Mechanisms of tumor-induced neutrophilia: constitutive production of colony-stimulating factors and their synergistic actions

Abstract

Transplantation of a murine mammary carcinoma (CE maca) into mice induces marked granulocytosis and hypercalcemia secondary to excessive bone resorption. Such responses are not induced by another murine mammary carcinoma Bc66. In order to understand the mechanisms of these unique phenomena, we analyzed mRNA of tumor cells for expression of murine granulopoietic growth factors and studied interactions of tumor- derived factors using antiserum to a growth factor in vitro and in vivo. The Northern blot analysis of CE tumor clones revealed the expression of granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF), but no other CSF genes, while the Bc66 clone expressed only M-CSF. The G-CSF and M-CSF gene expression in CE tumor clones was accompanied by secretion of these proteins in culture. The granulocyte stimulating activity of CE tumor- derived G-CSF or recombinant human G-CSF was markedly enhanced by purified M-CSF in vitro. Significant but variable neutrophilia was observed in mice inoculated with CE tumor clones. Anti-M-CSF treatment of CE tumor-bearing mice significantly reduced neutrophilia, but did not affect hypercalcemia. These studies document that G-CSF and M-CSF are produced constitutively from the CE maca, and G-CSF is likely responsible for granulocytosis induced by this tumor. G-CSF and M-CSF function synergistically in granulocyte stimulation in vitro and this synergism may also play a role in marked granulocytosis of tumor- bearing animals, providing further evidence of the effect of CSFs in vivo.

Paraneoplastic leukemoid reaction in a patient with metastatic adenocarcinoma of the lung

“…9,10 These cytokines tend to promote tumor growth in a paracrine manner. 8,11 Neutrophilia driven by leukogenic cytokines produced by tumor cells was also observed in nude mice upon tumor cells transplantation. 12,13 Eosinophilia can be a manifestation of a myriad of causes such as infections, drug reactions allergic, and autoimmune processes.…”

Animal Models of Cancer-Associated Hypercalcemia

“…Marrow granulocytic hyperplasia is associated with an increase in the number of osteoclasts lining endosteal surfaces and increased bone resorption [ 151 , 152 ]. Granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF) were detected by Northern blot analysis in CE maca tumors and treatment with anti-M-CSF reduced the neutrophilia, but did not affect the hypercalcemia [ 153 ]. Granulocytic hyperplasia has been associated with increased osteoclasts and osteoclast activity [ 154 ].…”

Systemic Leukocyte Alterations in Cancer and their Relation to Prognosis

“…One possible mechanism is the production of soluble factors such as granulocyte and macrophage colony stimulating factor (GM-CSF) by tumor cells, capable of mobilizing precursors in the bone marrow; or vascular endothelial growth factor (VEGF) and interleukin-6, both of which alter cell differentiation [30]. It was demonstrated that G-CSF and M-CSF are produced constitutively in murine mammary carcinoma cells, and that these factors act synergistically to stimulate granulocytes in vitro; this synergism may play a role in the marked granulocytosis observed in tumor-bearing animals [41].…”