Differential chemokine, chemokine receptor, cytokine and cytokine receptor expression in pulmonary adenocarcinoma: diffuse down-regulation is associated with immune evasion and brain metastasis.
Pulmonary adenocarcinoma is frequently associated with brain metastasis at some stage during the disease course. Host immunity, particularly T cell immunity, plays an important role in the clinicopathological features of carcinoma proliferation and metastasis. Cytokines and chemokines are members of a family of small secreted proteins. The relationships between the cytokines and cytokine receptor (R), and between chemokines and chemokine R are important determinants of selectivity in local immunity. RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) and Fas ligand (FasL) are present in neoplastic cells, induce apoptosis of NK/T cells, and play a role in immune evasion. To investigate differences in host immunity between pulmonary adenocarcinoma with and without brain metastasis, we performed gene expression profiling, using chemokine, chemokine R, cytokine and cytokine R DNA chips. In addition, to assess the extent of immune evasion, we examined the expression of RCAS and FasL. We studied five cases of pulmonary adenocarcinoma with brain metastasis (meta) and five cases without brain metastasis (non-meta). The brain meta cases exhibited diffuse down-regulated profiles, in comparison with normal non-carcinomatous lungs, which were used as controls. Non-meta cases also displayed diffuse down-regulation, however the degree was variable. Expression of RCAS and FasL was detected in almost all cases, but was stronger in meta than non-meta cases. Our findings suggested that tumor cells evaded host immunity. In the gene tree analysis, brain meta cases and non-meta cases exhibited distinct clustering. Brain meta cases exhibited significantly lower expression of interleukin 13 receptor alpha2 (IL-13Ralpha2) than non-meta cases. The reduction of IL-13Ralpha2 expression was confirmed by RT-PCR. Immunohistochemically, non-meta adenocarcinoma cells frequently expressed IL-13Ralpha2, however, IL-13Ralpha2 expression was rare or weak in adenocarcinomas with meta. Our results suggested that, in addition to immune evasion, the characteristics of the adenocarcinoma tumors themselves were important for brain metastasis. However, our study demonstrated the enormous potential of gene expression profiling in clarifying the pathogenesis of brain metastasis in pulmonary adenocarcinoma.
Ohshima
Koichi
K
Department of Pathology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan. ohshima@fukuoka-u.ac.jp
Hamasaki
Makoto
M
Makimoto
Yoshifumi
Y
Yoneda
Satoshi
S
Fujii
Akira
A
Takamatsu
Yasushi
Y
Nakashima
Manabu
M
Watanabe
Takeshi
T
Kawahara
Katunobu
K
Kikuchi
Masahiro
M
Shirakusa
Takayuki
T
D000230:Adenocarcinoma / Q000378:metabolism*; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000556:secondary*; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D005810:Multigene Family; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D018121:Receptors, Cytokine / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000951:Antigens, Neoplasm; D018925:Chemokines; D016207:Cytokines; C120762:EBAG9 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D004247:DNA