Hypoxia and proangiogenic proteins in human ameloblastoma

Abstract

Ameloblastomas are epithelial odontogenic tumours that, although benign, are locally invasive and may exhibit aggressive behaviour. In the tumour microenvironment, the concentration of oxygen is reduced, which leads to intratumoral hypoxia. Under hypoxia, the crosstalk between the HIF-1α, MMP-2, VEGF, and VEGFR-2 proteins has been associated with hypoxia-induced angiogenesis, leading to tumour progression and increased invasiveness. This work showcases 24 ameloblastoma cases, 10 calcifying odontogenic cysts, and 9 dental follicles, used to investigate the expression of these proteins by immunohistochemistry. The anti-HIF-1α, anti-MMP-2, anti-VEGF, and anti-VEGFR-2 primary antibodies are used in this work. The results have been expressed by the mean grey value after immunostaining in images acquired with an objective of 40×. The ameloblastoma samples showed higher immunoexpression of HIF-1α, MMP-2, VEGF, and VEGFR-2 when compared to the dental follicles and calcifying odontogenic cysts. Ameloblastomas show a higher degree of expression of proteins associated with intratumoral hypoxia and proangiogenic proteins, which indicates the possible role of these proteins in the biological behaviour of this tumour.

Expression of stem cell markers SALL4, LIN28A, and KLF4 in ameloblastoma

“…In response to this condition, hypoxia-induced factor-1 alpha (HIF-1α) regulates the expression of genes that help cells adapt to this environment [ 55 ]. Studies have indicated that HIF-1α is overexpressed in AME, suggesting that hypoxia is related to proliferation and invasion of the solid areas of this tumour [ 56 – 58 ]. It has been shown that HIF-1α binds directly to the LIN28A promoter and induces its transcription [ 59 ] and that hypoxia is capable of inducing the expression of stem cell markers in cancer cell lines, thereby contributing to the dedifferentiation and reprogramming process that induces the formation of cancer stem cells [ 59 – 61 ].…”

RANKL neutralisation prevents osteoclast activation in a human in vitro ameloblastoma-bone model

“… 29 Furthermore, incorporating endothelial cells such as HUVECs into the stromal compartment could aid in further investigating the intratumoral hypoxia observed in ameloblastoma. 30 It would also be of great value to incorporate primary ameloblastoma cells into the model due to the limitations of immortalised cell lines and their homogenous nature. Exploration of the RANKL antibody action of denosumab clearly showed significant inhibition of osteoclast activation in the presence of osteoblasts and ameloblastoma cells.…”

Single-Cell RNA Sequencing Reveals CXCLs Enriched Fibroblasts Within Odontogenic Keratocysts

“…OKCs are frequently local inflamed being caused by microbial infection or other unknown factors. 3 , 4 Even more, mechanical stress, including compressive and tensile force, triggers a local immunological response, inflammation and bone resorption. 13 , 14 In addition, marsupialization which reduced the hydrostatic pressure within OKC significantly boost the new bone formation and lower the proliferation of basal cells.…”

“… 3 Angiogenesis and cellular invasion are complex multistage processes that begin with the degradation of the extracellular matrix caused by proteolytic enzymes, and, especially, tumor-associated matrix metalloproteinases. 4 …”