Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations.
The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors. To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined. Advanced tumor stages (p<0.001), negative TTF-1 expression (p<0.001) and Akt activation (p=0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p=0.021), invasiveness (p=0.004), and not to mutations. TTF-1 expression associated with never-smoker (p=0.013), pre- or minimally invasiveness (p<0.001) and EGFR mutations (p=0.017) as well as with pERK (p=0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p=0.009). In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells.
Hiramatsu
Miyako
M
Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Ninomiya
Hironori
H
Inamura
Kentaro
K
Nomura
Kimie
K
Takeuchi
Kengo
K
Satoh
Yukitoshi
Y
Okumura
Sakae
S
Nakagawa
Ken
K
Yamori
Takao
T
Matsuura
Masaaki
M
Morikawa
Toshiaki
T
Ishikawa
Yuichi
Y
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018773:Genes, erbB-1; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins