Limits...
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

a Avascular micrometastasis (arrows) developed in the sinusoidal domain of an hepatic lobule, surrounded by tumor-activated hepatic stellate cells expressing smooth muscle alpha actin (red stained cells). Terminal portal venule (TPV). Hepatocytes (H). Bar: 25 μm. b Sinusoidal-type hepatic micrometastasis (MET) at the angiogenic phase, containing a dense network of sinusoidal neovessels, as revealed by reticulin stain according to Gordon–Sweets silver impregnation technique. Recruited microvessels form concentric interconnections. Liver architecture is not disturbed, and cancer cells co-opt the supportive fibrilar network of the sinusoids. Bar: 100 μm. c Avascular micrometastasis (arrows) developed in close proximity to a terminal portal vein (TPV) and surrounded by portal tract-derived cells expressing smooth muscle alpha actin (red stained cells). Bar: 25 μm. d Portal-type micrometastasis (MET) at the angiogenic phase. Here, the reticulin network supporting intratumoral angiogenesis is not conserved. Desmoplastic stroma surrounds and traverses metastasis, facilitating invasion of vascular-type angiogenic vessels. Necrotic areas frequently develop in this metastasis type. Bar: 100 μm
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Fig9: a Avascular micrometastasis (arrows) developed in the sinusoidal domain of an hepatic lobule, surrounded by tumor-activated hepatic stellate cells expressing smooth muscle alpha actin (red stained cells). Terminal portal venule (TPV). Hepatocytes (H). Bar: 25 μm. b Sinusoidal-type hepatic micrometastasis (MET) at the angiogenic phase, containing a dense network of sinusoidal neovessels, as revealed by reticulin stain according to Gordon–Sweets silver impregnation technique. Recruited microvessels form concentric interconnections. Liver architecture is not disturbed, and cancer cells co-opt the supportive fibrilar network of the sinusoids. Bar: 100 μm. c Avascular micrometastasis (arrows) developed in close proximity to a terminal portal vein (TPV) and surrounded by portal tract-derived cells expressing smooth muscle alpha actin (red stained cells). Bar: 25 μm. d Portal-type micrometastasis (MET) at the angiogenic phase. Here, the reticulin network supporting intratumoral angiogenesis is not conserved. Desmoplastic stroma surrounds and traverses metastasis, facilitating invasion of vascular-type angiogenic vessels. Necrotic areas frequently develop in this metastasis type. Bar: 100 μm

Mentions: Using several liver-metastasizing murine tumors (51b and C26 colon carcinoma, PAM squamous cell carcinomas and B16 melanoma), we also recognized two predominant stromal patterns (Fig. 9), according to expression of alpha-smooth muscle actin by intrametastatic myofibroblast-like cells [87]: sinusoid-associated metastases, which contained infiltrating, but not encapsulating, reticularly-arranged myofibroblasts; and portal tract-associated metastases, which were incompletely encapsulated, but not infiltrated, by fibrous tract-arranged myofibroblasts. Based on reticulin staining, the liver architecture was preserved in myofibroblast-infiltrated metastases because invasive cancer cells co-opted the supportive fibrillar network of sinusoids, and, thus, the limit between tumor and normal tissue was ill-defined (equivalent to replacement-type). In contrast, the reticulin network was not conserved within myofibroblast-encapsulated metastases, because the enlarging mass of cancer cells compressed surrounding parenchyma (pushing-type) and generated the formation of tumor lobules delineated by desmoplastic stroma (desmoplastic-type).Fig. 9


The prometastatic microenvironment of the liver.

Vidal-Vanaclocha F - Cancer Microenviron (2008)

a Avascular micrometastasis (arrows) developed in the sinusoidal domain of an hepatic lobule, surrounded by tumor-activated hepatic stellate cells expressing smooth muscle alpha actin (red stained cells). Terminal portal venule (TPV). Hepatocytes (H). Bar: 25 μm. b Sinusoidal-type hepatic micrometastasis (MET) at the angiogenic phase, containing a dense network of sinusoidal neovessels, as revealed by reticulin stain according to Gordon–Sweets silver impregnation technique. Recruited microvessels form concentric interconnections. Liver architecture is not disturbed, and cancer cells co-opt the supportive fibrilar network of the sinusoids. Bar: 100 μm. c Avascular micrometastasis (arrows) developed in close proximity to a terminal portal vein (TPV) and surrounded by portal tract-derived cells expressing smooth muscle alpha actin (red stained cells). Bar: 25 μm. d Portal-type micrometastasis (MET) at the angiogenic phase. Here, the reticulin network supporting intratumoral angiogenesis is not conserved. Desmoplastic stroma surrounds and traverses metastasis, facilitating invasion of vascular-type angiogenic vessels. Necrotic areas frequently develop in this metastasis type. Bar: 100 μm
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Related In: Results  -  Collection

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Fig9: a Avascular micrometastasis (arrows) developed in the sinusoidal domain of an hepatic lobule, surrounded by tumor-activated hepatic stellate cells expressing smooth muscle alpha actin (red stained cells). Terminal portal venule (TPV). Hepatocytes (H). Bar: 25 μm. b Sinusoidal-type hepatic micrometastasis (MET) at the angiogenic phase, containing a dense network of sinusoidal neovessels, as revealed by reticulin stain according to Gordon–Sweets silver impregnation technique. Recruited microvessels form concentric interconnections. Liver architecture is not disturbed, and cancer cells co-opt the supportive fibrilar network of the sinusoids. Bar: 100 μm. c Avascular micrometastasis (arrows) developed in close proximity to a terminal portal vein (TPV) and surrounded by portal tract-derived cells expressing smooth muscle alpha actin (red stained cells). Bar: 25 μm. d Portal-type micrometastasis (MET) at the angiogenic phase. Here, the reticulin network supporting intratumoral angiogenesis is not conserved. Desmoplastic stroma surrounds and traverses metastasis, facilitating invasion of vascular-type angiogenic vessels. Necrotic areas frequently develop in this metastasis type. Bar: 100 μm
Mentions: Using several liver-metastasizing murine tumors (51b and C26 colon carcinoma, PAM squamous cell carcinomas and B16 melanoma), we also recognized two predominant stromal patterns (Fig. 9), according to expression of alpha-smooth muscle actin by intrametastatic myofibroblast-like cells [87]: sinusoid-associated metastases, which contained infiltrating, but not encapsulating, reticularly-arranged myofibroblasts; and portal tract-associated metastases, which were incompletely encapsulated, but not infiltrated, by fibrous tract-arranged myofibroblasts. Based on reticulin staining, the liver architecture was preserved in myofibroblast-infiltrated metastases because invasive cancer cells co-opted the supportive fibrillar network of sinusoids, and, thus, the limit between tumor and normal tissue was ill-defined (equivalent to replacement-type). In contrast, the reticulin network was not conserved within myofibroblast-encapsulated metastases, because the enlarging mass of cancer cells compressed surrounding parenchyma (pushing-type) and generated the formation of tumor lobules delineated by desmoplastic stroma (desmoplastic-type).Fig. 9

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