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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

Light microscopic image of hepatic tissue. a Parenchymal cell heterogeneity across the hepatic lobule, as shown by immunohistochemical staining of nerve growth factor-expressing hepatocytes. Bar: 100 μm. b Periportal micrometastases (arrows) from intrasplenically-injected B16F10 melanoma cells. Terminal portal veins (TPV) and centrilobular veins (CLV). Bar: 100 μm
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Fig5: Light microscopic image of hepatic tissue. a Parenchymal cell heterogeneity across the hepatic lobule, as shown by immunohistochemical staining of nerve growth factor-expressing hepatocytes. Bar: 100 μm. b Periportal micrometastases (arrows) from intrasplenically-injected B16F10 melanoma cells. Terminal portal veins (TPV) and centrilobular veins (CLV). Bar: 100 μm

Mentions: Liver zonation is characterized by phenotypic variations of hepatocytes and sinusoidal cells along the length of the sinusoid from the portal vein to the central vein (Fig. 5a). Oxygen tension, which decreases by about 50% from the periportal to the perivenous regions, has been considered to be a key regulator for zonated gene expression [66]. Gradients of metabolic substrates, hormones, and extracellular matrix are thought to be other important regulators of these zonal variations. These environmental variations have implications for liver inflammation, fibrosis, aging, regeneration and infection [67].Fig. 5


The prometastatic microenvironment of the liver.

Vidal-Vanaclocha F - Cancer Microenviron (2008)

Light microscopic image of hepatic tissue. a Parenchymal cell heterogeneity across the hepatic lobule, as shown by immunohistochemical staining of nerve growth factor-expressing hepatocytes. Bar: 100 μm. b Periportal micrometastases (arrows) from intrasplenically-injected B16F10 melanoma cells. Terminal portal veins (TPV) and centrilobular veins (CLV). Bar: 100 μm
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654354&req=5

Fig5: Light microscopic image of hepatic tissue. a Parenchymal cell heterogeneity across the hepatic lobule, as shown by immunohistochemical staining of nerve growth factor-expressing hepatocytes. Bar: 100 μm. b Periportal micrometastases (arrows) from intrasplenically-injected B16F10 melanoma cells. Terminal portal veins (TPV) and centrilobular veins (CLV). Bar: 100 μm
Mentions: Liver zonation is characterized by phenotypic variations of hepatocytes and sinusoidal cells along the length of the sinusoid from the portal vein to the central vein (Fig. 5a). Oxygen tension, which decreases by about 50% from the periportal to the perivenous regions, has been considered to be a key regulator for zonated gene expression [66]. Gradients of metabolic substrates, hormones, and extracellular matrix are thought to be other important regulators of these zonal variations. These environmental variations have implications for liver inflammation, fibrosis, aging, regeneration and infection [67].Fig. 5

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