Tumor signaling to the bone marrow changes the phenotype of monocytes and pulmonary macrophages during urethane-induced primary lung tumorigenesis in A/J mice

Am J Pathol. 2007 Feb;170(2):693-708. doi: 10.2353/ajpath.2007.060566.


Little is known about how the composition of stromal cells within the lung cancer microenvironment varies during tumor progression. We examined by immunohistochemistry each of six different stromal cell populations during the development of chemically induced primary lung cancer in mice. Blood vessels were seen even in microscopic lesions, and their numbers increased with tumor size. Neutrophils infiltrated the alveoli of tumor-bearing lungs and within the periphery of macroscopic adenomas and adenocarcinomas. The numbers of peritumoral lymphocytes and macrophages increased during oncogeny, but quantitative changes in mast cells and fibroblasts were not evident. Because macrophage depletion reduces tumor growth and these cells are thus important to tumorigenesis, we also investigated their phenotype. Pulmonary macrophages expressed arginase I (subtype M2) but not inducible nitric-oxide synthase in lungs with premalignant lesions, whereas macrophages in carcinoma-bearing lungs expressed inducible nitric-oxide synthase (subtype M1) but not arginase I. Local pulmonary stimuli did not seem responsible for this shift in macrophage activation state because monocytes still residing within the bone marrow adopted these expression patterns before entering the circulation, presumably in response to tumor-derived signals. These biochemical markers of macrophage activation states would have diagnostic and/or therapeutic value if analogous systemic shifts occur in humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma* / blood supply
  • Adenocarcinoma* / chemically induced
  • Adenocarcinoma* / diagnosis
  • Adenocarcinoma* / enzymology
  • Adenocarcinoma* / pathology
  • Adenoma* / blood supply
  • Adenoma* / chemically induced
  • Adenoma* / diagnosis
  • Adenoma* / enzymology
  • Adenoma* / pathology
  • Animals
  • Biomarkers, Tumor / metabolism*
  • Bone Marrow* / enzymology
  • Bone Marrow* / pathology
  • Carcinogens / toxicity*
  • Cell Transformation, Neoplastic* / chemically induced
  • Cell Transformation, Neoplastic* / metabolism
  • Cell Transformation, Neoplastic* / pathology
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Lung / enzymology
  • Lung / pathology
  • Lung Neoplasms* / blood supply
  • Lung Neoplasms* / chemically induced
  • Lung Neoplasms* / diagnosis
  • Lung Neoplasms* / enzymology
  • Lung Neoplasms* / pathology
  • Macrophage Activation
  • Macrophages, Alveolar* / enzymology
  • Macrophages, Alveolar* / pathology
  • Male
  • Mast Cells / enzymology
  • Mast Cells / pathology
  • Mice
  • Monocytes / enzymology
  • Monocytes / pathology
  • Nitric Oxide Synthase Type II / metabolism
  • Signal Transduction / drug effects*
  • Urethane / toxicity*


  • Biomarkers, Tumor
  • Carcinogens
  • Urethane
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse