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The prometastatic microenvironment of the liver.

Vidal-Vanaclocha F - Cancer Microenviron (2008)

Bottom Line: Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases.Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes.Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, Bizkaia, Spain. fernando.vidal@ehu.es

ABSTRACT
The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients.

No MeSH data available.


Related in: MedlinePlus

Tumor-induced proinflammatory factors regulate melanoma cell adhesion to hepatic sinusoidal endothelium prior to metastasis formation
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Related In: Results  -  Collection


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Fig4: Tumor-induced proinflammatory factors regulate melanoma cell adhesion to hepatic sinusoidal endothelium prior to metastasis formation

Mentions: The experimental hepatic colonization of B16 melanoma cells supports the important prometastatic implications of inflammatory cytokine-dependent cancer-sinusoidal cell interactions. Using intrasplenically injected B16F10 melanoma cells, we showed that the expression of VCAM-1 significantly increased in hepatic sinusoidal endothelium cells within the first 24 h of metastatic cancer cell infiltration in the liver. In vivo VCAM-1 blockade with specific antibodies prior to B16 melanoma cell injection decreased microvascular retention of luciferase-transfected B16 melanoma cells by 85%, and metastasis development by 75%, indicating that VCAM-1 expression on tumor-activated hepatic sinusoidal endothelium cells had a prometastatic role [53]. Interestingly, in primary cultured hepatic sinusoidal endothelium cells treated with B16 melanoma-conditioned medium, a proinflammatory cytokine cascade occurred in which TNF-alpha induced IL-1beta; then, IL-1beta, either alone or with TNFalpha, induced IL-18 release [54]. Neither TNF-binding protein nor IL-1 receptor antagonist were able to inhibit the increase in adhesiveness in IL-18-treated hepatic sinusoidal endothelium cells, confirming that neither endogenous TNFalpha nor IL-1 mediated IL-18-induced endothelial cell adhesiveness. Conversely, IL-18 neutralization by using IL-18 binding protein [53] did not reduce tumor-induced TNF-alpha or IL-1beta release from endothelial cells, suggesting that their production was IL-18-independent. As such, TNFalpha and IL-1beta used the production of IL-18 to facilitate the increase in endothelial cell expression of VCAM-1 for arresting cancer cells during their transit through the hepatic microvasculature (Fig. 4).Fig. 4


The prometastatic microenvironment of the liver.

Vidal-Vanaclocha F - Cancer Microenviron (2008)

Tumor-induced proinflammatory factors regulate melanoma cell adhesion to hepatic sinusoidal endothelium prior to metastasis formation
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654354&req=5

Fig4: Tumor-induced proinflammatory factors regulate melanoma cell adhesion to hepatic sinusoidal endothelium prior to metastasis formation
Mentions: The experimental hepatic colonization of B16 melanoma cells supports the important prometastatic implications of inflammatory cytokine-dependent cancer-sinusoidal cell interactions. Using intrasplenically injected B16F10 melanoma cells, we showed that the expression of VCAM-1 significantly increased in hepatic sinusoidal endothelium cells within the first 24 h of metastatic cancer cell infiltration in the liver. In vivo VCAM-1 blockade with specific antibodies prior to B16 melanoma cell injection decreased microvascular retention of luciferase-transfected B16 melanoma cells by 85%, and metastasis development by 75%, indicating that VCAM-1 expression on tumor-activated hepatic sinusoidal endothelium cells had a prometastatic role [53]. Interestingly, in primary cultured hepatic sinusoidal endothelium cells treated with B16 melanoma-conditioned medium, a proinflammatory cytokine cascade occurred in which TNF-alpha induced IL-1beta; then, IL-1beta, either alone or with TNFalpha, induced IL-18 release [54]. Neither TNF-binding protein nor IL-1 receptor antagonist were able to inhibit the increase in adhesiveness in IL-18-treated hepatic sinusoidal endothelium cells, confirming that neither endogenous TNFalpha nor IL-1 mediated IL-18-induced endothelial cell adhesiveness. Conversely, IL-18 neutralization by using IL-18 binding protein [53] did not reduce tumor-induced TNF-alpha or IL-1beta release from endothelial cells, suggesting that their production was IL-18-independent. As such, TNFalpha and IL-1beta used the production of IL-18 to facilitate the increase in endothelial cell expression of VCAM-1 for arresting cancer cells during their transit through the hepatic microvasculature (Fig. 4).Fig. 4

Bottom Line: Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases.Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes.Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, Bizkaia, Spain. fernando.vidal@ehu.es

ABSTRACT
The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients.

No MeSH data available.


Related in: MedlinePlus