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Reconstitution of Amphiregulin–Epidermal Growth Factor Receptor Signaling in Lung Squamous Cell Carcinomas Activates PTHrP Gene Expression and Contributes to Cancer-Mediated Diseases of the Bone
Molecular Cancer Research, 10/20/09

Gilmore JL et al. – Ectopic expression of EGFR in a receptor–low but AREG–expressing cell line increased PTHrP mRNA levels in vitro, and induced the capability to cause HHM and rapid osteolytic growth in vivo. Taken together, the authors provide evidence that AREG stimulation of EGFR results in high levels of PTHrP gene expression, contributing to cancer–associated bone pathology.

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John Foley, 10/22/09

This paper addresses the continuum of bone pathologies associated with non-small lung cancers: hypercalcemia and bone metastasis. The work was built upon our previous manuscript that demonstrated the EGFR inhibitor gefitinib reduced hypercalcemia caused by human lung squamous carcinoma lines (Lorch et al., 2007). Here we report that ectopic expression of the EGFR in a lung squamous line that lacked the receptor was sufficient to induce high levels of PTHrP gene expression and hypercalcemia. In all hypercalcemia-producing cell lines studied to date, amphiregulin was the predominant ligand and it activated the EGFR; however, shedding of this agonist was differentially controlled among the lines. Additionally, ectopic expression of the EGFR conferred aggressive osteolytic growth when the engineered lines were placed in the bone. Recently, paracrine activation of the EGFR in cells of the osteoblast lineage has been reported to contribute to osteolytic growth of breast cancer cells (Zhu et al., 2007) (Lu et al, 2009). In contrast, our findings suggest that autocrine EGFR activation of bone resorbtion cytokines produced by the cancer cell may substantially contribute to osteolytic growth. Taken together, it appears that EGFR inhibitors provide a means of broadly inhibiting pathological growth factor production in both tumor cells and osteoblasts, and may provide an additional therapeutic option for patients with cancer-mediated diseases of the bone. Lorch, G., Gilmore, J. L., Koltz, P. F., Gonterman, R. M., Laughner, R., Lewis, D. A., Konger, R. L., Nadella, K. S., Toribio, R. E., Rosol, T. J., and Foley, J. (2007). Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice. Br J Cancer 97, 183-193. Lu, X., Wang Q, Hu G, Van Poznak C, Fleisher M, Reiss M, Massagué J, Kang Y. (2009). ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes and Development 23, 1882-1894. Zhu, J., Jia, X., Xiao, G., Kang, Y., Partridge, N. C., and Qin, L. (2007). EGF-like ligands stimulate osteoclastogenesis by regulating expression of osteoclast regulatory factors by osteoblasts: implications for osteolytic bone metastases. J Biol Chem 282, 26656-26664.

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