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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

Immunohistochemical detection of CD31-expressing angiogenic endothelial cells in portal-type (pushing growth pattern) (a) and sinusoidal-type (replacement growth pattern) (c) hepatic metastases from intrasplenically-injected head and neck squamous cell murine PAN-LY2 carcinoma cells. Immunohistochemical staining for smooth muscle alpha actin expression of serial tissue sections from the same livers (b and d). Notice the co-localization of CD31 and smooth muscle alpha actin expressing cells in both kinds of hepatic metastases. Bar: 150 μm. e High-magnification confocal microscopic image on intrametastatic neo-angiogenic vessels. CD31-expressing endothelial cells (green-stained) were surrounded by smooth muscle alpha actin-expressing vascular coverage cells (red stained). Bar: 20 μm
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Fig8: Immunohistochemical detection of CD31-expressing angiogenic endothelial cells in portal-type (pushing growth pattern) (a) and sinusoidal-type (replacement growth pattern) (c) hepatic metastases from intrasplenically-injected head and neck squamous cell murine PAN-LY2 carcinoma cells. Immunohistochemical staining for smooth muscle alpha actin expression of serial tissue sections from the same livers (b and d). Notice the co-localization of CD31 and smooth muscle alpha actin expressing cells in both kinds of hepatic metastases. Bar: 150 μm. e High-magnification confocal microscopic image on intrametastatic neo-angiogenic vessels. CD31-expressing endothelial cells (green-stained) were surrounded by smooth muscle alpha actin-expressing vascular coverage cells (red stained). Bar: 20 μm

Mentions: As above reported, infiltration of tumor-activated myofibroblasts precedes endothelial cell recruitment into avascular micrometastases. Endothelial cell migration only occurred towards avascular micrometastases containing a high density of myofibroblasts and not towards metastases not containing myofibroblasts (Fig. 8). Both myofibroblasts and endothelial cells co-localized, and their densities consistently correlated with the development of well-vascularized metastases [80]. Because hypoxic tissue has been identified as a potential source of angiogenic factors within the tumor, we analyzed the effect of hypoxia on myofibroblast production of angiogenic-stimulating factors. As confirmed by pimonidazole staining, hypoxia occurred in hepatic metastases of greater than 300 μm in diameter. However, onset of myofibroblast recruitment occurred in normoxic avascular micrometastases, whereas new intratumoral capillaries are constituted once micrometastases become hypoxic. In vitro, we [76] reported that hypoxia contributes to hepatic stellate cell production of VEGF, which in turn increases endothelial cell migration, reduction of apoptosis, and proliferation. Using an experimental model of liver cirrhosis, Corpechot et al. [81] also reported VEGF production by hypoxic hepatic stellate cell. Thus, their recruitment under normoxic conditions, followed by tumor growth-associated hypoxia, may constitute two synergistic stimuli for intratumoral migration and survival of endothelial cells during tumor blood vessel formation. Interestingly, endothelial cell recruitment also follows the penetration of hepatic stellate cells into hepatocyte clusters of regenerating liver [82]. This physiologic mechanism of tissue reconstitution may also account for the recruitment of endothelial cells into micrometastases containing activated hepatic stellate cells. Therefore, tumor-activated hepatic stellate cells may promote blood delivery to liver metastasis by triggering the onset of angiogenesis in avascular micrometastases and, then, by supporting their progressive vascularization. Not surprisingly, hepatic stellate cells exhibit pericyte-like functions [83] and their activation into a myofibroblast-like phenotype is involved in several hepatic disease processes associated to chronic and acute liver injury [84].Fig. 8


The prometastatic microenvironment of the liver.

Vidal-Vanaclocha F - Cancer Microenviron (2008)

Immunohistochemical detection of CD31-expressing angiogenic endothelial cells in portal-type (pushing growth pattern) (a) and sinusoidal-type (replacement growth pattern) (c) hepatic metastases from intrasplenically-injected head and neck squamous cell murine PAN-LY2 carcinoma cells. Immunohistochemical staining for smooth muscle alpha actin expression of serial tissue sections from the same livers (b and d). Notice the co-localization of CD31 and smooth muscle alpha actin expressing cells in both kinds of hepatic metastases. Bar: 150 μm. e High-magnification confocal microscopic image on intrametastatic neo-angiogenic vessels. CD31-expressing endothelial cells (green-stained) were surrounded by smooth muscle alpha actin-expressing vascular coverage cells (red stained). Bar: 20 μm
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Related In: Results  -  Collection

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

Fig8: Immunohistochemical detection of CD31-expressing angiogenic endothelial cells in portal-type (pushing growth pattern) (a) and sinusoidal-type (replacement growth pattern) (c) hepatic metastases from intrasplenically-injected head and neck squamous cell murine PAN-LY2 carcinoma cells. Immunohistochemical staining for smooth muscle alpha actin expression of serial tissue sections from the same livers (b and d). Notice the co-localization of CD31 and smooth muscle alpha actin expressing cells in both kinds of hepatic metastases. Bar: 150 μm. e High-magnification confocal microscopic image on intrametastatic neo-angiogenic vessels. CD31-expressing endothelial cells (green-stained) were surrounded by smooth muscle alpha actin-expressing vascular coverage cells (red stained). Bar: 20 μm
Mentions: As above reported, infiltration of tumor-activated myofibroblasts precedes endothelial cell recruitment into avascular micrometastases. Endothelial cell migration only occurred towards avascular micrometastases containing a high density of myofibroblasts and not towards metastases not containing myofibroblasts (Fig. 8). Both myofibroblasts and endothelial cells co-localized, and their densities consistently correlated with the development of well-vascularized metastases [80]. Because hypoxic tissue has been identified as a potential source of angiogenic factors within the tumor, we analyzed the effect of hypoxia on myofibroblast production of angiogenic-stimulating factors. As confirmed by pimonidazole staining, hypoxia occurred in hepatic metastases of greater than 300 μm in diameter. However, onset of myofibroblast recruitment occurred in normoxic avascular micrometastases, whereas new intratumoral capillaries are constituted once micrometastases become hypoxic. In vitro, we [76] reported that hypoxia contributes to hepatic stellate cell production of VEGF, which in turn increases endothelial cell migration, reduction of apoptosis, and proliferation. Using an experimental model of liver cirrhosis, Corpechot et al. [81] also reported VEGF production by hypoxic hepatic stellate cell. Thus, their recruitment under normoxic conditions, followed by tumor growth-associated hypoxia, may constitute two synergistic stimuli for intratumoral migration and survival of endothelial cells during tumor blood vessel formation. Interestingly, endothelial cell recruitment also follows the penetration of hepatic stellate cells into hepatocyte clusters of regenerating liver [82]. This physiologic mechanism of tissue reconstitution may also account for the recruitment of endothelial cells into micrometastases containing activated hepatic stellate cells. Therefore, tumor-activated hepatic stellate cells may promote blood delivery to liver metastasis by triggering the onset of angiogenesis in avascular micrometastases and, then, by supporting their progressive vascularization. Not surprisingly, hepatic stellate cells exhibit pericyte-like functions [83] and their activation into a myofibroblast-like phenotype is involved in several hepatic disease processes associated to chronic and acute liver injury [84].Fig. 8

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