmed death ligand-1, matrix metalloproteinases, and the Casitas B-cell lymphoma family of ubiquitin ligases. While growing understanding of the pathways leading to TGCT has resulted in the development of both regulatory approved and investigational therapies, more detail on underlying disease mechanisms still needs to be elucidated in order to improve the choice of individualized therapies and to enhance treatment outcomes.

Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition.

Sepsis is a systemic inflammatory state that occurs in response to infection and significantly increases mortality in combination with acute kidney injury (AKI). Macrophages accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1) phenotype to an alternatively activated (M2) phenotype that is required for normal repair. However, the specific signals that regulate the transition from the M1 to M2 phenotype in vivo are unknown. Here, we found an unexpected role of Colony stimulating factor 2 (Csf2) in controlling macrophage transition in vitro and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). We first co-cultured human M1 macrophages with HK-2 cells and characterized cytokine/chemokine profiles via Luminex. Of the cytokines and chemokines that were overexpressed in medium from M1 macrophages cocultured with human kidney-2 (HK-2) cells compared with that from M1 macrophages cultured alone, Csf2 and IL6 showed the greatest increases. Csf2 was exclusively secreted by HK-2 cells but not by M1 macrophages. Furthermore, recombinant human Csf2 protein promoted transition of M1 macrophages to the M2 phenotype in a dose and time-dependent manner. The apoptosis and reactive oxygen species (ROS) release induced by M1 macrophages in HK-2 cells was attenuated after exposure to exogenous Csf2. In addition, the switch from the proinflammatory M1 phenotype to the M2 phenotype occurred via the p-Stat5 pathway, which was activated by Csf2. Importantly, we found that intraperitoneal injection of a Csf2-neutralizing antibody after CLP aggravated kidney injury and suppressed tubular proliferation, subsequently decreasing survival. However, administration of recombinant mouse Csf2 protein could rescue mice with sepsis. Together, our results indicate that Csf2 plays critical roles in regulating macrophage transition via activation of p-STAT5. These data form a foundation upon which new therapeutic strategies can be designed to improve the therapeutic efficacy of cytokine-based treatments for sepsis-induced AKI.

G-CSF and GM-CSF Modify Neutrophil Functions at Concentrations found in Cystic Fibrosis

The role of colony stimulating factors (CSFs) in cystic fibrosis (CF) circulating neutrophils has not been thoroughly evaluated, considering that the neutrophil burden of lung inflammation in these subjects is very high. The aim of this study was to assess granulocyte-CSF (G-CSF) and granulocyte-macrophage-CSF (GM-CSF) levels in CF patients in various clinical conditions and how these cytokines impact on activation and priming of neutrophils. G-CSF and GM-CSF levels were measured in sputum and serum samples of stable CF patients (n = 21) and in CF patients with acute exacerbation before and after a course of antibiotic therapy (n = 19). CSFs were tested on non CF neutrophils to investigate their effects on reactive oxygen species (ROS) production, degranulation (CD66b, elastase, lactoferrin, MMP-9), and chemotaxis. At very low concentrations found in CF patients (0.005–0.1 ng/ml), both cytokines inhibited ROS production, while higher concentrations (1–5 ng/ml) exerted a stimulatory effect. While either CSF induced elastase and MMP-9 secretion, lactoferrin levels were increased only by G-CSF. Chemotaxis was inhibited by GM-CSF, but was increased by G-CSF. However, when present together at low concentrations, CSFs increased basal and fMLP-stimulated ROS production and chemotaxis. These results suggest the CSF levels that circulating neutrophils face before extravasating into the lungs of CF patients may enhance their function contributing to the airway damage.

The role of colony stimulating factors and immunoglobulin in the prevention and treatment of neonatal infection

Bacterial systemic infection (SI) remains one of the unresolved challenges of neonatal intensive care, directly and indirectly responsible for infant death and impaired neuro-developmental outcomes. The incidence increases with lower...

Role of colony-stimulating factors in atherosclerosis

The varied effects of colony-stimulating factors (CSFs) on monocytes and macrophages during inflammation and atherosclerosis and its clinical presentation prompt the question whether the differing effects of CSFs dictate macrophage function and disease progression. CSFs can give rise to heterogeneous populations of monocyte-derived macrophages that are characterized by disparate expression of distinct molecules which dictate their ability to process lipid and regulate inflammatory and immune responses. The CSFs have been found within atherosclerotic plaques and in the circulation where their levels may act as predictive biomarkers of disease progression. Accordingly, differing exposure to these factors imparts divergent genomic signatures and functional properties on macrophages and may impact the multifactorial steps involved in atherogenesis, plaque progression and instability. Great interest in macrophage heterogeneity in the genesis and progression of atherosclerosis has led to the search for consistent markers of specific subsets in both animal models and humans. A better understanding of the overlap and competition between CSF regulation of macrophage phenotypes is therefore warranted, to allow their characterization in plaques. Subsequent targeted genetic and pharmacological intervention will facilitate the generation of therapeutic approaches to halt the progression and rupture of advanced atherosclerotic plaques.

Stem cell and progenitor cell therapy in peripheral artery disease

Atherosclerotic peripheral artery disease (PAD) is a common manifestation of atherosclerosis. The occlusion of large limb arteries leads to ischaemia with claudication which can progress to critical limb ischaemia (CLI) with pain at rest, and to tissue loss. At present, common therapy for CLI is either surgical or endovascular revascularisation aimed at improving blood flow to the affected extremity. However, major amputation and death are still frequent complications. Exploring new strategies for revascularisation of ischaemic limbs is thus of major importance. Bone marrow (BM)-derived stem and progenitor cells have been identified as a potential new therapeutic option to induce therapeutic angiogenesis. Encouraging results of preclinical studies have rapidly led to several small clinical trials, in which BM-derived mononuclear cells were administered to patients with limb ischaemia. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO2), reduction of pain, and decreased need for amputation. Nonetheless, large randomised, placebo-controlled, double-blind studies are necessary and currently ongoing (BONMOT-CLI, JUVENTUS and NCT00498069). Further research relates to the optimal cell type and dosage, the isolation method, the role of colony-stimulating factors, administration route, and the supportive stimulation of cells with reduced functioning due to advanced PAD. Autologous stem cell therapy for ischaemic peripheral disease seems to be a promising new tool for the treatment of severe limb ischaemia. Preliminary evidence has established its safety, feasibility and effectiveness on several important endpoints. Several large endpoints studies are underway to further consolidate this evidence.

Reduced PMN beta 2 integrins after trauma: a possible role for colony-stimulating factors.

The beta 2 integrins are composed of a common 95-kD beta-subunit (CD18) and one of three possible alpha-subunits: CD11a, CD11b, or CD11c. These molecules are involved in neutrophil adhesion, diapodesis, chemotaxis and phagocytosis. In this study, the effects of traumatic injury on neutrophil expression of these alpha-subunits were investigated. Neutrophils from patients with severe trauma (n = 30) were stained with fluorescent anti-CD11a, -CD11b, or -CD11c. The percentage of positive neutrophils and the mean channel fluorescence were assayed by flow cytometry. In 10 patients and 10 normals, the effects of granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on alpha-subunit expression were evaluated. Ninety-four +/- 2% (s.e.m.) of normal neutrophils were CD11a+, 89 +/- 1% were CD11b+ and 89 +/- 8% were CD11c+. Only 65 +/- 2% of patient neutrophils were CD11a+, 45 +/- 5% were CD11b+ and 8 +/- 1% were CD11c+. Culture of normal neutrophils without colony-stimulating factors resulted in reduced expression of CD11a and CD11c, but up-regulation of CD11b. Down-regulation of CD11a and CD11c was partially reversed by colony-stimulating factors (30 U/ml). CD11b receptor density was further up-regulated by GM-CSF and G-CSF. Treatment of patient neutrophils with colony-stimulating factors in culture resulted in up-regulation of alpha-subunits as well. GM-CSF appeared to have the greater effect. These results indicate that colony-stimulating factors may have a clinical role in improving beta 2 integrin expression, and suggest a use in these infection-prone patients.

Colony-stimulating factors for prevention of myelosuppressive therapy-induced febrile neutropenia in children with acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) is the most common cancer in childhood and febrile neutropenia is a potentially life-threatening side effect of its treatment. Current treatment consists of supportive care plus antibiotics. Clinical trials have attempted to evaluate the use of colony-stimulating factors (CSF) as additional therapy to prevent febrile neutropenia in children with ALL. The individual trials do not show whether there is significant benefit or not. Systematic review provides the most reliable assessment and the best recommendations for practice. To evaluate the safety and effectiveness of the addition of G-CSF or GM-CSF to myelosuppressive chemotherapy in children with ALL, in an effort to prevent the development of febrile neutropenia. Evaluation of number of febrile neutropenia episodes, length to neutrophil count recovery, incidence and length of hospitalisation, number of infectious disease episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction), relapse and overall mortality (death). The search covered the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT, LILACS, and SciElo. We manually searched records of conference proceedings of ASCO and ASH from 1985 to 2003 as well as databases of ongoing trials. We consulted experts and scanned references from the relevant articles. We looked for randomised controlled trials (RCTs) comparing CSF with placebo or no treatment as primary or secondary prophylaxis to prevent febrile neutropenia in children with ALL. Two authors independently selected, critically appraised studies and extracted relevant data. The end points of interest were:* Primary end points: number of febrile neutropenia episodes and overall mortality (death) * Secondary end points: time to neutrophil count recovery, incidence and length of hospitalisation, number of infectious diseases episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction) and relapse. We conducted a meta-analysis of these end points and expressed the results as Peto odds ratios. For continuous outcomes we calculated a weighted mean difference and a standardised mean difference. For count data, meta-analysis of the logarithms of the rate ratios using generic inverse variance was employed. We scanned more than 5500 citations and included six studies with a total of 332 participants in the analysis. There were insufficient data to assess the effect on survival. The use of CSF significantly reduced the number of episodes of febrile neutropenia episodes (Rate Ratio = 0.63; 95% confidence interval (CI) 0.46 to 0.85; p =0.003, with substantial heterogeneity), the length of hospitalisation (weighted mean difference (WMD) = -1.58; 95% CI -3.00 to -0.15; p = 0.03), and number of infectious diseases episodes (Rate Ratio=0.44; 95%CI 0.24 to 0.80; p=0.002). In spite of these results, CSF did not influence the length of episodes of neutropenia (WMD = -1.11; 95% CI -3.55 to 1.32; p = 0.4) or delays in chemotherapy courses (Rate Ratio=0.77; 95%CI 0.49 to 1,23; p=0.28) . Children with ALL treated with CSF benefit from shorter hospitalisation and fewer infections. However, there was no evidence for a shortened duration of neutropenia nor fewer treatment delays, and no useful information about survival. The role of CSF regarding febrile neutropenia episodes is still uncertain. Although current data shows statistical benefit for CSF use, substantial heterogeneity between included trials does not allow this conclusion.

Current management of chemotherapy-induced neutropenia: the role of colony-stimulating factors

Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms. One important consequence, chemotherapy-induced neutropenia (CIN), places patients at risk of developing fever and life-threatening infections. These complications have substantial economic impact and may severely affect the quality of life of patients undergoing treatment of cancer. Currently, CIN is managed by delaying and reducing chemotherapy treatment with hematopoietic growth factors and with intravenous antibiotic therapy. Reducing chemotherapy may compromise treatment outcomes in potentially curable malignancies, such as early stage breast cancer and non-Hodgkin’s lymphoma. Randomized clinical trials have clearly shown that granulocyte colony-stimulating factor (filgrastim) and the longer-acting pegylated granulocyte colony-stimulating factor pegfilgrastim, when administered 24 hours after chemotherapy before the occurrence of CIN, are effective in reducing the incidence and severity of neutropenia and its complications, including administration of full doses of chemotherapy without treatment delay. Dose-dense chemotherapy, ie, the administration of standard-dose chemotherapy in shorter cycles (made feasible with growth factor support), has recently been shown to improve outcomes in early stage breast cancer and non-Hodgkin’s lymphoma. This review summarizes the clinical consequences of CIN and describes current best practices for the management of patients at risk for CIN.

The role of colony-stimulating factors and granulocyte transfusion in treatment options for neutropenia in children with cancer.

Children with cancer receiving anticancer therapy always experience neutropenia, and as a result often develop serious neutropenic infections that cause morbidity and/or mortality. Intensive chemotherapy with improved supportive care for neutropenia contribute to the recent advances in treatment outcome in children with cancer. Recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) can shorten the duration and decrease the severity of neutropenia, and thus support intensive chemotherapy. Both G-CSF and GM-CSF stimulate proliferation and maturation of myeloid progenitor cells and are thus used to help mobilization of peripheral blood progenitor cells, and after stem-cell transplantation. The American Society of Clinical Oncology 2000 Guidelines recommended that colony-stimulating factors (CSFs) can be administered as a primary prophylaxis with a chemotherapy regimen if previous experiences with chemotherapy regimens have shown that the incidence of febrile neutropenia (neutropenic fever) is > or =40%. The routine use of CSFs for secondary prophylaxis or for patients with afebrile neutropenia is not recommended in order to avoid the overuse of CSFs. The use of a CSF may be considered in children with febrile neutropenia with a neutrophil count <100/microL, uncontrolled primary disease, pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or invasive fungal infection. Although these guidelines are generally applicable to children with cancer, further studies on CSFs are certainly needed in pediatric oncology. The recent advances in granulocyte collection, using healthy volunteer donor stimulation with G-CSF and/or dexamethasone to yield large numbers of granulocytes has made granulocyte transfusion a more realistic option. Granulocyte transfusion has shown promising results in treating children with severe neutropenic infection; however, controlled trials are warranted to clarify the efficacy and cost-effectiveness of this procedure.

The role of colony stimulating factors in small cell lung cancer: Why the question is still unsolved

The use of Colony Stimulating Factors (CSF) to reduce the incidence and consequences of chemotherapy-induced febrile neutropenia was approved more than 10 years ago on the basis of two randomised trials [1,2] evaluating Granulocyte Colony Stimulating Factors (G-CSF) in small cell lung cancer (SCLC). The American Society of Clinical Oncology then recommended the prophylactic use of either G-CSF or Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in addition to any chemotherapy regimen associated with a more than 40% risk of febrile neutropenia [3]. Since then, various attempts have been made to test their ability to improve the therapeutic effects of cytotoxic chemotherapy in SCLC, either by increasing the dose per course, or by reducing the interval between the courses, or by using the recruitment and re-infusion of haematopoietic stem cells. Overall, the conclusions drawn from the potential impact of these strategies on treatment results are controversial. Furthermore, although the pivotal studies using G-CSF were randomised and placebo controlled, and despite the demonstration of long term response and survival equivalence of both arms in one of them [4], some studies have raised the question of a possible deleterious effect of GM-CSF [5,6] and generated uncertainties in the scientific community. In such a context, the publication of the paper by Berghmans et al. in the present issue of the ‘Lung Cancer’ journal [7] is particularly appropriate. The authors present the results of a meta-analysis based on the data from the literature on the potential impact of G-CSF and GM-CSF on anti-cancer treatment outcomes in SCLC. They have pooled 12 randomised studies and applied to the 12 corresponding publications two previously published quality scales. The scores proved to be satisfying to this group who has wellknown expertise in the field [8] and led the authors to consider these publications as adequate to perform the meta-analysis. Because of the above-mentioned heterogeneity in the design and objectives of the different studies, they have artificially chosen to split them into three subgroups based on arbitrarily applied endpoint criteria, namely ‘maintenance of planned dose-intensity’, ‘accelerated chemotherapy’ and ‘concentrated chemotherapy’. Since they find a detrimental effect on response in the first group and a reduced survival in the third (which only contains one study, the negative trial by Pujol et al. [6]) they come to the conclusion that ‘the published data do not support the routine use of haematological CSF in the treatment of SCLC’. Although the weakness of meta-analyses based on published data only is well-known, the provocative paper by Berghmans et al. has the considerable interest to offer a useful selection of the appropriate trials to be included in a meta-analysis on individual data, a much more valid method to answer such a difficult question. In 1996, the meta-analysis group in cancer, which conducted and published several meta-analyses based on individual patient data in the past 10 years [9 /11] decided to perform a meta-analysis on survival in SCLC by pooling the seven randomised studies on GCSF available at that time, most of them in abstract forms. These clinical trials had been promoted either by an institutional group of investigators [12 /15] or by the pharmaceutical industry [1,2,16]. The principal investigators of these studies gave us consent to collaborate. The Chugai corporation gave us full access to their data base. Unfortunately, despite multiple contacts with the Amgen corporation, including specific requests from the trial investigators, we never obtained the authorization to use the data from the Amgen G-CSF trials [1,2] and had to give up the project. Finally, the paper by Berghmans et al. raises the issue of the accessibility of data collected in clinical trials. We * Corresponding author Lung Cancer 37 (2002) 125 /126

Hematopoiesis in HIV infection: use of colony stimulating factors and cytokines.

HIV infection is frequently accompanied by defects in hematopoiesis, particularly in those who have advanced HIV disease. There are multiple potential causes, including disorders that occur secondary to the HIV infection (e.g., infection, bone marrow infiltration by lymphoma), its treatment (e.g., sulfa, zidovudine), or primary infection of hematopoietic cells or stromal cells. Even those HIV-infected patients who have apparently normal hematopoiesis and normal blood counts are more prone to the myelosuppressive effects of cytotoxic therapy or other hematosuppressive medications. This chapter will discuss the potential causes of abnormal hematopoiesis that occurs in HIV infection, and the role of colony stimulating factors (CSFs) and cytokines in their management.KeywordsHuman Immunodeficiency VirusHuman Immunodeficiency Virus TypeHuman Immunodeficiency Virus InfectionBone Marrow InfiltrationOral GanciclovirThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Comment: Response to an article by Hamilton et al. on 'Effects of colony stimulating factor-1 on human extravillous trophoblast growth and invasion'

We wish to comment on the article by Hamilton et al. 1998. Table 1 shows the similarities and differences between the observations made in the two papers (Lewis et al. 1996, Hamilton et al. 1998) which have investigated the roles of colony-stimulating factor-1 (CSF-1) and its receptor (c-fms) in human extravillous cytotrophoblast (EVCT). Both types of EVCT show the components of a CSF-1/ c-fms autocrine loop, and it is clear that there is no role for CSF-1 in controlling EVCT invasion (Table 1). However, in primary cells (designated EVT), CSF-1 was a positive regulator of cell proliferation (Hamilton et al. 1998), whereas in immortalised TCL-1 cells (and in BeWo choriocarcinoma) CSF-1 appeared to be an inhibitor of such proliferation (Lewis et al. 1996). There are a number of factors which may contribute to this difference in the data obtained, but we must firstly point out that Hamilton et al. have not reported our previous data accurately. In the last paragraph of the discussion they state ‘‘. . . those cells (TCL-1 cells) also exhibited an autocrine CSF-1 loop which enhanced proliferation.’’ This is the opposite of what we reported (Lewis et al. 1996), that ‘‘Proliferation of TCL-1 cells . . . . was elevated in response to treatment with a CSF-1 neutralising antibody.’’ (abstract). We therefore suggested that CSF-1 may be a differentiation or maturation factor which suppresses the proliferation of trophoblasts (Aplin 1991). Possible explanations for the differences in effects of CSF-1 include the following: (1) EVT were obtained by culture of adherent cells and explants from minced first trimester villi (Hamilton et al. 1998), whereas TCL-1 were from chorionic membranes and immortalised with the SV40 large-T antigen (Lewis et al. 1996). There may be a change in trophoblast response to CSF-1 depending on gestational age, intrauterine location or, as described by Hamilton et al., the fact that TCL-1 were immortalised. (2) TCL-1 cells did not respond to CSF-1, and the levels of CSF-1 released were sufficient to saturate the c-fms receptor (Lewis et al. 1996). The release of CSF-1 from EVT cells was not quantified, but the response of the cells to CSF-1 in vitro suggested that the receptor would not be saturated. The quantity of CSF-1 needed (62·5 ng/ml, or 2750 nM) is higher than the accepted affinity of the c-fms receptor (230 nM). (3) The proliferation indices of the cells seem to differ markedly. In serum-free medium, EVT incorporated 400–1000 c.p.m./6 h (Hamilton et al. 1998). TCL-1 cells incorporated about 300 000 dpm/h (our unpublished data), a rate substantially greater. The EVT cells were examined on day 5 of culture, in contrast to TCL-1 cells

Serum levels of macrophage colony-stimulating factor-1 in cervical human papillomavirus infection and intraepithelial neoplasia

Objective: Our goal was determine the correlation between serum colony stimulating factor-1 levels, cervical human papillomavirus infection, and dysplasia. Study Design: Serum samples were obtained from control subjects from the United States and from a group of Panamanian women. Members of the latter group fell into 3 categories: those who serve as Panamanian control subjects and who test negative for human papillomavirus (n = 10); those who are high risk by history and test positive for human papillomavirus types 16/18 and 30s (n = 10); and those with the same high-risk history with biopsy-proven cervical intraepithelial neoplasia (n = 8). Serum colony-stimulating factor-1 levels were determined using enzyme-linked immunosorbent assay. Data were analyzed with the Student-Newman-Keuls and t tests. Results: Mean serum colony-stimulating factor-1 levels of patients with a positive test result for human papillomavirus (1166 ± 949 pg/mL) and cervical intraepithelial neoplasia (1295 ± 314 pg/mL) were higher than those of control subjects from the United States (584 ± 237 pg/mL) and those of Panamanian control subjects (520 ± 229 pg/mL). Statistical analysis revealed the concentration of colony-stimulating factor in patients with positive test results for human papillomavirus or cervical intraepithelial neoplasia were significantly higher than in control groups. In addition, combining patients with human papillomavirus with those who have cervical intraepithelial neoplasia results in a group that has significantly higher colony-stimulating factor levels compared with control subjects. Conclusions: Both high-grade cervical dysplasia and high-risk human papillomavirus infection are associated with higher mean serum colony-stimulating factor levels, suggesting a possible role for colony-stimulating factor-1 in cervical neoplasia. Further studies are needed to understand the mechanism of colony- stimulating factor activation in human papillomavirus infection. This may assist in designing therapeutic approaches for the management of this disease. (Am J Obstet Gynecol 1999;180:28-32.)

Colony-Stimulating Factor-1 Plays a Major Role in the Development of Reproductive Function in Male Mice

Colony-stimulating factor-1 (CSF-1) is the principal regulator of cells of the mononuclear phagocytic lineage that includes monocytes, tissue macrophages, microglia, and osteoclasts. Macrophages are found throughout the reproductive tract of both males and females and have been proposed to act as regulators of fertility at several levels. Mice homozygous for the osteopetrosis mutation (csfmop) lack CSF-1 and, consequently, have depleted macrophage numbers. Further analysis has revealed that male csfmop/csfmop mice have reduced mating ability, low sperm numbers, and 90% lower serum testosterone levels. The present studies show that this low serum testosterone is due to reduced testicular Leydig cell steroidogenesis associated with severe ultrastructural abnormalities characterized by disrupted intracellular membrane structures. In addition, the Leydig cells from csfmop/csfmop males have diminished amounts of the steroidogenic enzyme proteins P450 side chain cleavage, 3β-hydroxysteroid dehydrogenase, and P450 17α-hydroxylase-lyase, with associated reductions in the activity of all these steroidogenic enzymes, as well as in 17β-hydroxysteroid dehydrogenase. The CSF-1-deficient males also have reduced serum LH and disruption of the normal testosterone negative feedback response of the hypothalamus, as demonstrated by the failure to increase LH secretion in castrated males and their lack of response to exogenous testosterone. However, these males are responsive to GnRH and LH treatment. These studies have identified a novel role for CSF-1 in the development and/or regulation of the male hypothalamic-pituitary-gonadal axis.

The Role of Colony-Stimulating Factors in the Treatment of Acute Leukaemia

The currently available haemopoietic growth factors granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used in the treatment of acute leukaemia with 2 objectives: to reduce the time to neutrophil recovery after intensive chemotherapy and/or haemopoietic progenitor transplantation; andin acute myeloid leukaemia, to recruit leukaemic cells into the cell cycle in order to increase the number of blasts susceptible to cycle-specific cytotoxic drugs. In acute lymphoblastic leukaemia, the use of G-CSF or GM-CSF shortens the duration of neutropenia, and may facilitate adherence to the chemotherapy schedule. However, only 1 study has demonstrated an increase in the complete remission rate, and this was in only 1 subgroup of patients (>60 years old). In acute myeloid leukaemia, the administration of G-CSF or GM-CSF after chemotherapy is well tolerated and is not associated with a stimulation of the leukaemic clone. In 4 out of 5 large randomised placebo-controlled studies, use of colony-stimulating factors led to a reduction of the duration of neutropenia. The complete remission rate was significantly higher for patients receiving growth factors in 2 studies, 1 with G-CSF and 1 with GM-CSF. However, only 1 of these studies, that with GM-CSF, demonstrated improved patient survival. The effect of G-CSF or GM-CSF given before and/or during chemotherapy of acute myeloid leukaemia has been evaluated in 4 randomised studies. The results are currently not sufficient to recommend the use of either growth factor in this indication. Many questions remain regarding the optimal dosage and schedule of administration of G-CSF or GM-CSF in acute leukaemia. The reduction of time to neutrophil recovery observed when the growth factor is administered after chemotherapy is not always translated into a benefit for the patient. Careful clinical and cost-effectiveness studies are necessary before routinely using these factors in clinical practice.

Absence of colony stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice disrupts estrous cycles and ovulation.

Colony stimulating factor-1 (CSF-1) is a hematopoietic growth factor required for the recruitment, proliferation, and differentiation of mononuclear phagocytes. In addition, CSF-1 is expressed in the female reproductive tract coincident with CSF-1 receptor localization on preovulatory oocytes, ovarian and uterine macrophages, decidual cells, and trophoblast. A role for CSF-1 in female reproduction was confirmed by studies on CSF-1-deficient, osteopetrotic (csfmop/csfmop) mice, which suffer from low pregnancy rates and smaller litter sizes compared to wild-type mice. The present study was designed to determine the exact causes of the preimplantation fertility defects in these mutant mice. Female csfmop/csfmop mice have extended estrous cycles compared to wild-type females, and s.c. administration of CSF-1 from birth restores estrous cyclicity. These mice fail to display the characteristic proestrous surge in circulating estradiol-17beta. However, concentrations of this hormone are normal during the remainder of the cycle. Furthermore, csfmop/csfmop females have significantly lower ovulation rates than wild-type mice, but the implantation rates of fertilized oocytes are normal. Serum pregnancy concentrations of progesterone are also normal in csfmop/csfmop females, in line with the relatively normal progression of pregnancy in these mice. Thus, the major effect of CSF-1 on female reproductive function is on the frequency and rate of ovulation, indicating a major role for this growth factor in regulating follicular development and ovulation.

Partial characterization of an immortalized human trophoblast cell-line, TCL-1, which possesses a CSF-1 autocrine loop

Many previous studies in both mouse and human placenta have implicated a role for colony stimulating factor-1 (CSF-1) in the regulation of placental development. In this study we have examined CSF-1 production by an immortalized cell line (TCL-1) derived from the choriodecidua, transfected with a retrovirus gene coding for the large-T antigen. TCL-1 cells were uniformly positive by immunocytochemistry for the composite sub-units of human chorionic g gonadotrophin (hCG) but were negative for markers of other cell types localized at the fetal-maternal interface. Gelatinase enzymes were secreted by TCL-1 cells cultured on extracellular matrix in a manner indicative of extra-villous trophoblast. Dot-blot immunoassays and ELISA indicated that CSF-1 was secreted by TCL-1 cells, at levels comparable to primary trophoblast cells and BeWo choriocarcinoma (trophoblast tumour) cells. Reverse transcriptase-polymerase chain reaction analysis confirmed the presence in TCL-1 cells of CSF-1 receptor mRNA (c-fms gene product), indicating that the components of a potential autocrine loop were present in these cells. Proliferation of TCL-1 cells was not affected by the addition of exogenous CSF-1 but was elevated in response to treatment with a CSF-1 neutralizing antibody. The immortalized cell line, TCL-1, provides a potential model in which to investigate regulation of growth and differentiation of trophoblast cells in vitro.

Bone marrow involvement, in intensively treated patients with intermediate grade non-Hodgkin's lymphoma, is a risk factor for granulocytopenia and fever.

Intensive combination chemotherapy administered to patients with non-Hodgkin's lymphoma (NHL) is inevitably associated with neutropenia and fever. However, the subset of patients who are at increased risk for myelotoxicity has not been clearly identified as yet. We evaluated 58 patients with NHL in order to verify whether bone marrow involvement (BMI) at diagnosis is a risk factor for neutropenia and infection following intensive chemotherapy. Patients with bone marrow involvement had significantly lower neutrophil counts both at diagnosis and following chemotherapy. An higher percentage of patients with BMI developed neutropenia (< 1000/mm3) following chemotherapy. Furthermore events of febrile neutropenia were more frequently encountered in patients with BMI. We conclude that BMI in patients with NHL is a risk factor for chemotherapy induced neutropenia and fever. The role of colony stimulating factors, administered in an attempt to prevent this complication, should be explored.

Thrombosis in Cancer Patients Treated with Hematopoietic Growth Factors - A Meta-Analysis

SummaryHematopoietic colony-stimulating factors (CSFs) are largely used in patients with cancer undergoing cytotoxic treatment to accelerate neutrophil recovery and decrease the incidence of febrile neutropenia. Clinical practice guidelines for their use have been recently established (1), taking into account clinical benefit, but also cost and toxicity. Vascular occlusions have been recently reported among the severe reactions associated with the use of CSFs, in anedoctal case reports (2, 3), consecutive case series (4) and randomized clinical trial (5, 6). However, the role of CSFs in the pathogenesis of thrombotic complications is difficult to ascertain, because pertinent data are scanty and widely distributed over a number of heterogenous investigations. We report here a systematic review of relevant articles, with the aims to estimate the prevalence of thrombosis associated with the use of CSFs and to assess if this rate is significantly higher than that observed in cancer patients not receiving CSFs.