Heterogeneous tumor microenvironment - A hallmark of ameloblastoma invasive phenotype

Ameloblastoma is a benign odontogenic tumor with an aggressive growth phenotype orchestrated by a complex and heterogeneous tumor microenvironment. This review addresses how tumor cells, cancer-associated fibroblasts, mesenchymal stem cells, endothelial cells, and immune cells interact with non-cellular elements especially the extracellular matrix and hypoxic niches to drive invasive growth and recurrence. Several genetic changes associated with ameloblastoma activate mitogen-activated protein kinase (MAPK), Hedgehog (HH), Wnt/β-catenin, and less commonly PI3K/AKT signaling pathways. These pathways increase matrix-degrading enzymes such as matrix metalloproteinases and heparanase and reorganize collagen to create paths for local spread of ameloblastoma cells. Hypoxic niches in ameloblastoma stabilize hypoxia-inducible factor (HIF-1)α and activate vascular endothelial growth factor (VEGF) thereby linking low oxygen tension to new blood vessel growth within the microenvironment. Crosstalk between ameloblastoma epithelium and stroma through interleukin-6, transforming growth factor (TGF)-β, and connective tissue growth factor (CTGF) activates a positive feedback loops that stiffen the extracellular matrix and promote collective invasion. Within the encompassing jaw bone, a higher receptor activator of nuclear factor kappa-Β ligand/osteoprotegerin (RANKL/OPG) ratio and parathyroid hormone-related protein (PTHrP) level stimulate osteoclastogenesis, which accounts for the characteristic osteolysis displayed by ameloblastoma. Additionally, PD-L1 expression in ameloblastoma weakens T-cell activity in spite of the high population of M1 macrophages at the tumor leading edge. Collectively, coordinated interplay of these molecular processes define the invasive and aggressive growth phenotypes of ameloblastoma. Opportunities abound for development of targeted therapies for management of ameloblastoma. Potential candidates are inhibitors of BRAF/MEK and smoothened (SMO) gene/HH pathways, interruption of the TGF-β-Cancer-associated fibroblast axis, anti-angiogenic strategies, immune checkpoint blockade, and RANKL-directed therapy.