The Prometastatic Microenvironment of the Liver

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 antitumor hepatic defense and to take advantage of hepatic cellderived factors are key phenotypic properties of livermetastasizing 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.

Immunological aspect of the liver and metastatic uveal melanoma

“…Slow flow in the liver sinusoids maximizes the contact between hepatic cells and pathogenic molecules to filter them prior to circulation. The slow and tortuous sinusoidal blood flow can trap UM cells in the liver [13,14] .…”

“…Vascular cell adhesion molecule-1 (VCAM-1) is expressed on sinusoidal endothelial cells and might trap tumor cells in slow blood flow [13,25] . VCAM-1 is expressed on endothelial cells under inflammatory conditions, and mediate rolling and adhesion of various subsets of leukocytes as well as tumor cells for the recruitment and settlement of these cells from the blood stream.…”

Role of liver ICAM-1 in metastasis

“…The liver is the main target organ for metastatic CRC cells and the second most commonly invaded organ, after the lymph nodes (3). In fact, 15-25% of CRC patients present with synchronous hepatic metastases at the time of diagnosis, and a further 30% will later develop liver metastasis (4,5).…”

IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

“…Moreover, the role of IQGAP1 in myofibroblastic activation in the tumor microenvironment remains entirely unexplored. Recent descriptions that IQGAP1 binds to receptors of VEGF, FGF, and EGF (13,20,21) and links growth factor signaling to the actin cytoskeleton prompted us to explore a potential role for IQGAP in the regulation of TGF-β receptors and their signaling in mesenchymal-type cells that activate into tumor-associated myofibroblasts, such as hepatic stellate cells (HSCs) (22), which are resident liver pericytes.…”