Individuals with advanced papillary thyroid cancer (PTC) that are associated with the BRAFV600E gene mutation have a higher risk of recurrent disease and progression to more advanced, poorly differentiated thyroid cancer, according to data presented today at the 81st Annual Meeting of the American Thyroid Association (ATA). An understanding of the biological processes that underlie this progression could lead to the development of more effective therapies.
One approach to studying the role of BRAFV600E in PTC initiation and progression is to create mice in which the gene mutation (BRAFV600E) has been introduced and activated in the thyroid. These transgenic mice develop advanced PTCs that closely resemble human poorly differentiated PTCs. Mabel Ryder, MD, and colleagues from Memorial Sloan-Kettering Cancer Center and the Sloan-Kettering Institute (New York, NY) used BRAFV600E transgenic mice to study the effects of tumor-associated macrophages (TAMs), a type of white blood cell, on PTC initiation and progression. In cancers, TAMs are versatile and can either support or inhibit cancer progression. In PTCs, BRAF activation in the thyroid is accompanied by increased levels of colony stimulating factor 1, which stimulates the recruitment of TAMs to the thyroid. Once in the thyroid, TAMs accumulate alongside cancer-associated myofibroblasts (CAMs) to form a dense layer within and around the thyroid. The researchers used genetic techniques to kill the TAMs in PTCs. The result was a significant reduction in PTC size, total tumor cell volume and a more well-differentiated, less advanced PTC. The authors also demonstrated a functional link between TAMs, the recruitment of CAMs and PTC initiation. The researchers observed that when TAMs are depleted during PTC initiation, the density of CAMs is significantly diminished along with an impairment of PTC initiation.
"Many of the new treatments for thyroid cancer, such as kinase inhibitors, aim to block the activity of oncoproteins present within tumor cells. Our data suggests that immune cells in the tumor microenvironment play an important role in the biology of these cancers. This may be clinically relevant since there are new agents in development that can target TAMs, and we believe these should be explored, particularly in patients with advanced forms of the disease," said Dr. Ryder.
Based on these findings, the researchers concluded that TAMs have an important role in the initiation and progression of PTC and may represent a potent therapeutic target for combating advanced thyroid cancers that do not respond to conventional therapies.
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