Adenoid cystic carcinoma (ACC) is a rare type of cancer that primarily arises in the salivary glands but can also occur in other locations such as the lacrimal glands, respiratory tract, and breast. Understanding what causes ACC involves exploring its genetic, molecular, and cellular origins, as well as the environmental and biological factors that may contribute to its development.
At the core of ACC’s cause is a distinctive genetic alteration involving a fusion between two genes: MYB and NFIB. This fusion results from a chromosomal translocation, specifically t(6;9)(q23;p23), where parts of chromosome 6 and chromosome 9 swap places. The fusion gene produces an abnormal MYB-NFIB fusion protein that acts as a powerful oncogene, meaning it drives the uncontrolled growth and survival of cancer cells. The MYB protein normally regulates gene expression related to cell growth and differentiation, but when fused with NFIB, it becomes overactive, leading to excessive cell proliferation and tumor formation. This fusion is considered a hallmark of ACC and is found in a majority of cases, making it a key molecular cause of the disease.
Beyond the MYB-NFIB fusion, other molecular pathways and factors contribute to ACC development. For example, signaling pathways involving insulin-like growth factor receptor 1 (IGF1R) and protein kinase B (PKB/Akt) have been implicated in regulating the activity of the MYB-NFIB fusion protein. These pathways promote cell survival and proliferation, further supporting tumor growth. Additionally, factors like hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) contribute to the tumor’s ability to survive in low oxygen environments and stimulate the formation of new blood vessels, which supply nutrients to the growing tumor.
ACC is also characterized by a dense fibrous stroma, a supportive tissue environment around the tumor cells, which plays a significant role in its behavior. This stroma is rich in cancer-associated fibroblasts (CAFs) and immune cells that create an immunosuppressive microenvironment. The CAFs produce extracellular matrix proteins like collagen, forming a dense barrier that not only physically protects tumor cells but also secretes signaling molecules such as CXCL12 and transforming growth factor-beta (TGF-β). These molecules suppress the immune system’s ability to attack the tumor and promote tumor cell invasion along nerves, a phenomenon known as perineural invasion, which is common in ACC and contributes to its aggressive nature and recurrence.
Environmental and lifestyle factors are not well established as direct causes of ACC, unlike other head and neck cancers where tobacco, alcohol, and viral infections such as human papillomavirus (HPV) or Epstein-Barr virus (EBV) play significant roles. ACC does not have a strong association with these common carcinogens or infections. Instead, its cause is more tightly linked to the specific genetic and molecular abnormalities described above.
In summary, the primary cause of adenoid cystic carcinoma is the genetic fusion of the MYB and NFIB genes, which produces an oncogenic fusion protein driving tumor growth. This genetic event, combined with the activation of growth and survival pathways, the creation of an immunosuppressive tumor microenvironment, and the tumor’s ability to invade nerves, underlies the development and progression of ACC. Unlike many other cancers, ACC’s cause is less related to external carcinogens and more to intrinsic genetic alterations and the complex interactions within its microenvironment.
