The pathogenesis and source of OM is still controversial. Some authors have proposed an odontogenic origin, particularly from the dental follicle or from the periodontal ligament [20, 21]. Other authors have suggested that OM may be the result of a myxoid change in a pre-existing mesenchymal lesion or that it may represent a degenerative form of odontogenic fibroma . In contrast, some authors have posed that the OM has a myofibroblastic origin [23, 24]. Nevertheless, in the last years many studies have compared the biochemical composition, particularly in the extracellular matrix, of OM with organs (dental pulp, dental follicles, gingival tissue and periodontal ligament) of a developing tooth [11, 25, 26]. The results obtained in the present study showed that the protein profiles of OM and DF are very similar; supporting the notion that OM could originate from DF.
To analyze proteins differentially expressed in OM and DF we used a proteomic approach based on 2-DE and peptide mass fingerprint by LC-MS/MS. This proteomic analysis revealed the variation of eight proteins identified (Table1).
Expression of carbonic anhydrase I (CA I) and glutathione S-transferase (GST) was downregulated in OM. Carbonic anhydrases catalyze the hydration of carbon dioxide and forms bicarbonate. CA I not only enhances the hydration reaction of CO2, but it also promotes the combining of bicarbonate with calcium to form the solid precipitant of calcium carbonate , a principal component of bones. Although OM is considered a benign neoplasm, it shows a high potential for bone resorption . Thus, downregulation of CA I may affect the balance between bone resorption and apposition. On the other hand, GSTs are a large family of enzymes that catalyze the conjugation of reduced glutathione through a sulfhydryl group to electrophilic sites on a wide variety of substrates that could lead to the generation of reactive oxygen species (ROS) . The products of GST catalysis are more water soluble, promoting ROS detoxification and thereby protecting tissues from oxidative damage. Thus, GST could be acting as a caretaker protein by protecting cells against genome damage induced by carcinogens and as a tumor-suppressor protein leading to tumor growth when inactivated . It is, therefore, speculative that downexpression of GST in OM would lead to genome damage accumulation and be further injurious to the oral tissue.
A glucose-regulated protein (GRP94), albumin in a complex with myristic acid and tri-iodobenzoic acid, the tropomyosin alpha-4, the 14-3-3 protein zeta/delta, the apolipoprotein A-I, and the orosomucoid-1 protein were up-regulated in OM. Interestingly, overexpression of tropomyosin alpha-4 was also detected in esophageal squamous cell carcinoma , although their participation in tumor development remains to be investigated.
GRPs refer to a set of endoplasmic reticulum (ER) chaperones that have multiple functions in maintaining cellular homeostasis . The endoplasmic reticulum stress pathways and the GRPs have been linked to cancer growth and drug resistance . GRPs represent novel markers for cancer progression and chemo-responsiveness, as well as targets for cancer therapy. GRP94, also known as gp96, is the most abundant glycoprotein in ER and its overexpression associates with cellular transformation, tumorigenicity and decreased sensitivity to X-rays, whereas suppression of GRP94 sensitizes cells to etoposide treatment .
The 14-3-3 proteins belong to a family consisting of highly conserved acidic proteins with molecular weights of 25–30 kDa. They participate in phosphorylation-dependent protein-protein interactions that control progression through the cell cycle, initiation and maintenance of DNA damage checkpoints, activation of MAP kinases, prevention of apoptosis and coordination of integrin signaling and cytoskeletal dynamics . Accumulating evidence now supports the concept that either an abnormal state of 14-3-3 protein expression, or dysregulation of 14-3-3/client protein interactions, contributes to the development of a large number of human diseases. In particular, clinical investigations in the field of oncology have demonstrated a correlation between upregulated 14-3-3 levels and poor survival of cancer patients .
ApoA-I is the major protein in HDL and plays an important role in reverse cholesterol transport by extracting cholesterol and phospholipids from peripheral cells and transferring it to the liver for excretion. In addition to its antiatherogenic properties, apoA-I also possesses anti-inflammatory and antioxidant properties . Decreased levels of Apolipoprotein were found in a variety of cancer [37–39], but such as in OM, Apolipoprotein A-I was increased in breast cancer and brain metastases in lung cancer [40, 41]. This controversy about the regulation of ApoA-I in cancer cells needs to be clarified in future studies.
By proteomics,Western blot and immunohistochemical assays, in the present study we showed that the ORM1 protein is overexpressed in OM. Interestingly, the same strategies allowed the identification of increased levels of ORM1 in urine samples of patients with urinary bladder cancer . Moreover, increased levels of ORM1 have been reported in the sera of patients with different malignant diseases, including squamous cell carcinoma of head and neck [42–46].
ORM1 belongs to a group of acute-phase proteins found in plasma. Such proteins undergo dramatic changes in concentration as a response of the organism to a disturbance of its homeostasis. These plasmatic proteins constitute a group of serum factors related to different immunological regulator functions and they have also been associated with tumor development and growth. However, it is uncertain whether the serum levels of acute-phase proteins, such as ORM1, increase as a response of the host to tumor growth or as a consequence of neoplastic cell production.
Human hepatocytes are normally the site of ORM1 production, but endothelial cells and some tumor cells can also produce it [16, 45, 47]. Additionally, some studies have shown that ORM1 is synthesized by lymphocytes, granulocytes, macrophages and monocytes [48, 49]. In the present study the expression of ORM1 in OM was mainly detected in the cytoplasm of stellate and spindle-shaped cells. However, this protein was also detected in the endothelial cells of blood vessels in both OM and DF tissue samples. It has been reported that ORM1 alone enhances migration but not the proliferation of human dermal microvascular endothelial cells, but in the presence of ORM1 and the vascular endothelial growth factor A (VEGF-A) the endothelial cells are capable to induce the development of endothelial tubes, suggesting that ORM1 seems to be involved in the regulation of angiogenesis . Irmak et al.  proposed that the highest increase of ORM1 levels in advanced stages of urinary bladder cancer, which correspond to a vascularized tumor, could be due in part to the production of this protein by the augmented number of endothelial cells of angiogenically active blood vessels. The pro-angiogenic collaborative property of ORM1 may possibly occur in OM, but further studies with the association of angiogenic markers and ORM1 in OM are needed to test this hypothesis.
The presence of ORM1 in odontogenic myxoma also suggests a possible immunomodulatory function and a role in the growth and invasion potential of the tumoral cells. ORM1 is able to inhibit polymorphonuclear neutrophil activation and is considered a natural anti-inflammatory, anti-neutrophil, anti-complement and immunomodulatory agent . Thus, the overexpression of ORM1 in OM may inhibit the immune response, resulting in an increase of tumor cell proliferation. Alternatively, the high expression of ORM1 in OM could represent a defense mechanism against proliferation and invasion of the tumor cells, similar to what occurs in colon cancer cells. In the latter neoplastic cells, the overexpression of ORM1 results in a reduced colony-forming capacity, as well as in a decrease of invasion and adhesion, whereas the inhibition of the expression of ORM1 by antisense oligodeoxynucleotides produces an increase of these events . However, due to the multiple roles that have been described for ORM1 , it is difficult at this moment to assign just one specific function of this protein in OM.
On the other hand, ORM1 has very high carbohydrate content (45%). Glycoproteins contain carbohydrate residues from less than 1% until 80% of their total molecular weight and when glycoproteins include more than 4% of carbohydrates they are often called mucoproteins, because they have a high viscosity . Macroscopically OM is an infiltrative mass of mucoid or slimy material, with a high viscosity. It is a slow growing tumor consisting of an accumulation of mucoid ground substance and, in some instances this mucoid mass can be infiltrative and destructive. The presence of ORM1 in OM possibly can justify the classical mucoid appearance of this tumor. However, in the immunohistochemical assays we only observed a cytoplasmic expression of this protein, whereas extracellular expression was not detected.