The liver is one of the most common and damaging sites for breast cancer metastasis, classified as Stage IV disease. When breast cancer cells establish growth in the liver, they remain breast cancer cells growing in a new location. Understanding the biological mechanism of how these cells escape the breast and successfully colonize the liver is paramount to developing effective treatments.
The Journey from Breast to Liver
The metastatic cascade begins when cells acquire the ability to move through Epithelial-Mesenchymal Transition (EMT). This transition causes stationary cells to shed their connections and adopt a mobile phenotype. These newly mobile cells then invade the surrounding tissue, breaking through the basement membrane and migrating toward local blood or lymphatic vessels.
Once they reach a vessel, the tumor cells enter the circulation in a step known as intravasation. During their journey through the bloodstream, these circulating tumor cells (CTCs) are vulnerable to destruction by the immune system or physical forces. Many CTCs gain protection by aggregating with blood platelets, which form a protective cloak against immune cells and mechanical stress. Platelets also facilitate the cell’s survival by releasing growth factors and helping the CTCs stick to the vessel walls at the new site.
The next step, extravasation, involves the CTCs arresting at the liver’s capillary walls and exiting the bloodstream into the organ’s tissue. This process is aided by the platelets, which can induce the retraction of endothelial cells lining the vessel, creating gaps for the CTCs to squeeze through. Once the breast cancer cells have crossed the vessel barrier, they must adapt to the new liver microenvironment to survive and proliferate.
Factors That Make the Liver a Target
The liver is a preferred destination for breast cancer cells due to its distinct architecture and highly nutritive environment, often described by the “seed and soil” hypothesis. A significant factor is the liver’s dual blood supply, receiving nutrient-rich blood from the portal vein and oxygenated blood from the hepatic artery. Tumor cells from the breast arrive via the hepatic artery, where the dense, low-pressure network of liver sinusoids acts like a filter, effectively trapping the circulating cells.
The liver’s microenvironment is highly hospitable, rich in growth factors and nutrients that promote cell survival and growth. Specialized immune cells, such as Kupffer cells and hepatic stellate cells, are abundant and often manipulated by the arriving cancer cells.
Instead of attacking the cancer cells, these host liver cells can be co-opted to create a supportive niche. Breast cancer cells can induce these host cells to release factors like Transforming Growth Factor-Beta (TGF-B), which signals the cancer cells to grow. The liver’s unique immunological tolerance, necessary for processing gut-derived antigens, also makes it less aggressive toward foreign cancer cells.
How Cancer Cells Establish Growth
Once the breast cancer cells have successfully extravasated, they must colonize the liver tissue, a process that begins with adaptation and can lead to either immediate proliferation or a state of latency. Some cells immediately begin to multiply, while others enter a period of dormancy, remaining undetectable for years or even decades. The transition from dormancy to active growth is often regulated by the immediate microenvironment, particularly the nearby blood vessels.
A dormant cell cluster, or micrometastasis, can be awakened by an “angiogenic switch,” which involves a change in the balance of factors secreted by the tumor cells and surrounding liver cells. When the cancer cells begin to signal for the growth of new blood vessels (angiogenesis), the local environment becomes highly pro-growth. The new, sprouting blood vessels release growth-promoting molecules like TGF-Beta 1, which signals the dormant cells to begin rapid division.
To fully establish a growing tumor, the cells must interact with and remodel the surrounding Extracellular Matrix (ECM), the scaffolding of the liver tissue. Cancer cells release enzymes like matrix metalloproteases and adhesion molecules that alter the ECM, creating a supportive structure that enhances their adhesion and facilitates expansion. This remodeling results in a stiffer, more favorable niche that feeds the growing secondary tumor.
Signs and Detection of Liver Metastasis
Liver metastasis often presents silently in its early stages, meaning regular monitoring is an important part of follow-up care for breast cancer survivors. As the tumor burden increases, however, several generalized and specific symptoms may develop. Common symptoms include persistent, unexplained fatigue and a dull, aching pain or discomfort in the upper right quadrant of the abdomen.
Other signs reflect the liver’s declining function, such as jaundice, which is a yellowing of the skin and eyes caused by the buildup of bilirubin. Patients may also experience a loss of appetite, unexplained weight loss, and fluid buildup in the abdomen. These symptoms prompt physicians to order diagnostic tests to confirm the presence of metastases.
Diagnosis relies on a combination of blood tests and imaging studies. Blood tests often show abnormal liver function tests, specifically elevated levels of enzymes like alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Imaging tests, such as computed tomography (CT) scans, magnetic resonance imaging (MRI), or positron emission tomography (PET) scans, are used to visualize the liver and detect the size and location of metastatic lesions.