Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung.
The epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor alpha (TGF-alpha), are thought to function as a potential autocrine loop in non-small cell lung cancer (NSCLC). However, the expression pattern of EGFR and the TGF-alpha-related ligands have not been fully characterized in primary NSCLC and adjacent benign lung tissue. For this reason, we comprehensively examined the coexpression and differential expression of EGFR and its ligands, TGF-alpha, epidermal growth factor (EGF), and amphiregulin (AR), by Northern analysis, in paired samples of primary tumors and uninvolved lung. For those RNA species overexpressed in malignant lung, single cell expression patterns were studied by immunohistochemistry. Specimens were obtained from 57 consecutive patients who underwent resection of carefully staged resectable NSCLC and were followed prospectively. Most (112 of 114) tissue samples yielded high-quality RNA. EGFR was expressed in 82 of 88 (93%) tissue samples, while TGF-alpha was expressed in 62 of 72 (86%) samples, and AR was expressed in 64 of 70 (92%) samples. EGF was unexpressed in total cellular RNA in both tumor and uninvolved lung. In a comparison of RNA expression patterns in tumors and uninvolved lung, overexpression of EGFR was found in 45% (22 of 44) of tumors, while overexpression of TGF-alpha was seen in 61% (22 of 36) of tumors, and decreased expression of AR was seen in 63% (22 of 35) of tumors. Cell type and stage did not influence differential expression, indicating that this is a frequent event in primary NSCLC. Simultaneous overexpression of EGFR and TGF-alpha was seen in only 38% of tumors. Simultaneous overexpression of EGFR and decreased expression of AR were seen in only 21% of tumors. Thus far, the differential expression of EGFR, TGF-alpha, and AR does not correlate with either disease-free or overall survival. These findings indicate that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops. Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology.
Rusch
V
V
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Baselga
J
J
Cordon-Cardo
C
C
Orazem
J
J
Zaman
M
M
Hoda
S
S
McIntosh
J
J
Kurie
J
J
Dmitrovsky
E
E
D000230:Adenocarcinoma / Q000737:chemistry / Q000601:surgery / Q000648:ultrastructure; D000328:Adult; D000368:Aged; D066258:Amphiregulin; D015152:Blotting, Northern; D002289:Carcinoma, Non-Small-Cell Lung / Q000601:surgery / Q000648:ultrastructure*; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression / Q000235:genetics; D006023:Glycoproteins / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008168:Lung / Q000737:chemistry / Q000648:ultrastructure*; D008175:Lung Neoplasms / Q000737:chemistry / Q000601:surgery / Q000648:ultrastructure*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D012313:RNA / Q000032:analysis / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000502:physiology; D015291:Transforming Growth Factors / Q000502:physiology
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D016211:Transforming Growth Factor alpha; D012313:RNA; D015291:Transforming Growth Factors; D066246:ErbB Receptors