Angiosarcoma is a rare and aggressive cancer that originates from the cells lining blood vessels, known as endothelial cells. Understanding what causes angiosarcoma involves looking at a complex interplay of genetic, molecular, and environmental factors that lead to the abnormal growth and proliferation of these vascular cells.
At the molecular level, one key factor implicated in angiosarcoma development is the **IL-13/IL-13 receptor alpha 2 (IL-13Rα2) axis**. Interleukin-13 (IL-13) is a signaling molecule, or cytokine, that normally plays a role in immune responses. In angiosarcoma, IL-13 and its receptor IL-13Rα2 are found to be abnormally elevated. This axis promotes the proliferation of angiosarcoma cells by activating pathways that increase the expression of vascular endothelial growth factor A (VEGF-A), a protein that stimulates the formation of new blood vessels. This process is partly driven by the activation of a signaling molecule called STAT6, which enhances the growth and survival of the cancer cells. This creates a positive feedback loop where IL-13 increases IL-13Rα2 and VEGF-A expression, further fueling tumor growth and blood vessel formation within the tumor environment.
Genetic mutations also play a crucial role in angiosarcoma. While the exact mutations can vary, some studies have identified mutations in genes involved in cell signaling and growth regulation, such as phospholipase C gamma 1. These mutations can disrupt normal cellular controls, leading to unchecked cell division and tumor formation. High levels of nonsynonymous mutations—mutations that change the amino acid sequence of proteins—have been associated with increased IL-13Rα2 expression, suggesting a link between genetic changes and the molecular pathways driving angiosarcoma.
Environmental and external factors can contribute to the risk of developing angiosarcoma as well. Exposure to certain chemicals, such as vinyl chloride (used in plastics manufacturing), arsenic, and thorium dioxide, has been linked to angiosarcoma, particularly in the liver. Chronic lymphedema, which is swelling caused by lymphatic fluid buildup often after surgery or radiation therapy, can also predispose individuals to angiosarcoma in the affected limb. Radiation exposure itself is a known risk factor, with angiosarcomas sometimes developing in areas previously treated with radiation for other cancers.
Angiosarcoma can arise in various parts of the body, including the skin, breast, heart, liver, and deep soft tissues. The tumor’s aggressive nature is partly due to its origin in blood vessel cells, allowing it to spread quickly through the bloodstream to other organs such as the lungs and spleen.
In summary, angiosarcoma is caused by a combination of genetic mutations and molecular signaling abnormalities, particularly involving the IL-13/IL-13Rα2 axis that promotes tumor cell proliferation and blood vessel growth. Environmental exposures and prior radiation or chronic lymphedema also contribute to its development. These factors together disrupt normal endothelial cell behavior, leading to the formation of this aggressive vascular cancer.
