Abstract
Tumor cells are particularly adept at exploiting the immunosuppressive potential of neutrophils as a strategy to achieve uncontrolled proliferation and spread. Recruitment of neutrophils, particularly those of an immature phenotype, known as granulocytic myeloid-derived suppressor cells, is achieved via the production of tumor-derived granulocyte colony-stimulating factor (G-CSF) and neutrophil-selective chemokines. This is not the only mechanism by which G-CSF contributes to tumor-mediated immunosuppression. In this context, the G-CSF receptor is expressed on various cells of the adaptive and innate immune systems and is associated with induction of T cell polarization towards the Th2 and regulatory T cell (Treg) phenotypes. In contrast to the potentially adverse effects of sustained, endogenous production of G-CSF by tumor cells, stringently controlled prophylactic administration of recombinant (r) G-CSF is now a widely practiced strategy in medical oncology to prevent, and in some cases treat, chemotherapy-induced severe neutropenia. Following an overview of the synthesis, structure and function of G-CSF and its receptor, the remainder of this review is focused on: (i) effects of G-CSF on the cells of the adaptive and innate immune systems; (ii) mechanisms by which this cytokine promotes tumor progression and invasion; and (iii) current clinical applications and potential risks of the use of rG-CSF in medical oncology.
Highlights
Colony-stimulating factors (CSFs) are hematopoietic growth factors that are released in response to infection or inflammation to stimulate hematopoietic stem cells to proliferate and generate colonies of differentiated progeny such as neutrophils or macrophages
On the one hand, controlled and appropriate production of granulocyte colony-stimulating factor (G-CSF) plays a critical role in anti-infective host defense, while on the other hand, inappropriate production by tumor cells appears to contribute to tumor growth and invasion
Of which many clinicians may be unaware, the pro-tumorigenic effects are achieved via a dual mechanism of immunosuppression, seemingly by directing T cell polarization towards the T helper 2 (Th2) and T regulatory cell (Treg) phenotypes, and, most prominently, via induction of production of myeloid-derived suppressor cells (MDSCs)
Summary
Colony-stimulating factors (CSFs) are hematopoietic growth factors that are released in response to infection or inflammation to stimulate hematopoietic stem cells to proliferate and generate colonies of differentiated progeny such as neutrophils or macrophages. Major applications of administration of recombinant (r) G-CSF include: (i) attenuation of the magnitude and duration of chemotherapy-induced neutropenia in cancer patients [2], described in greater detail below; (ii) treatment of cyclic and chronic neutropenias [3,4]; and (iii) mobilization of hematopoietic progenitor cells into peripheral blood to be harvested for stem cell transplantation In the latter setting, the incidence and severity of experimental acute graft-versus-host disease (aGVHD) are reduced by administration of rG-CSF [5,6], seemingly due to the immunoregulatory effects of rG-CSF on cells of both the innate and adaptive immune systems, especially T cells, as reviewed earlier by Yang et al [7], as well as immature neutrophils [7,8]. Other topics covered include the involvement of tumor-derived G-CSF in tumorigenesis, as well as the therapeutic applications of rG-CSF in medical oncology, in addition to the associated potential risks
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