Mechanism of initial distribution of blood-borne colon carcinoma cells in the liver.
OBJECTIVE
The distribution characteristics of a human colon carcinoma cell line, KM12-HX cells, were examined. After intraportal vein (i.p.v.) or intravenous (i.v.) injection into rats, almost all the injected tumor cells are distributed to liver or lung, respectively, both after 30 s and 30 min. Our previous kinetic analysis of the fate of tumor cells revealed that the cumulative amount of tumor cells distributed in the liver is a factor determining the degree of metastasis. Thus, we examined the mechanism of initial efficient trapping of tumor cells by the liver in more detail.


RESULTS
Thirty minutes after tumor cells were injected into the left ventricle of the heart, the distribution of tumor cells was more restricted in several tissues (kidney, small intestine, large intestine and spleen), as compared with the distribution of microspheres undergoing 100% extraction, indicating that the first-pass extraction of KM12-HX cells is incomplete in these organs. The hepatic first-pass distribution of these tumor cells was unaffected by pretreatment of liposomes, such that the preinjected amount was sufficient to saturate the phagocytotic function of macrophages. Thus, the mechanism of initial distribution of the tumor cells to the liver is different from the mechanism of liposome uptake by macrophages. Considering that the diameter of microvessels in sinusoid and KM12-HX cells is approximately 7 and 12 microm, respectively, it is possible that these tumor cells are trapped physically in hepatic microvessels. In fact, after i.p.v. injection of microspheres 5 microm in diameter, only 20% of the dose was distributed to liver and the rest to other tissues. In contrast, almost 100% of microspheres 10 microm in diameter were distributed to the liver.


CONCLUSIONS
These results support the hypothesis that the initial organ distribution of blood-borne tumor cells is determined by mechanical and physical properties of the cells.
Mizuno
N
N
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Shirota
K
K
Izumi
Y
Y
Irimura
T
T
Harashima
H
H
Kiwada
H
H
Motoji
N
N
Shigematsu
A
A
Sugiyama
Y
Y
D000818:Animals; D003110:Colonic Neoplasms / Q000097:blood* / Q000473:pathology*; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008264:Macrophages / Q000502:physiology; D008297:Male; D008863:Microspheres; D008954:Models, Biological; D011169:Portal Vein; D051381:Rats; D017208:Rats, Wistar; D013936:Thymidine / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium; D014407:Tumor Cells, Cultured
D008081:Liposomes; D014316:Tritium; D013936:Thymidine