Gastrointestinal stromal tumors (GISTs) are a type of tumor that arises in the digestive tract, most commonly in the stomach or small intestine. The primary cause of GISTs is genetic mutations that lead to abnormal activation of certain proteins called tyrosine kinases, which are involved in cell growth and division. Specifically, mutations in the KIT gene or the PDGFRA gene are the main drivers behind the development of these tumors.
The KIT gene produces a protein that acts as a receptor tyrosine kinase, which normally helps regulate cell functions such as growth and survival. When the KIT gene mutates, it causes the receptor to be constantly active without the normal regulatory signals. This uncontrolled activation leads to excessive cell proliferation and tumor formation. Similarly, mutations in the PDGFRA gene, which encodes another receptor tyrosine kinase, can also cause continuous signaling that promotes tumor growth. These mutations are typically somatic, meaning they occur in the tumor cells themselves rather than being inherited, although rare inherited forms exist.
Beyond these genetic mutations, the tumor microenvironment plays a significant role in the progression of GISTs. Cancer-associated fibroblasts (CAFs), which are specialized cells in the tumor’s surrounding tissue, become activated and contribute to tumor growth and metastasis. These fibroblasts are influenced by various signaling molecules such as transforming growth factor beta 1 (TGF-β1), interleukins, and tumor necrosis factor, which promote their activation and support the tumor’s development. The metabolic activity of these fibroblasts is altered in a way that supports cancer cell survival and spread, including changes in glycolysis and lipid metabolism.
Inflammation and damage to the lining of the gastrointestinal tract can also contribute indirectly to tumor development. Chronic inflammation may cause changes in the normal cells lining the stomach or intestines, leading to the appearance of abnormal cells that express different genes and proteins. These changes can create an environment conducive to tumor formation, although this is more relevant to other gastrointestinal cancers than to GISTs specifically.
In summary, the root cause of gastrointestinal stromal tumors lies in mutations of the KIT or PDGFRA genes, which lead to abnormal activation of tyrosine kinase signaling pathways. This genetic alteration drives the uncontrolled growth of the interstitial cells of Cajal, the cells from which GISTs originate. The tumor microenvironment, including activated fibroblasts and inflammatory signals, further supports tumor progression and metastasis. Understanding these causes is crucial for developing targeted therapies that inhibit the aberrant tyrosine kinase activity and improve patient outcomes.
