Skip to main content
Journal cover image

Effect of host microenvironment on the microcirculation of human colon adenocarcinoma.

Publication ,  Journal Article
Fukumura, D; Yuan, F; Monsky, WL; Chen, Y; Jain, RK
Published in: The American journal of pathology
September 1997

It is generally accepted that the host microenvironment influences tumor biology. There are discrepancies in growth rate, metastatic potential, and efficacy of systemic treatment between ectopic and orthotopic tumors. Liver is the most common and critical site of distant metastasis of colorectal carcinoma. Tumorigenicity and efficacy of chemotherapeutic agents in colorectal tumors are different in liver and subcutaneous sites. Thus, we hypothesize that the liver (orthotopic) versus subcutaneous (ectopic) microenvironment would have different effects on the angiogenesis and maintenance of the microcirculation of colorectal tumor. To this end, we developed a new method to monitor and to quantify microcirculatory parameters in the tumor grown in the liver. Using this approach, we compared the microcirculation of LS174T, a human colon adenocarcinoma, metastasized to the liver with that of the host liver vessels and that of the same tumor grown in the subcutaneous space. In the liver metastasis model, 5 x 10(6) LS174T cells were injected into the spleen of nude mice. Four to eight weeks later, the liver with metastatic tumors was exteriorized and placed on a special stage and observed under an intravital fluorescence microscope. The dorsal skinfold chamber model was used to study the subcutaneous tumors. Red blood cell velocity, vessel diameter, density, permeability, and leukocyte-endothelial interactions were measured using fluorescence microscopy and image analysis. Vascular endothelial growth factor/ vascular permeability factor (VEGF/VPF) mRNA expression was determined by the Northern blot analysis. LS174T tumor foci in the liver had tortuous vascular architecture, heterogeneous blood flow, significantly lower vascular density, and significantly higher vascular permeability than normal liver tissue. Tumors grown in the liver had significantly lower vessel density, especially in the center coincident with central necrosis, than the subcutaneous tumors. The frequency distribution of vessel diameters of liver tumor was slightly shifted to smaller size compared with that of subcutaneous tumor. Leukocyte rolling in liver tumor was twofold lower than that in subcutaneous tumor. These physiological findings were consistent with the measurement of VEGF/VPF in that the VEGF/VPF mRNA level was lower in the liver tumor than that in the subcutaneous tumor. However, macromolecular vascular permeability in the liver tumor was significantly higher than in the subcutaneous tumor. Liver sinusoidal endothelial cells, the origin of liver tumor vessel endothelium, are known to be fenestrated and not to have a basement membrane, suggesting that the difference in endothelial cell origin may explain the difference in tumor vascular permeability in two sites. These findings demonstrate that liver microenvironment has different effects on some aspects of the tumor angiogenesis and microcirculation compared with the subcutaneous tissues. The new model/method described in this paper has significant implications in two research areas: 1) the liver microenvironment and its effect on tumor pathophysiology in conjunction with cytokine/ growth factor regulation and 2) the delivery of drugs, cells, and genes to liver tumors.

Duke Scholars

Published In

The American journal of pathology

EISSN

1525-2191

ISSN

0002-9440

Publication Date

September 1997

Volume

151

Issue

3

Start / End Page

679 / 688

Related Subject Headings

  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor A
  • Tumor Cells, Cultured
  • RNA, Messenger
  • Pathology
  • Neoplasm Transplantation
  • Microcirculation
  • Mice, SCID
  • Mice, Nude
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Fukumura, D., Yuan, F., Monsky, W. L., Chen, Y., & Jain, R. K. (1997). Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. The American Journal of Pathology, 151(3), 679–688.
Fukumura, D., F. Yuan, W. L. Monsky, Y. Chen, and R. K. Jain. “Effect of host microenvironment on the microcirculation of human colon adenocarcinoma.The American Journal of Pathology 151, no. 3 (September 1997): 679–88.
Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. The American journal of pathology. 1997 Sep;151(3):679–88.
Fukumura, D., et al. “Effect of host microenvironment on the microcirculation of human colon adenocarcinoma.The American Journal of Pathology, vol. 151, no. 3, Sept. 1997, pp. 679–88.
Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. The American journal of pathology. 1997 Sep;151(3):679–688.
Journal cover image

Published In

The American journal of pathology

EISSN

1525-2191

ISSN

0002-9440

Publication Date

September 1997

Volume

151

Issue

3

Start / End Page

679 / 688

Related Subject Headings

  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor A
  • Tumor Cells, Cultured
  • RNA, Messenger
  • Pathology
  • Neoplasm Transplantation
  • Microcirculation
  • Mice, SCID
  • Mice, Nude
  • Mice