IGF1R facilitates implantation and progression of lung metastasis acting in the tumor microenvironment

Abstract

Lung cancer is the leading cause of cancer death worldwide. The tumor microenvironment (TME) comprising blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix modulates tumor implantation and progression, thus its blockade is of therapeuthical interest. IGF1R (Insulin-like Growth Factor type 1 Receptor) is an ubiquitous membrane-bound tyrosine kinase receptor with recognized protumoral activity in the lung. In order to understand the role of IGF1R in the lung TME we generated Lewis and melanoma (LLC1/B16F10) lung cancer models using Igf1r-deficient mice and their controls (Transgenic Res 24:279, 2015): i) LLC1 cells were intratracheally administered, awaiting for lung tumors to be developed after 21 days; ii) LLC1 cells were subcutaneously inoculated, followed by primary tumor resection on day (D)14 to allow pulmonary metastasis to be triggered until D35; and iii) LLC1 and B16F10 cells were administered via tail vein injection, awaiting for lung tumors to be developed after 14 days. IGF1R deficiency diminished BALF and bone marrow inflammatory total cell counts, and reduced lung tumor burden. Additionally, lack of IGF1R lowered mRNA expression of metastasis, hypoxia, tumor associated macrophage, tumor infiltrating lymphocyte, neutrophil and dendritic cell markers. Tumors of Igf1r-depleted mice also presented reduced proliferation, vascularization and presence of activated fibroblasts, sustained by decreased expression of epithelial to mesenchymal transition markers. Our results support that IGF1R acts as a cancer-promoting factor in the TME contributing to implantation and progression of lung metastases.