Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

Simple Summary: Emerging evidence points to succinate as an important oncometabolite in cancer development; however, the contribution of the succinate-SUCNR1 axis to cancer progression remains unclear. Head and neck squamous cell carcinoma (HNSCC) is associated with disease and treatmentrelated morbidity so there is an urgent need for innovation in treatment and diagnosis practices. Our aim was to evaluate the potential of the succinate-related pathway as a diagnostic and prognostic biomarker in HNSCC. The circulating succinate levels are increased in HNSCC, being a potential noninvasive biomarker for HNSCC diagnosis. Moreover, the succinate receptor (SUCNR1) and genes related to succinate metabolism, which are predominantly expressed in the tumoral mucosa as compared with healthy tissue, are positively associated with plasma succinate. Remarkably, we found that SUCNR1 and SDHA expression levels predict prognosis

Impacte d’alteracions metabòliques associades a l'obesitat sobre el paper de la survivina en càncer

La survivina és una proteïna multifuncional, històricament associada a processos tumorals i al desenvolupament embrionari que regula la proliferació i l’apoptosi cel·lular. Tot i que la seva funció en càncer està àmpliament estudiada, la seva implicació en altres patologies relacionades no està tan definida. De fet, estudis recents suggereixen que la survivina podria tenir un paper important en la fisiopatologia de l'obesitat, patologia metabòlica d’elevada prevalença considerada un factor de risc associat al desenvolupament de diversos càncers. Aquesta tesi doctoral se centra en l'estudi del paper de la survivina en les relacions entre cèl·lules del microambient tumoral, cèl·lules mare del teixit adipós (ASCs), macròfags i cèl·lules tumorals en el context de l'obesitat. També analitzem el paper que podria tenir la survivina en la progressió i resposta a la radioteràpia de pacients amb càncer de cap i coll (CCC) i la seva relació amb l’estat metabòlic. Identifiquem que la survivina del secretoma de les ASCs de pacients amb obesitat promou la polarització protumoral dels macròfags i que aquests tenen la capacitat d’internalitzar-la i secretar-la. Trobem que la survivina activa un fenotip híbrid dels macròfags i els promou l’activitat protumoral amb dependència de la fosforilació en la Treonina 34. A més, establim la survivina com nexe molecular entre ASCs, macròfags i cèl·lules tumorals, així com a possible nou marcador específic de macròfag associat a tumors. En el context del CCC, associem l’expressió de survivina en la mucosa tumoral amb el risc de recurrència, resposta al tractament i glucosa circulant de pacients amb CCC. En un model in vitro demostrem que en cèl·lules poc o mitjanament radioresistents la sobreexpressió de survivina regulada per la radiació s’associa a un fenotip protumoral. També trobem que els nivells elevats de glucosa inhibeixen la regulació de la survivina per la radiació i augmenten la sensibilitat a l’apoptosi.La survivina es una proteína multifuncional, históricamente asociada a procesos tumorales y al desarrollo embrionario que regula proliferación y apoptosis celular. Aunque su función en cáncer está ampliamente estudiada, su implicación en otras patologías relacionadas no está tan definida. De hecho, estudios recientes sugieren que la survivina podría tener un papel importante en la fisiopatología de la obesidad, patología metabólica de elevada prevalencia considerada factor de riesgo asociado al desarrollo de diferentes tumores. Esta tesis doctoral se centra en el estudio del papel de la survivina en las relaciones entre las células del microambiente tumoral, células madre de tejido adiposo (ASCs), macrófagos y células tumorales en el contexto de la obesidad. También analizamos el papel que podría tener la survivina en la progresión y respuesta a la radioterapia de pacientes con cáncer de cabeza y cuello (CCC) y su relación con el estado metabólico. Identificamos que la survivina del secretoma de ASCs de pacientes con obesidad promueve la polarización protumoral de los macrófagos y que estos tienen la capacidad de internalizarla y secretarla. Encontramos que la survivina activa un fenotipo híbrido de los macrófagos y les promueve actividad protumoral con dependencia de la fosforilación en la Treonina 34. Además, establecemos la survivina como nexo molecular entre ASCs, macrófagos y células tumorales, así como posible marcador específico de macrófago asociado a tumores. En el contexto del CCC, asociamos la expresión de survivina en la mucosa tumoral con el riesgo de recurrencia, respuesta al tratamiento y glucosa circulante de pacientes con CCC. En modelos in vitro demostramos que en células poco o medianamente radioresistentes la sobreexpresión de survivina regulada por la radiación se asocia a un fenotipo protumoral. También encontramos que los niveles incrementados de glucosa inhiben la regulación de la survivina por la radiación y aumentan la sensibilidad a la apoptosis.Survivin is a multifunctional protein, historically associated with tumoral processes and embryonic development that regulates cellular proliferation and apoptosis. Although its function in cancer is widely studied, its implication with other pathologies is not well defined. In fact, recent studies suggest that survivin might have an important role in the physiopathology of obesity, a metabolic pathology with high prevalence and an acknowledged risk factor for development of different types of cancer. This doctoral thesis is focused on identifying the role of survivin in the relationship between the cells from the tumor microenvironment, namely, adipose-derived stem cells (ASCs), macrophages and tumoral cells in the context of obesity. We also analyze the role of survivin in the progression and response to radiotherapy of patients with head and neck squamous carcinoma (HNSCC) and its relationship with the metabolic state. We show that survivin from ASCs’ secretome of patients with obesity promotes protumoral polarization of macrophages, which are both capable of internalize and secrete survivin. We find that survivin activates a hybrid phenotype of macrophages and promotes their protumoral activity with dependence of the phosphorylation in Threonine 34. Importantly, we establish survivin as a new molecular link between ASCs, macrophages, and tumor cells, as well as a new specific marker of tumor-associated macrophages. In the context of HNSCC, we associate survivin expression in tumoral mucosa with recurrence risk, treatment response and circulating glucose in patients with HNSCC. In an in vitro model we demonstrate that survivin expression regulated by radiation in low-medium radioresistant cells is associated with a protumoral phenotype. We also find that high glucose levels inhibit survivin regulation by radiation and increase cells sensitivity to apoptosis

Succinate Pathway in Head and Neck Squamous Cell Carcinoma : Potential as a Diagnostic and Prognostic Marker

Emerging evidence points to succinate as an important oncometabolite in cancer development; however, the contribution of the succinate-SUCNR1 axis to cancer progression remains unclear. Head and neck squamous cell carcinoma (HNSCC) is associated with disease and treatment-related morbidity so there is an urgent need for innovation in treatment and diagnosis practices. Our aim was to evaluate the potential of the succinate-related pathway as a diagnostic and prognostic biomarker in HNSCC. The circulating succinate levels are increased in HNSCC, being a potential noninvasive biomarker for HNSCC diagnosis. Moreover, the succinate receptor (SUCNR1) and genes related to succinate metabolism, which are predominantly expressed in the tumoral mucosa as compared with healthy tissue, are positively associated with plasma succinate. Remarkably, we found that SUCNR1 and SDHA expression levels predict prognosis. Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1α, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9-100.0] vs. 16.7% [95% CI: 0.0-44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis

Pharmacokinetics in morbid obesity: influence of two bariatric surgery techniques on paracetamol and caffeine metabolism

PURPOSE: The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). MATERIALS AND METHODS: In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. RESULTS: Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. CONCLUSIONS: Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity)

Pharmacokinetics in morbid obesity: influence of two bariatric surgery techniques on paracetamol and caffeine metabolism

PURPOSE: The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). MATERIALS AND METHODS: In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. RESULTS: Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. CONCLUSIONS: Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity)