When cancer cells break away from where they first formed and travel through the blood or lymph system to form new tumors (called metastasis), they become what is currently the major cause leading to death from cancer. Treating metastasis is complex since in many cases, this spreading of the cancer cells has already occurred by the time the disease is diagnosed. The growth and progression of cancer cells spreading to other parts of the body is dependent on the traits of the tumor, and how the cancer cells interact with the cells and cell secretions from the part of the body where it has landed.
Researchers have relatively little information on how the parts of the brain with normal brain cells interact with the spreading brain tumor. Studying this interaction, and understanding the basis for the spread of melanoma and the molecular activity in the brain in this environment, is important in order to develop new therapeutic and targeted solutions for this disease.
The study, published in Oncotarget, Volume 8, Issue 44, entitled “ANGPTL4 promotes the progression of cutaneous melanoma to brain metastasis,” showed that a protein called ANGPTL4 (Angiopoietin-like 4) that in humans is encoded by the ANGPTL4 gene, is more highly expressed in melanoma brain metastasis (MBM) cells than in corresponding skin melanoma cells in human models as well as in clinical samples. Interestingly, MBM exhibited higher expression of ANGPTL4 than paired Lymph Node Metastasis (LNM), when cancer from the lymph nodes spreads. In other words the results of this research emphasize the importance and selectivity of the gene ANGPTL4 for metastasis spreading in the brain.
A proposed process for intervening in the progression of ANGPTL4-mediated melanoma malignancy is shown.
Longer life can mean an increased chance of the cancer spreading
Since deadly (malignant) melanoma has a high tendency to develop when brain cancer spreads, consulting melanoma patients is a very poor predictor of outcomes because they already have the disease, which spreads quickly. The disease typically has a poor outcome, since the primary tumors start on the head, neck, trunk, or abdomen and spread quickly to the brain. As disease management improves, prolonging the survival rates of melanoma patients, the number of patients that eventually develop clinical brain metastasis increases. Beyond surgery, treatment options are limited, and survival of treated patients depends on tumor size, metastasis location, and number of tumor metastasis.
A vast, interconnected network
To understand how brain metastasis develops, one must consider that the brain microenvironment has several permanently-housed cell types including endothelial cells, astrocytes, microglia, and neurons. To develop brain metastasis, melanoma cells must reach the brain network of veins and arteries, attach to the inner surface of the cells in the small vessels, force out the cells to invade the brain tissues, multiply and induce formation of new blood vessels. This interaction in the brain causes the cancer cells to break away and travel through the body (metastasis).
The researchers developed models using local tumor cells to better understand how the tumor microenvironment influences the function of the gene ANGPTL4 in the early stages of melanoma brain metastasis. By understanding the interaction, researchers hope to eventually find ways to control the microenvironment of the primary tumor at diagnosis using gene therapy, and prevent the spreading of the tumor cells to the brain. Further investigation is needed.