Abel García-García

Multidrug resistance in oral squamous cell carcinoma: The role of vacuolar ATPases

Resistance to chemotherapy agents is the main reason for treatment failure in patients with cancer. Multidrug resistance (MDR) is the primary mechanism that leads to the acquisition of the multiresistant phenotype through the overexpression of drug efflux transporters such as the P-glycoprotein (Pgp), encoded by the MDR1 gene, at the plasma membrane. Other molecules that have been implicated in drug resistance include multidrug resistance-associated proteins, glutathione S-transferase-pi, and DNA topoisomerase II. These molecules, however, cannot fully explain MDR in oral squamous cell carcinoma. Vacuolar ATPase (V-ATPase), which is largely responsible for regulating acidity in the microenvironment of solid tumors (and hence interfering with the absorption of chemotherapy drugs), seems to be the most important molecule involved in MDR in such tumors. Specific V-ATPase inhibitors, thus, may be useful, not only as coadjuvants in antitumor treatments but also as a mechanism for controlling resistance to antitumor drugs.

Hypoxia-inducible factors in OSCC.

Oral squamous cell carcinoma (OSCC) is a characteristic locally aggressive tumor in which hypoxia levels are very high, causing a low response to chemotherapy and providing basic resistance to anticancer drugs. Tumoral hypoxia directly depends on hypoxia-inducible factors (HIF). The goal of this paper is to describe HIF basic biology and tumor cells (HIF-1α, mainly), analyzing the effects of its expression in OSCC, study its relation with other molecules such as nitric oxide (NO), carbonic anhydrase (CA) or VEGF and assess the possibility of its manipulation as a therapeutic target.

Oral bisphosphonate-related osteonecrosis of the jaws: Clinical characteristics of a series of 20 cases in Spain

Objective: The objective of this study was to define the clinical characteristics of osteonecrosis of the jaws (ONJ) induced by oral bisphosphonates in a series of patients from a circumscribed area in northwest Spain. Study Design:A retrospective multicentre study was undertaken in 3 hospitals in an area with a radius less than 100 km in the Autonomous Community of Galicia (Spain). The medical records were reviewed and an oral examination was performed of patients diagnosed with oral bisphosphonate-related ONJ in the previous 3 years. Results: We detected 20 cases of ONJ (24 lesions) related to oral bisphosphonates (alendronate [16 patients] and ibandronate [4 patients]), which were mainly administered as treatment for osteoporosis (17 patients). The mean interval between initiation of treatment and confirmation of a diagnosis of ONJ was 66±43 months (range, 6-132 months); in 7 patients (35%) the interval was less than 36 months. The past history revealed hypertension in 13 cases (65%) and diabetes in 4 (20%); 7 patients (35%) were on corticosteroid treatment. Oral surgery had been previously performed in 13 patients (65%) and the remaining 7 patients (35%) had removable dental prostheses. The lesions most frequently affected the posterior mandible (62.5%). The majority of the lesions (75%) were classified as stage 2, although lesions were identified in all established clinical stages (including 2 stage 0 lesions). Conclusion: In conclusion, in the present series, ONJ induced by oral bisphosphonates typically develops in women around 70 years of age, taking alendronate, that underwent oral surgery. Most lesions are located in the posterior mandible and are classified as stage 2 at diagnosis. Some patients presented no known risk factors, suggesting that there may be risk factors still to be identified. There are well-defined patterns of clinical presentation that can facilitate early diagnosis of ONJ. Key words:Oral bisphosphonates, osteonecrosis of the jaws, alendronate.

Measurement of ATP6V1C1 expression in brush cytology samples as a diagnostic and prognostic marker in oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Brush cytology has reemerged as a molecular tool for diagnosing this cancer. ATP6V1C1, one of the main genes regulating V-ATPase activity, has been implicated in metastasis and multiple drug resistance. The aim of this study was to measure ATP6V1C1 expression levels in OSCC and to evaluate the value of this test in the diagnosis and prognosis of OSCC. Material and Methods: Patients with OSCC and a control group of healthy individuals were studied. The clinical and demographic variables analyzed included age, sex, smoking, tumor location, and tumor stage. Brush cytology samples were obtained using a cytology brush and analyzed by real-time quantitative polymerase chain reaction for ATP6V1C1 expression. Results: The differences in ATP6V1C1 expression between patients and controls were statistically significant (Mann-Whitney U test = 26, p

p16INK4a/CDKN2 expression and its relationship with oral squamous cell carcinoma is our current knowledge enough?

Oral squamous cell carcinomas (OSCC) are the most common malignancy of the oral cavity and their multistep development requires the accumulation of multiple genetic and epigenetic alterations. Inactivation of p16(INK4a), encoded by the CDKN2 gene has been widely associated with this type of tumors. The purpose of this review is to elucidate the relationship between p16(INK4a) expression and the different clinical and pathological aspects of OSCC, analyze the variation in results between studies, detailing the described genetic/epigenetic alterations that result in gene silencing and the relationship between p16(INK4a) and HPV infection.

Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients

INTRODUCTION Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues. MATERIAL AND METHODS This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves. RESULTS Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III-IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I-II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank=6.1, P value=0.0484. CONCLUSIONS Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor.

Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - a therapeutic target?

Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet.

The role of the adenomatous polyposis coli (APC) in oral squamous cell carcinoma.

The main cause of death in oral squamous cell carcinomas (OSCC) is metastasis. Intercellular adhesion is mediated by a family of glycoproteins called cadherins and other molecules like catenins and APC (adenomatous polyposis coli) among other. The WNT (wingless-type) gene family is a group of genes, key signaling pathway for embryonic development and oncogenesis. The goal of this paper is to describe the role of the APC gene, and its derivatives, in the carcinogenicity pathway of WNT-1, identifying its role as a tumor suppressor gene in OSCC, while describing the genetic (loss of heterozygosity and mutations) and epigenetic alterations that modulate its expression and evaluate its relationship with the clinicopathological parameters of this type of tumors. As for APC, its activity as a tumor suppressor gene appears muted on a relatively frequent basis in these tumors, either by LOH, mutations or epigenetic control mechanisms, thus resulting in a low degree of agreement between the results of different studies.

What real influence does the proto-oncogene c-myc have in OSCC behavior?

The influence of c-myc in the carcinogenic process has been previously described although in the specific case of oral tumors it has been poorly tested. Myc proteins are a family of proto-oncogenes involved in the cell proliferation regulation, differentiation and apoptosis. The goal of this paper is to describe the functions of c-myc and its role as oncogene, assessing its expression by immunohistochemistry and genetic amplification studies, and studying its relationship with tumoral clinical and pathological variables, and describing genetic and molecular interactions in OSCC.

Current trends in miRNAs and their relationship with oral squamous cell carcinoma

A micro RNA (miRNA) is a single-stranded endogenous, non-coding RNA, with length ranging between 18 and 24 nucleotides and the ability of regulating the expression of other genes on a post-transcriptional level by means of various processes, degradation or repression of target mRNA. miRNAs play a crucial role in regulating fundamental processes such as cell cycle, differentiation and apoptosis; thus, their deregulation can affect normal cell growth and development, and even participate in carcinogenesis. The goals of this paper are: to outline the formation and functions of miRNAs; to determine their role in oral squamous cell carcinoma; to analyze the different miRNAs described and their roles as oncogenes or tumor suppressor genes, depending on their overexpression or subexpression; to describe the different polymorphisms and epigenetic alterations identified; and to determine their role in multidrug resistance.