Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1.
OBJECTIVE
Recent studies of cancer metastasis have focused on the role of premetastatic gene expression and circulating tumor cells. We did a blind prospective study in gastric cancer to assess the significance of isolated tumor cells (ITC) and to test the hypothesis that vascular endothelial growth factor receptor-1 (VEGFR-1) is expressed within the bone marrow at tumor-specific, premetastatic sites.


METHODS
Both bone marrow and peripheral blood samples from 810 gastric cancer patients were collected at the Central Hospital, National Cancer Center (Tokyo, Japan). The samples were transferred to Kyushu University Hospital (Beppu, Japan) where they were analyzed by quantitative real-time reverse transcription-PCR for three epithelial cell markers, carcinoembryonic antigen, cytokeratin-19, and cytokeratin-7, as well as VEGFR-1.


RESULTS
ITCs were observed in peripheral blood and bone marrow even in early stages of gastric cancer. The frequency of ITC in bone marrow was significantly associated with the stage of disease by ANOVA (P < 0.01). Gastric cancer metastasized when ITCs were observed in the presence of VEGFR-1. In the 380 patients who were ITC negative and showed low VEGFR-1 expression, synchronous (at the time of surgery) and heterochronous (recurrent) metastases were not observed.


CONCLUSIONS
ITCs circulate even in early stages of disease. Furthermore, elevated expression of VEGFR-1 facilitates the establishment of hematogenous metastases in gastric cancer. This study indicates that the simultaneous presence of ITC and VEGFR-1 expression at premetastatic sites is clinically significant for disease progression.
Mimori
Koshi
K
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Fukagawa
Takeo
T
Kosaka
Yoshimasa
Y
Kita
Yoshiaki
Y
Ishikawa
Kenji
K
Etoh
Tsuyoshi
T
Iinuma
Hisae
H
Sasako
Mitsuru
M
Mori
Masaki
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D005260:Female; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
D002272:Carcinoembryonic Antigen; D053539:Keratin-19; D053552:Keratin-7; D040281:Vascular Endothelial Growth Factor Receptor-1