Autocrine Growth Regulation by Granulocyte Colony-Stimulating Factor and Granulocyte Macrophage Colony-Stimulating Factor in Human Gliomas with Tumor Progression

Abstract

Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSFGliomas are the most common primary malignant brain tumors in adults. Their most malignant form, the glioblastoma multiforme, forms highly vascularized, uniformly fatal neoplasms. Glioma cells, like all tumor cells, are characterized by their uncontrolled growth and increasing escape from regulatory mechanisms of the environment. Current research on brain tumor biology focuses on the mechanisms underlying the stimulation of tumor proliferation and/or angiogenesis. In the past several years a number of growth factors have been identified that stimulate glioma cell growth and glioma-induced angiogenesis through autocrine or paracrine mechanisms (ref 1 and references therein, and refs 2-4). These new insights into the biology of gliomas offer promising therapeutic concepts that are currently under investigation. [5][6][7][8] To date the prognosis of patients with malignant glioma remains poor, offering a median survival time of only 1 year, despite aggressive treatments, including surgical resection and radio-and chemotherapy.9,10 The latter two treatments are limited by two major complications, neutropenia and sepsis. The hematopoietic growth factors granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) were shown to be of therapeutic value in different conditions of primary and secondary bone marrow dysfunction.11 Consequently they now find widespread clinical application in reducing the duration and severity of neutropenic periods in routine cancer therapy. [12][13][14][15]

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…Although PI3-K regulation of GM-CSF was not demonstrated in BLV infection, it does suggest that GM-CSF induction might be common to a number of B-cell lymphomas. Indeed, GM-CSF induction and increased proliferation may contribute to a more aggressive pathology of Theileria-transformed leucocytes in a way similar to that proposed for human glioblastomas (Mueller et al, 1999).…”

Analysis of the antibody repertoire of astrocytoma patients against antigens expressed by gliomas

“…Whereas the expression of granulocyte and granulocyte/macrophage colony-stimulating factors has been shown in human gliomas, 20 expression of proinflammatory genes such as B7-2 and interleukin-12 is lacking in these tumors. 21 Finally, a factor(s) of a minimum weight of 49 kDa has recently been identified in the supernatant of glioblastoma cell cultures that not only suppresses T-cell responses but also alters the cytokine profiles of monocytederived antigen-presenting cells, 22 which, in turn, might also inhibit T-cell help for B cells which is needed for the production of antibodies against antigens expressed by gliomas.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…In most cases, IL-8 is secreted by the tumor cells themselves [210], while in others, other stromal cells such as fibroblasts [273] and macrophages [274] secrete IL-8. Some human cancers secrete high levels of G-CSF and GM-CSF [275,276], acting as both potent mediators of neutrophil mobilization, recruitment and activation (Fig. 2).…”