Galectin-3 Explained: The Key to Cancer and Inflammatory Human Disease?

First described in 1971, recent research brought clarity to the role that galectin-3 plays in a wide range of human diseases, including inflammation and cancers. In the liver, galectin-3 plays a significant role in diseases such as non-alcoholic steatohepatitis (NASH) and its complication, liver cirrhosis.

What are galectins?

Galectins are a class of proteins that act as a molecular glue in the body. There are many galectin subtypes, but all with the characteristic of binding to molecules with specific sugars. The most relevant galectin for human diseases is galectin-3.

While galectin-3 is normally found in small amounts in many different cell types, it is mostly produced by a white blood cell known as ‘macrophage,’ a cell that is part of the immune system and is activated by tissue damage. Chronic inflammation in organs such as the liver, for example, can induce galectin-3 to trigger scar tissue, which over time can interfere with liver function and lead to liver cirrhosis.

Galectin-3 and liver fibrosis and cirrhosis

Scientific research suggests galectin-3 is essential for developing NASH, liver fibrosis and, ultimately, NASH cirrhosis. Over 500,000 patients have liver cirrhosis in the United States, with close to 50,000 dying each year.

In non-alcoholic fatty liver disease (NAFLD) — the precursor to NASH — fat starts to build up in the liver. In this organ, this is an abnormal phenomenon. This buildup causes inflammation, an immune response against fat. Galectin-3 involved in this inflammation, and its presence triggers scarring, also called liver fibrosis. As the fibrosis perturbs healthy liver cells, they begin to die. The continued scarring, the cell death and the attempt of the liver to regenerate them, causes cirrhosis. At this stage, liver function start to be impaired, even to the point of a failure incompatible with a normal life.

Currently, short of a liver transplantation, there is no treatment for NASH cirrhosis. A liver transplantation is a complicated surgical act and costly procedure. To make matters worse, there are far more people who need a liver transplant than there are available organ donors. As a result, there is an urgent need of new medical treatment for NASH cirrhosis. Researchers are currently exploring if a galectin-3 inhibitor might play a role in treating NASH cirrhosis and its complications.

The role of galectin-3 in cancer

Galectin proteins, notably galectin-3, are also present in increased amounts in many cancerous tumors. In fact, the amount of galectin-3 appears to be higher in the many solid tumors, including skin (melanoma), head and neck cancer, and lung cancer (such as non-small cell lung cancer).

In thyroid cancers, for example, pathologists stain tumor biopsies for galectin-3 to distinguish malignant tissue from normal tissue, potentially reducing unnecessary thyroid surgeries.

The amount of galectin-3 in some cancers correlates with the aggressiveness of the cancer and the ultimate prognosis of the patient which may be useful in clinical practice and help with the choice of treatment.

Galectin-3 promotes the spread of cancer in three ways:

• Invasiveness. Galectin proteins help cancer cells migrate into surrounding tissues.
• Metastasis. In colon cancer, tumors that have metastasized elsewhere in the body have the highest levels of galectin-3, while the lowest is in the cancer cells located in the original tumor.
• Tumor growth. Galectin-3 promotes the growth of blood vessels that bring blood supply to the tumor.

Galectin-3 also inhibits the patient’s immune system, thereby preventing immune cells from killing tumor cells. This immune effect of galectin-3 in cancer is particularly interesting because of the rising importance of cancer immunotherapy. Could a galectin-3 inhibitor play a role in fighting cancer? Researchers are currently testing this hypothesis in the clinic by combining a galectin-3 inhibitor with an immune checkpoint inhibitor in patients with melanoma and head and neck cancer.

The potential for a galectin-3 inhibitor in treating diseases

Since galectin-3 is heavily involved in so many human diseases, could the development of a galectin-3 inhibitor become a treatment option for people affected by these diseases? Galectin Therapeutics, for example, and other research groups have spent the past decade working on this very question. Galectin Therapeutics is in the midst of a Phase 2b/3 clinical trial to test whether its novel galectin-3 inhibitor, belapectin, could prevent the development of esophageal varices in patients suffering with NASH cirrhosis. Another clinical trial is testing belapectin in combination with cancer immune therapies, such as KEYTRUDA™, in metastatic melanoma and advanced head and neck cancers.