Breast cancer liver metastasis: Pathogenesis and clinical implications

Abstract

Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process. Although the hepatic microenvironment and liver sinusoidal structure are crucial factors for the initial arrest of breast cancer and progression within the liver, the biological basis of BCLM remains to be elucidated. Importantly, further understanding of the interaction between breast cancer cells and hepatic microenvironment in the liver metastasis of breast cancer will suggest ways for the development of effective therapy and prevention strategies for BCLM. In this review, we provide an overview of the recent advances in the understanding of the molecular mechanisms of the hepatic microenvironment in BCLM formation and discuss current systemic therapies for treating patients with BCLM as well as potential therapeutic development based on the liver microenvironment-associated signaling proteins governing BCLM.

Keywords: breast cancer; clinical implications; hepatic microenvironment; liver metastasis; pathogenesis.

Figure 1

The process of liver metastasis formation in breast cancer. The whole process can be separated into six steps: 1) Intravasation phase: cancer cells intravasate into the circulation system under help of immune cells; 2) Premetastatic phase: HSCs, KCs, and immune cells in hepatic microenvironment form premetastatic niche; 3) Tumor-infiltrating microvascular phase: cancer cells extravasate into liver parenchyma through LSECs; 4) Pre-angiogenic micrometastatic phase: HSCs and immune cells are recruited into micrometastases and activate local stromal response; 5) Angiogenic micrometastatic phase: micrometastases become vascularized and interact with cells in the microenvironment; 6) Growth phase: metastases expansion under the stimulation of hepatocytes, HSCs, and immune cells. (HSC, Hepatic stellate cell; KC, Kupffer cell; LSEC, Liver sinusoidal endothelial cells).