TGFβ signaling in head and neck cancer development and metastases

Transforming growth factor beta (TGFβ) signaling impacts the HSNCC development and metastases by affecting many critical processes including cell growth, proliferation, apoptosis, epithelial-to-mesenchymal transition, invasion, angiogenesis, and immune surveillance. Typically, TGFβ functions as a tumor suppressor in epithelial cells by inhibiting cell growth, promoting apoptosis, stimulating epithelial differentiation, enhancing genetic stability, and promoting cellular senescence, hence, reduced expression of TGFβ signaling components is observed in many malignancies, including HNSCC. Through a combination of genetic and epigenetic changes, TGFβ type II receptor expression is frequently reduced in HNSCC and is reduced TGFβRII expression is associated with more aggressive tumor behavior. Similarly, Smad4 expression is also commonly reduced in HNSCC and is associated with increased genomic instability. Tumor epithelial cells with TGFβ signaling defects increase TGFβ1 ligand production, which paradoxically promotes tumor growth and metastases by activating tumor-associated fibroblasts, increasing matrix degradation and angiogenesis, suppressing immune surveillance, and inducing inflammation; accordingly elevated local TGFb1 expression correlates with numerous negative clinical parameters. Given its broad role in tumor development and progression, TGFβ signaling remains an attractive therapeutic target, though the multifaceted roles of TGFβ in normal tissue homeostasis and the biphasic role of TGFβ in tumor development and progression have-complicated attempts to modulate TGFβ signaling in the clinical setting.