Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors

• Published in: Experimental and molecular pathology 2007-02, Vol.82 (1), p.12-24
• Main Authors: duPre', Sally A., Hunter, Kenneth W.
• Format: Article
• Language: English
• Subjects: 4T1; Animals; Biological and medical sciences; Bone Marrow - pathology; Colony-Stimulating Factors; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor - blood; Granulocyte-Macrophage Colony-Stimulating Factor - blood; Granulocytes - pathology; Growth factors; Gynecology. Andrology. Obstetrics; Investigative techniques, diagnostic techniques (general aspects); Leukemoid; Leukemoid Reaction - etiology; Lymphocytes - pathology; Mammary carcinoma; Mammary gland diseases; Mammary Neoplasms, Experimental - complications; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Reverse Transcriptase Polymerase Chain Reaction; Splenomegaly; Splenomegaly - etiology; Tumors
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2006.06.007

A leukemoid reaction with granulocytosis and splenomegaly has been observed in animals and humans with a variety of tumors. We have employed four color flow cytometry to characterize the leukemoid reaction induced by the transplantable mouse mammary carcinoma 4T1 in female BALB/c mice. Gr-1 + myeloid cells with the morphology of granulocytes increased in peripheral blood from < 15% pre-transplant to nearly 80% of total CD45 + leukocytes at four weeks post-transplant. Though the granulocyte:lymphocyte ratio increased markedly, the absolute numbers of CD19 + B lymphocytes, CD4 + and CD8 + T lymphocytes, and the CD4/CD8 ratio in peripheral blood did not change significantly. Femurs from tumor-bearing mice showed myeloid hyperplasia of the fatty marrow. There was a notable increase in cells with a Gr-1 dim/CD11b bright immature granulocyte phenotype, and these cells were also found in peripheral blood and spleen. Spleen weights had increased 8.5-fold by four weeks post-tumor transplant, mainly due to granulocytic hyperplasia. Cultured 4T1 tumor cells constitutively expressed mRNA for the myeloid colony-stimulating factors G-CSF and GM-CSF, and IFN-γ-inducible M-CSF transcripts were also detected. Tumors excised from mice had transcripts for G-CSF and GM-CSF, but only G-CSF protein was found in high levels in serum of tumor-bearing mice. These data demonstrate that 4T1 tumor-bearing mice exhibit a leukemoid reaction that apparently is caused by the production of colony-stimulating factors produced by the tumor. The 4T1 tumor may serve as an excellent model for the study of this reaction.