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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

Scanning electron microscopic images on the intrahepatic pathway of metastatic cancer cells. a Cross section of a 9-μm in diameter hepatic sinusoid (S), lined by the fenestrated sinusoidal endothelium (E), and surrounded by hepatocytes (H), bar: 5 μm. b An intrasinusoidal Kupffer cell occupying the sinusoidal lumen and connected to the endothelial wall by filopodia and a long citoplasmic prolongation (arrows), bar: 5 μm. c Fenestrated surface of the hepatic sinusoidal endothelium. Under physiological conditions, endothelial fenestrae are transcellular structures of 100–150 nm in diameter that cluster forming highly filtrating microdomains named sieve plates, bar: 1 μm. d Mouse liver tissue on the fifth day post-intrasplenic injection of Lewis lung carcinoma cells. Circulating cancer cells first interact with non-fenestrated endothelial cells and adhered leukocytes and macrophages at perilobular terminal portal veins (TPV). Pre-sinusoidal gates for intralobular access of cancer cells (S). Intrasinusoidal retention of cancer cells (arrows) within the periportal area of the hepatic lobule. Surrounding hepatocytes (H) and endothelial cells (E) lining sinusoids (S). Bar: 10 μm
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Fig2: Scanning electron microscopic images on the intrahepatic pathway of metastatic cancer cells. a Cross section of a 9-μm in diameter hepatic sinusoid (S), lined by the fenestrated sinusoidal endothelium (E), and surrounded by hepatocytes (H), bar: 5 μm. b An intrasinusoidal Kupffer cell occupying the sinusoidal lumen and connected to the endothelial wall by filopodia and a long citoplasmic prolongation (arrows), bar: 5 μm. c Fenestrated surface of the hepatic sinusoidal endothelium. Under physiological conditions, endothelial fenestrae are transcellular structures of 100–150 nm in diameter that cluster forming highly filtrating microdomains named sieve plates, bar: 1 μm. d Mouse liver tissue on the fifth day post-intrasplenic injection of Lewis lung carcinoma cells. Circulating cancer cells first interact with non-fenestrated endothelial cells and adhered leukocytes and macrophages at perilobular terminal portal veins (TPV). Pre-sinusoidal gates for intralobular access of cancer cells (S). Intrasinusoidal retention of cancer cells (arrows) within the periportal area of the hepatic lobule. Surrounding hepatocytes (H) and endothelial cells (E) lining sinusoids (S). Bar: 10 μm

Mentions: On the other hand, the microenvironment of the liver is biologically unique (Fig. 2a–c). First of all, fenestrated endothelial cells and organ-specific macrophages (Kupffer cells) lining hepatic sinusoids constitutively express a rich profile of surface oligosaccharides [7], cell adhesion proteins [8], and recognition receptors for a variety of pathogen-associated molecular patterns [9], and are endowed with very efficient receptor-mediated endocytotic mechanisms [10]. These properties are cytokine-inducible [11, 12] and account for the efficient hepatic uptake and clearance of circulating waste molecules, death cells, microorganisms, and even cancer cells. Second, the liver also contains a large resident population of activated defense cells—including macrophages [13], dendritic cells [14], mast cells [15], cytotoxic natural killer (NK) cells and T lymphocytes [16]—that provide an enhanced innate immune response, while are maintaining a tolerogenic state to avoid chronic inflammation [17, 18]. In turn, hepatic immune tolerance may be responsible for the increased prevalence of autoimmunity, infectious diseases and malignancies, because the hepatic territory does not significantly object the implantation and growth of microorganisms—as for example malaria sporozoites [19], fungi [20], progenitor hematopoietic cells [21], and even cancer cells. Third, the liver contains a heterogeneous population of parenchyma cells—hepatocytes and cholangiocytes—and non-parenchymal stromal cells—mainly portal fibroblasts and perisinusoidal stellate cells— [22, 23]. These cells can contribute to intratumoral stroma and blood vessel generation in response to tumor-derived factors, providing a favorable milieu for the survival and growth of cancer cells from outside the liver.Fig. 2


The prometastatic microenvironment of the liver.

Vidal-Vanaclocha F - Cancer Microenviron (2008)

Scanning electron microscopic images on the intrahepatic pathway of metastatic cancer cells. a Cross section of a 9-μm in diameter hepatic sinusoid (S), lined by the fenestrated sinusoidal endothelium (E), and surrounded by hepatocytes (H), bar: 5 μm. b An intrasinusoidal Kupffer cell occupying the sinusoidal lumen and connected to the endothelial wall by filopodia and a long citoplasmic prolongation (arrows), bar: 5 μm. c Fenestrated surface of the hepatic sinusoidal endothelium. Under physiological conditions, endothelial fenestrae are transcellular structures of 100–150 nm in diameter that cluster forming highly filtrating microdomains named sieve plates, bar: 1 μm. d Mouse liver tissue on the fifth day post-intrasplenic injection of Lewis lung carcinoma cells. Circulating cancer cells first interact with non-fenestrated endothelial cells and adhered leukocytes and macrophages at perilobular terminal portal veins (TPV). Pre-sinusoidal gates for intralobular access of cancer cells (S). Intrasinusoidal retention of cancer cells (arrows) within the periportal area of the hepatic lobule. Surrounding hepatocytes (H) and endothelial cells (E) lining sinusoids (S). Bar: 10 μm
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Fig2: Scanning electron microscopic images on the intrahepatic pathway of metastatic cancer cells. a Cross section of a 9-μm in diameter hepatic sinusoid (S), lined by the fenestrated sinusoidal endothelium (E), and surrounded by hepatocytes (H), bar: 5 μm. b An intrasinusoidal Kupffer cell occupying the sinusoidal lumen and connected to the endothelial wall by filopodia and a long citoplasmic prolongation (arrows), bar: 5 μm. c Fenestrated surface of the hepatic sinusoidal endothelium. Under physiological conditions, endothelial fenestrae are transcellular structures of 100–150 nm in diameter that cluster forming highly filtrating microdomains named sieve plates, bar: 1 μm. d Mouse liver tissue on the fifth day post-intrasplenic injection of Lewis lung carcinoma cells. Circulating cancer cells first interact with non-fenestrated endothelial cells and adhered leukocytes and macrophages at perilobular terminal portal veins (TPV). Pre-sinusoidal gates for intralobular access of cancer cells (S). Intrasinusoidal retention of cancer cells (arrows) within the periportal area of the hepatic lobule. Surrounding hepatocytes (H) and endothelial cells (E) lining sinusoids (S). Bar: 10 μm
Mentions: On the other hand, the microenvironment of the liver is biologically unique (Fig. 2a–c). First of all, fenestrated endothelial cells and organ-specific macrophages (Kupffer cells) lining hepatic sinusoids constitutively express a rich profile of surface oligosaccharides [7], cell adhesion proteins [8], and recognition receptors for a variety of pathogen-associated molecular patterns [9], and are endowed with very efficient receptor-mediated endocytotic mechanisms [10]. These properties are cytokine-inducible [11, 12] and account for the efficient hepatic uptake and clearance of circulating waste molecules, death cells, microorganisms, and even cancer cells. Second, the liver also contains a large resident population of activated defense cells—including macrophages [13], dendritic cells [14], mast cells [15], cytotoxic natural killer (NK) cells and T lymphocytes [16]—that provide an enhanced innate immune response, while are maintaining a tolerogenic state to avoid chronic inflammation [17, 18]. In turn, hepatic immune tolerance may be responsible for the increased prevalence of autoimmunity, infectious diseases and malignancies, because the hepatic territory does not significantly object the implantation and growth of microorganisms—as for example malaria sporozoites [19], fungi [20], progenitor hematopoietic cells [21], and even cancer cells. Third, the liver contains a heterogeneous population of parenchyma cells—hepatocytes and cholangiocytes—and non-parenchymal stromal cells—mainly portal fibroblasts and perisinusoidal stellate cells— [22, 23]. These cells can contribute to intratumoral stroma and blood vessel generation in response to tumor-derived factors, providing a favorable milieu for the survival and growth of cancer cells from outside the liver.Fig. 2

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