Hepatic expression of ANG2 RNA in metastatic colorectal cancer.
We examined the RNA content of the gene encoding angiopoietin (Ang)-2, a modifier of angiogenesis, in hepatic metastases of colorectal cancer (CRC) to explore the role of this protein in neovascularization of metastatic foci. Metastatic CRC exhibited notable blood flow and tumor vessel formation at tumor frontiers. Reverse-transcription polymerase chain reaction assays indicated that the ANG2 RNA content was greater in metastatic CRC than in primary CRC. Investigation of metastatic foci using laser capture microdissection revealed that the RNA content of ANG2, but not ANG1, increased from the bordering liver region to the periphery of the metastatic disease, and also from the periphery to the intermediate portion of the metastatic lesion; immunohistochemical analysis confirmed that there was a corresponding gradual increase in Ang-2 protein expression. Tie-2, a receptor for angiopoietins, was preferentially expressed in the bordering liver region rather than in metastatic CRC. Vascular endothelial growth factor (VEGF) also exhibited an expression pattern similar to that of Ang-2, and there was a significant correlation between the RNA content of ANG2 and that of VEGF in dissected samples (P =.002). Western blot analysis suggested that expression of Ang-1, Ang-2, Tie-2, and VEGF may be regulated at a transcriptional level. The increase in ANG2 RNA content from the peripheral portion of the tumor to the intermediate portion, coinciding with the decrease in recruitment of periendothelial supporting cells around the vascular endothelial cells, suggests that Ang-2 may play a role in the immaturity of tumor vessels. In conclusion, the current study suggests that Ang-2 and VEGF may cooperate to enhance the formation of new blood vessels in metastases of CRC to the liver.
Ogawa
Minoru
M
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Yamamoto
Hirofumi
H
Nagano
Hiroaki
H
Miyake
Yasuhiro
Y
Sugita
Yurika
Y
Hata
Taishi
T
Kim
Byung-No
BN
Ngan
Chew Yee
CY
Damdinsuren
Bazarragchaa
B
Ikenaga
Masakazu
M
Ikeda
Masataka
M
Ohue
Masayuki
M
Nakamori
Shoji
S
Sekimoto
Mitsugu
M
Sakon
Masato
M
Matsuura
Nariaki
N
Monden
Morito
M
D042683:Angiopoietin-1 / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000502:physiology; D008113:Liver Neoplasms / Q000098:blood supply* / Q000503:physiopathology / Q000556:secondary*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D042787:Receptor, TIE-2 / Q000235:genetics; D014057:Tomography, X-Ray Computed; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2