Hemophagocytosis‐mediated keratinization in oral carcinoma in situ and squamous cell carcinoma: A possible histopathogenesis of keratin pearls

Abstract

Although the histopathogenetic process of keratin pearls is still poorly understood, acceleration of keratinization in squamous cell carcinoma (SCC) cells may represent one possible therapeutic avenue. Based on our histopathological observations, we have hypothesized that SCC cells are keratinized by phagocytosis of extravasated erythrocytes. To confirm this hypothesis, we firstly examined immature keratin pearls in oral carcinoma in situ (CIS) and mature ones in SCC by immunohistochemistry. Concentric dyskeratotic cells in CIS keratin pearls became positive for keratin (K) 10, K17, heme oxygenase-1 (HO-1), or protease activated receptor-2 (PAR-2), a candidate regulator for hemophagocytosis. When ZK-1 cells, an SCC cell system, were incubated with human peripheral blood erythrocytes, or with crude and purified hemoglobins (Hbs), their erythro-hemophagocytotic activities were confirmed by immunofluorescence. Immunofluorescence signals for K10, K17, and HO-1 were enhanced due to hemophagocytosis in time-dependent manners. mRNA expression levels for the three molecules were most enhanced by purified Hb, followed by crude Hb and erythrocytes. K17/K10 mRNA expression levels were more elevated when PAR-2 was activated in ZK-1 cells. The results indicated that immature and mature keratin pearls in CIS and SCC were generated by oxidative stresses derived from erythro-hemophagocytosis, which might mediate HO-1 expression and be regulated by PAR-2. Thus, hemorrhage from the rupture of blood vessels can be one of the triggers for keratin pearl formation in oral CIS and SCC.

MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells

“…Rather than engulfing apoptotic cancer cells, [27][28][29] cancer cells are also able to phagocytose neutrophils, 30 lymphocytes, 31 and erythrocytes. 32,33 This has been was widely recognized in diagnostic cytology, in which these cell-engulfing features have practically been used as the definitive evidence of malignancy. 34 However, the molecular mechanisms underlying this phenomenon still remain entirely unknown.…”

Lack of Utility of Cytokeratins in Differentiating Pseudocarcinomatous Hyperplasia of Granular Cell Tumors from Oral Squamous Cell Carcinoma

“…Immunohistochemical experiments were performed using the EnVision/HRP system (Dako) as detailed previously (Al-Eryani, 2013). After deparaffinization, sections were autoclaved in citrate buffer (pH 6.0) at 121°C for 10 min, to restore antigenicities of CK13, CK17 and P75.…”

Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells

“…As mentioned above, it remains totally unknown how PAR-2 functions in oral SCC or CIS in terms of their growth or invasion, other than its hemophagocytosis-related expression, which we have determined in oral SCC cells [14]. The aims of this study are to characterize PAR-2 expression profiles in the oral mucosal epithelia from normal, dysplastic, CIS, and SCC stages and to determine the effect of PAR-2 activation by agonist peptides on oral SCC cells in their proliferation and invasion potentials.…”

“…Seeking the molecular mechanism of abnormal keratinization in oral CIS and SCC, we have come to find that the expression levels of K17 and K10 were elevated in roundshaped dyskeratosis in CIS as well as in keratin pearls in SCC by hemoglobin derived from extravasated erythrocytes via intraepithelial blood vessels [13,14]. Interestingly, this hemophagocytosis activity is mediated by protease-activated receptor 2 (PAR-2) through heme oxygenase 1 activation pathways [14], whereas PAR-2 had previously been known to up-regulate keratinocyte phagocytosis [15].…”

“…Interestingly, this hemophagocytosis activity is mediated by protease-activated receptor 2 (PAR-2) through heme oxygenase 1 activation pathways [14], whereas PAR-2 had previously been known to up-regulate keratinocyte phagocytosis [15]. PAR-2 is one of the four PAR family members.…”