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Summary: Various combinations of the SIBLING family of proteins have been found to be up-regulated in many human cancers and have been linked to different stages of tumor progression, including metastasis. Bone sialoprotein (BSP), osteopontin (OPN) and dentin matrix protein 1 (DMP1) specifically bind and activate MMP-2, MMP-3, and MMP-9, respectively. These proteases have also been shown to play important roles in oral squamous cell carcinoma (OSCC) invasion and metastasis. However, with the exception of OPN, there are no reports on the expression of the family of five SIBLING proteins in OSCC. This study examines the expression patterns of the SIBLING family (and MMP partners when known) in OSCC, correlating expression to outcome variables. Archived paraffin sections of 87 cases of primary OSCC were screened by immunohistochemistry for the SIBLINGs and their MMP partners. Three SIBLINGs (BSP, DSPP, and OPN), were expressed in OSCC, while DMP1 and MEPE expression were never observed. Furthermore, BSP and OPN were always expressed with their known MMP partners, MMP-2 and MMP-3, respectively. Poorly differentiated tumors exhibited reduced or no immunoreactivity for BSP and OPN but increased immunoreactivity for DSPP. Seventy eight (90%) cases were positive for BSP and DSPP, while 79 cases (91%) were positive for OPN. Overall, 91% of the cases were positive for at least one SIBLING. There were no correlations between SIBLING expression and tumor size (“T”; of the Union Internationale Contre le Cancer [UICC]-TNM classification for OSCC), and between SIBLING expression and lymph node spread for the T1/T2 tumors. The levels of DSPP expression for floor of mouth and retromolar region tumors were higher than for tongue tumors. Statistically significant correlations were, however, found between the expression levels of BSP and MMP-2 (p <0.0001), BSP and MMP-3 (p <0.0001), and OPN and MMP-3 (p <0.0024). We conclude that BSP, DSPP, and OPN are highly up-regulated in OSCC. While the production of these SIBLINGs is independent of T, they correlate with oral location of tumor, cognate MMP expression, and for DSPP, the degree of tumor differentiation. [Copyright &y& Elsevier]

Sulindac has antineoplastic effects on various cancer cell lines; consequently, we assessed sulindac's effects on laryngeal squamous cell carcinoma (SCC) cells in vitro and in vivo. In vitro, SCC (HEP-2) cells treated with various cyclooxygenase inhibitors or transfected with constitutively active signal transducer and activator of transcription 3 (Stat3) or survivin vectors were analyzed using Western blot analysis, annexin V assay, and cell proliferation assay. In parallel, nude mice injected subcutaneously with HEP-2 cells were either treated intraperitoneally with sulindac or left untreated, and analyzed for tumor weight, survivin expression, and tyrosine-phosphorylated Stat3 expression. In vitro studies confirmed the selective antiproliferative and proapoptotic effects of sulindac, which also downregulated Stat3 and survivin protein expression. Stat3 or survivin forced expression partially rescued the antiproliferative effects of sulindac. In vivo studies showed significant repression of HEP-2 xenograft growth in sulindactreated mice versus controls, with near-complete resolution at 10 days. Additionally, tumor specimens treated with sulindac showed downregulation of phosphorylated tyrosine-705 Stat3 and survivin expression. Taken together, our data suggest, for the first time, a specific inhibitory effect of sulindac on tumor growth and survivin expression in laryngeal cancer, both in vitro and in vivo, in a Stat3-dependent manner, suggesting a novel therapeutic approach to head and neck cancer. [ABSTRACT FROM AUTHOR]

The pathogenesis of oral cancer is a complex and multifactorial process that requires a deep understanding of the underlying mechanisms involved in the development and progress of malignancy. The ever-improving comprehension of the diverse molecular characteristics of cancer, the genetic and epigenetic alterations of tumor cells, and the complex signaling pathways that are activated and frequently cross talk open up promising horizons for the discovery and application of diagnostic molecular markers and set the basis for an era of individualized management of the molecular defects underlying and governing oral premalignancy and cancer. The purpose of this article is to review the key molecular concepts that are implicated in oral carcinogenesis, especially focusing on oral squamous cell carcinoma, and to review selected biomarkers that play a substantial role in controlling the so-called "hallmarks of cancer," with special reference to recent advances that shed light on their deregulation during the different steps of oral cancer development and progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Identification and management of potentially premalignant oral epithelial lesions (PPOELs) at highest risk of malignant transformation holds great promise for successful secondary prevention of oral squamous cell carcinoma, potentially reducing oral cancer morbidity and mortality. However, to date, neither clinical nor histopathologic validated risk predictors that can reliably predict which PPOELs will definitively progress to malignancy have been identified. In addition, the management of PPOELs remains a major challenge. Arguably, progress in the prevention and treatment of oral premalignancy and cancer will require improved understanding of the underlying molecular mechanisms, facilitating the discovery of diagnostic, prognostic, and predictive markers, as well as the identification of novel targeted therapeutics. This review provides a synopsis of the molecular biomarkers that have been studied in PPOELs and have been correlated with the presence and grade of dysplasia and/or their propensity to undergo malignant transformation to oral squamous cell carcinoma. The emphasis is on highlighting new emerging research fields, particularly epigenetic events, including methylation and micro-RNA regulation. Several promising biomarkers are highlighted. Current limitations and challenges are discussed. Recommendations for future focused research areas, to validate and promote clinically useful applications, are offered., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Recent identification of altered molecular signaling pathways in neoplasia has begun to elucidate mechanisms of oncogenesis, differentiation, and tumor progression, and to suggest plausible nonsurgical considerations for treatment. Here we review the sonic hedgehog (SHH) and PI3K/Akt/mTOR signaling pathways, their role in ameloblastoma, a locally aggressive odontogenic tumor, and evidence for consideration of therapeutic approaches that target these molecular pathways. In so doing, some of the gaps will be revealed that may impel investigations and translate to patient care, helping to minimize or eliminate the need for extensive surgery., Study Design: This is a comprehensive review of the literature regarding alterations in signaling mechanisms associated with ameloblastomas. In addition, this review attempts to explore and discuss possible inhibitors to these pathways that may have utility in treating ameloblastoma., Results: The expression of SHH signaling molecules in ameloblastomas at the mRNA and protein levels has intimated that these molecules may play a role in cell proliferation of these tumors. Immunohistochemical analysis has revealed aberrant signaling in the PI3K/Akt/mTOR pathway in ameloblastomas and appears to be a valuable tool for elucidating pathogenesis and aggressiveness, and selecting optimal therapeutics., Conclusion: The understanding of altered pathways in ameloblastoma may soon provide nonsurgical options for the treatment of this condition. The demonstration of cross talk in SHH signal transduction with PI3K signaling through Akt has shown that these pathways converge to control the Gli transcription factors. Thus, tumors that entirely depend on active SHH signaling for survival/growth and maintenance may well be susceptible targets for combined chemotherapy with SHH-specific inhibitors together with PI3K, Akt, or mTOR blocking agents. Some of these inhibitors could be used locally, thereby minimizing major systemic effects., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Orbital floor injuries are a common form of traumatic craniofacial injury that may not heal properly through the body's endogenous response. Reconstruction is often necessary, and an optimal method does not exist. We propose a tissue engineering approach for orbital bone repair based upon a cyclic acetal biomaterial formed from 5-ethyl-5-(hydroxymethyl)-beta,beta-dimethyl-1,3-dioxane-2-ethanol diacrylate (EHD) and poly(ethylene glycol) diacrylate (PEGDA). The EHD monomer and PEGDA polymer may be fabricated into an EH-PEG hydrogel by radical polymerization. The objectives of this work were to study (1) the tissue response to EH-PEG hydrogels in an orbital bone defect and (2) the induction of bone formation by delivery of bone morphogenetic protein-2 (BMP-2) from EH-PEG hydrogels. EH-PEG hydrogels were fabricated and implanted into an 8-mm rabbit orbital floor defect. Experimental groups included unloaded EH-PEG hydrogels, and EH-PEG hydrogels containing 0.25 microg and 2.5 microg BMP-2/implant. Results demonstrated that the unloaded hydrogel was initially bordered by a fibrin clot and then by fibrous encapsulation. BMP-2 loaded EH-PEG hydrogels, independent of concentration, were surrounded by fibroblasts at both time points. Histological analysis also demonstrated that significant bone growth was present at the 2.5 microg BMP-2/implant group at 28 days. This work demonstrates that the EH-PEG construct is a viable option for use and delivery of BMP-2 in vivo.

Objective: Signal transducer and activator of transcription 3 (Stat3) and survivin have been shown to exert oncogenic effects in various human neoplasms. The purpose of this study was to evaluate the expression of tyrosine phosphorylated (active) Stat3 and survivin in various benign and malignant salivary gland tumors (SGTs)., Study Design: Eighty-six SGTs (65 malignant and 21 benign tumors of various histopathologic subtypes) were immunohistochemically stained with antisurvivin or anti-phosphorylated tyrosine-705 (p-tyr) Stat3 antibodies. Immunohistochemical reactivity was graded in a semiquantitative manner; a combined score of immunohistochemical positivity (0-6) was calculated for each tumor by adding the individual scores for percentage of tumor cells (0-3) and intensity of staining (0-3)., Results: Survivin was immunohistochemically detected in all studied benign and malignant SGTs; p-tyr Stat3 was also detected in the majority (91%) of SGTs. The average combined scores for survivin and p-tyr Stat3 immunohistochemical expression in the studied malignant SGTs was 4.40 and 3.35, respectively; the corresponding combined scores for survivin and p-tyr Stat3 in the studied benign SGTs were 4.37 and 3.22, respectively. No statistically significant differences (P > .05) in p-tyr Stat3 or survivin expression were detected between the benign and malignant groups, or among the various examined histopathologic subtypes of SGTs. In contrast, normal salivary gland tissues revealed only weak and focal survivin or p-tyr Stat3 immunoreactivity, mainly localized to ductal and mucous cells., Conclusions: Our data indicate an almost universal expression of activated Stat3 and survivin in benign and malignant SGTs. Considering the well established proliferative and antiapoptotic properties of these molecules and their functional interrelationship, selective targeting techniques against Stat3 and/or survivin may represent promising therapeutic strategies against neoplasms of salivary gland origin.

Purpose: Clefts of the lip and palate are the most prevalent congenital craniofacial birth defect in humans. The developing field of tissue engineering is considered for the management of clefts of the lip and palate., Materials and Methods: A review of the literature was carried out by using electronic databases (such as PubMed and ISI Web of Science) to search topics including "cleft palate," "tissue engineering," "bone engineering," "palate engineering," and "alveolar bone grafting." To reflect current practice and research, these searches were limited primarily to articles published after the year 2000., Results: Current approaches for the treatment of clefts of the lip and palate include surgery and bone grafts; however, there are limitations associated with these therapies. Tissue engineering strategies, particularly alveolar bone engineering and soft tissue engineering, may provide clinicians with new alternatives. The application of these emerging technologies to a pediatric population must be well considered., Conclusions: A tissue engineering approach may be a useful alternative for the treatment of cleft palates as it mitigates the concerns of donor site morbidity as well as provides additional options including scaffold implantation and growth factor delivery.

Purpose: Lymph node metastasis from oral squamous cell carcinoma (SCC) correlates with a poor prognosis. Therefore, accurate assessment of lymph node status is crucial in treatment planning. Furthermore, prediction of delayed neck metastasis (DNM), especially in early stage tumors with a clinically negative (N0) neck, will determine the need for neck dissection or irradiation. In this study, we assess various clinical, histopathological and lymphangiogenic parameters in early stage oral SCC and their association with DNM., Materials and Methods: Clinical, histological, and immunohistochemical analyses were undertaken for 29 patients with T1N0M0 or T2N0M0 oral SCC affecting the tongue or floor of mouth and correlated with the development of DNM., Results: Tumor thickness, nuclear pleomorphism, pattern of invasion, and immunohistochemical expression of the lymphangiogenesis-associated molecules VEGFR-3 and VEGF-C were associated with DNM., Conclusions: Analysis of these parameters may help to identify patients who would benefit from a neck dissection or irradiation by predicting the likelihood of lymph node metastasis.

Background: Cyclooxygenase (COX) inhibitors are reported to exert anti-proliferative and pro-apoptotic effects on cancer. The effects of COX inhibitors on oral squamous cell carcinoma (SCC) and survivin expression were assessed., Materials and Methods: Primary oral SCC were analyzed immunohistochemically, and oral SCC cell lines were assessed using RT-PCR, Western blot, cell proliferation and apoptosis assays, following treatment with various COX inhibitors, SiRNA against survivin, or survivin forced expression., Results: Survivin was expressed in all studied tumors. SiRNA against survivin or treatment with sulindac, but not other COX inhibitors, decreased survivin expression and tumor cell proliferation and increased apoptosis. Forced expression of survivin attenuated sulindac's effects., Conclusion: Survivin is implicated as a marker and treatment target in oral SCC, inhibition of which causes reduction of cell proliferation and induction of apoptosis. Down-regulation of survivin expression by sulindac provides an explanation for its antineoplastic effects.

Cowden syndrome is a rare condition defined by multiple hamartomatous growths and a guarded prognosis owing to the high risk of cancer development. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. The PTEN/MMAC1/TEP1 tumor suppressor gene on chromosome 10q23.3, has proven to contain a germline mutation predisposing for uncontrolled cell growth and survival via the PI3K/AKT pathway. Presented here is a case of Cowden syndrome in a patient with multiple hamartomas of the nose, midfacial skin and oral mucosa, and fissured tongue; plus a history of bipolar disease, iron deficiency anemia, basal cell carcinoma, fibroids of the uterus, and arthritis. The family history was significant for a daughter diagnosed with lung cancer. A final diagnosis of Cowden syndrome was made on the basis of established criteria and confirmed using immunohistochemistry directed against PTEN and phosphorylated-AKT.

Plasmablastic lymphoma is an HIV-associated non-Hodgkin's lymphoma that primarily affects the oral cavity and jaws. The purpose of this report is to describe the first case of plasmablastic lymphoma occurring in an HIV-negative, nonimmunocompromised individual, and to review the histopathologic and immunohistochemical phenotype of this lymphoma. Histopathologically, our case exhibited a dense, diffuse lymphocytic infiltrate of noncohesive large lymphocytes with plasmacytoid features. Immunohistochemical analysis revealed positivity for the B-cell marker CD79a, VS38c, Epstein-Barr virus latent membrane protein (LMP), immunoglobulin G (IgG), and lambda light chain restriction. Neoplastic cells were negative for leukocyte common antigen, CD20, CD3, CD10, CD138, Bcl-2, Bcl-6, desmin, actin, EMA, S-100, HMB45, Alk-1, HHV8, IgA, IgM, and cytokeratin. The features of this rare disease are summarized based on a comprehensive review of the epidemiologic, clinical and immunohistochemical findings of previously reported cases.

Inflammatory myofibroblastic tumor (IMT) is a controversial lesion composed of myofibroblasts, accompanied by varying numbers of inflammatory cells. Various pathogenetic factors have been proposed (ie, reactive, infectious, autoimmune, and neoplastic) but the etiology of most IMTs remains unknown. Here we review the literature of oral IMTs, detailing the demographic profile of these rare lesions. Moreover, we present an unusual case of IMT arising from the mandibular alveolar mucosa of an 82-year-old female. Microscopic examination revealed plump spindle cells set in a myxoid vascular stroma admixed with inflammatory cells. Numerous large ganglion cell-like cells were seen, some exhibiting emperipolesis of neutrophils. Ultrastructurally, prominent myofibroblasts with abundant rough endoplasmic reticulum were noted. Tumor cells were immunoreactive for vimentin, smooth muscle actin, and KP1 (CD68), and negative for desmin, S-100, and EBV-LMP. The lesion was excised without margins and the patient has manifested no evidence of disease at an 18-month recall. In an attempt to further delineate the potential neoplastic nature of this lesion, we assessed the immunohistochemical expression of various markers that have been linked to neoplastic transformation. The recorded positivity for ALK, p53, MDM2, CDK4, pRb, and Ki-67, despite the absence of bcl-2 reactivity, strongly favors the neoplastic origin of the studied tumor.

Myofibroma and myofibromatosis have been described under different names since 1951. These lesions are a benign fibroblastic and myofibroblastic proliferation containing a biphasic presentation of spindle-shaped cells surrounding a central zone of less differentiated cells focally arranged in a hemangiopericytoma-like pattern. Classically, these lesions are described in children younger than 2, with two thirds present at birth, and rarely in adults. The typical clinical presentation shows variable growth pattern of a painless purple to pink soft tissue mass, often showing secondary ulceration. Controversy exists as to an autosomal dominant or recessive inheritance versus sporadic occurrence. Presented here is a unique case of myofibromatosis presenting first as a superficial scalp lesion at age 2, followed by other primary lesions of the right mandibular vestibule, right temple, and left mandibular vestibule at ages 9, 12, and 23, respectively. All were treated with excision, without recurrence at the primary site.

Apoptosis is a genetically programmed form of cell death, which primarily functions to eliminate senescent or altered cells that are useless or harmful for the multicellular organism. Contrary to necrosis, apoptosis represents a physiologic cellular mechanism, normal function and control of which are critical for the development and homeostasis of multicellular organisms. In contrast, aberrations of the apoptotic mechanisms that cause excessive or deficient programmed cell death have been linked to a wide array of pathologic conditions. This review briefly summarizes the major apoptotic pathways and molecules and presents the most important oral diseases that are related to dysregulation of apoptosis. Knowledge of the association between aberrations in apoptotic mechanisms and human pathology hopefully will be implemented for the design of improved diagnostic and prognostic assays and the development of novel, more efficient, therapeutic strategies.

Tumor progression is dependent in large part on angiogenesis and angiogenesis inhibitors have repeatedly been shown to inhibit tumor growth. The present study sought to determine whether the oral squamous carcinoma cells expressed and produced collagen XVIII, a known precursor of endostatin. Four established cell lines of oral squamous cell carcinoma (SCC) were employed for these studies. Quantitative Real-Time RT-PCR was used to assess the expression of collagen XVIII and CBP2/Hsp47, an ostensible chaperone for fibrillar and basement membrane collagens. Real-Time PCR assessment of collagen XVIII with primers selected to the common region of collagen XVIII revealed variable expression among cell lines of oral SCC. Conversely, the long form of collagen XVIII revealed no products. Comparatively, the lowest level of expression of CBP2/Hsp47 was observed in SCC4 that also had the lowest level of collagen XVIII. However, there was no direct relationship between the levels of CBP2/Hsp47 and collagen XVIII expression across the four cell lines. Treatment of SCC cells with CBP2/Hsp47 antisense phosphorothioate oligonucleotides modulated the production of collagen XVIII but not its expression. These findings imply that CBP2/Hsp47 may play a role in tumor progression by mediating the endogenous processing of collagen XVIII in tumor cells.

The nonsteroidal anti-inflammatory drug sulindac exerts a significant antineoplastic effect on several types of human cancers including oral squamous cell carcinoma (SCCa). Because constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been linked to carcinogenesis of various tumors including head and neck SCCa, we studied whether sulindac treatment affects the Stat3 signaling pathway in oral SCCa cells. Western blot experiments showed that short-term treatment of cells with sulindac resulted in a large reduction of phosphorylated Stat3, without significantly affecting Stat3 protein levels. In contrast, 3 days of sulindac treatment eliminated both phosphorylated and unphosphorylated Stat3 protein levels. Also, sulindac treatment exerted a significant time-dependent cell growth-inhibitory effect on oral SCCa cells under the same conditions shown to induce Stat3 down-modulation. The sulfone metabolite of sulindac, which lacks cyclooxygenase-inhibitory activity, did not affect either Stat3 expression or Stat3 phosphorylation. Antisense oligonucleotide treatment against peroxisome proliferator-activated receptor gamma did not attenuate the ability of sulindac to down-regulate Stat3. Our results suggest that down-modulation of Stat3 can be induced by sulindac treatment, thus possibly contributing to the antineoplastic effect of this drug.