Pulmonary Adenocarcinomas with Mutant Epidermal Growth Factor Receptors
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Activating mutations of the DNA sequence encoding the catalytic kinase domain of the epidermal growth factor receptor (EGFR) have been shown to underlie responsiveness to gefitinib in some cases of non–small-cell lung cancer.1,2,3 Oncogenic mutations in growth factor receptors typically result in constitutive signaling, which increases cell proliferation without requiring the growth factor. In contrast, these mutant EGFR proteins require the ligand.1 This observation raises the possibility that the EGFR ligands — epidermal growth factor and transforming growth factor — are secreted by tumor cells themselves (an autocrine loop) or by surrounding stromal cells (a paracrine loop). Distinguishing between these two models has implications for the design of new treatments.
We used immunohistochemistry to identify the cells that contain epidermal growth factor and transforming growth factor in a total of 10 formalin-fixed, paraffin-embedded pulmonary adenocarcinomas, 4 with mutant EGFR proteins and 6 without. The four EGFR alterations included the major mutation types: missense mutations within exon 18 (G719C) and exon 21 (L861Q) and deletions within exon 19 (delL747-P753insS and delL747-T751insS). All specimens containing these mutant receptors showed strong expression of both ligands in the tumor cells but not in the surrounding stromal cells (Figure 1). Similar results were observed in the six cases with wild-type EGFR proteins, in agreement with prior reports.4 Thus, pulmonary adenocarcinomas with EGFR mutations are similar to more common forms of lung cancer, in which autocrine secretion of EGFR ligands by tumor cells stimulates the receptors. The exceptional response of tumors with mutant EGFR proteins to gefitinib most likely results from distinct downstream signaling from the receptor after the ligand binds.5 Our observations raise the possibility that mutations of EGFR arise within a pulmonary epithelial cell that is already secreting epidermal growth factor and transforming growth factor , thus initiating a proliferative stimulus.
Figure 1. Autocrine Ligand Expression in Pulmonary Adenocarcinomas.
Immunohistochemical analysis (avidin–biotin–peroxidase staining with 3,3-diaminobenzidine tetrahydrochloride as the chromogen and hematoxylin counterstaining in which positive cells stain brown) shows expression of epidermal growth factor (Panel A) and transforming growth factor (Panel B) in a tumor with a mutation of the EGFR gene (delL747-P753insS, in exon 19) resulting in a change in the catalytic domain of the protein. Both ligands are expressed by the tumor cells themselves (i.e., in an autocrine manner), with no expression detected in the stromal cells.
Markus J. Riemenschneider, M.D.
Daphne W. Bell, Ph.D.
Daniel A. Haber, M.D., Ph.D.
David N. Louis, M.D.
Massachusetts General Hospital
Boston, MA 02129
mriemenschneider@partners.org
References
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-13311.
Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53:Suppl 10:2379-2385.
Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-1167.
We used immunohistochemistry to identify the cells that contain epidermal growth factor and transforming growth factor in a total of 10 formalin-fixed, paraffin-embedded pulmonary adenocarcinomas, 4 with mutant EGFR proteins and 6 without. The four EGFR alterations included the major mutation types: missense mutations within exon 18 (G719C) and exon 21 (L861Q) and deletions within exon 19 (delL747-P753insS and delL747-T751insS). All specimens containing these mutant receptors showed strong expression of both ligands in the tumor cells but not in the surrounding stromal cells (Figure 1). Similar results were observed in the six cases with wild-type EGFR proteins, in agreement with prior reports.4 Thus, pulmonary adenocarcinomas with EGFR mutations are similar to more common forms of lung cancer, in which autocrine secretion of EGFR ligands by tumor cells stimulates the receptors. The exceptional response of tumors with mutant EGFR proteins to gefitinib most likely results from distinct downstream signaling from the receptor after the ligand binds.5 Our observations raise the possibility that mutations of EGFR arise within a pulmonary epithelial cell that is already secreting epidermal growth factor and transforming growth factor , thus initiating a proliferative stimulus.
Figure 1. Autocrine Ligand Expression in Pulmonary Adenocarcinomas.
Immunohistochemical analysis (avidin–biotin–peroxidase staining with 3,3-diaminobenzidine tetrahydrochloride as the chromogen and hematoxylin counterstaining in which positive cells stain brown) shows expression of epidermal growth factor (Panel A) and transforming growth factor (Panel B) in a tumor with a mutation of the EGFR gene (delL747-P753insS, in exon 19) resulting in a change in the catalytic domain of the protein. Both ligands are expressed by the tumor cells themselves (i.e., in an autocrine manner), with no expression detected in the stromal cells.
Markus J. Riemenschneider, M.D.
Daphne W. Bell, Ph.D.
Daniel A. Haber, M.D., Ph.D.
David N. Louis, M.D.
Massachusetts General Hospital
Boston, MA 02129
mriemenschneider@partners.org
References
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-13311.
Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53:Suppl 10:2379-2385.
Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-1167.