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PURPOSE: Despite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance. METHODS: Two independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 µm haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low (≤ 50%) or TSR-high (> 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan-Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I-II, TNM-stage III and patients with an indication for chemotherapy separately. RESULTS: We found that high TSR was associated with poor cancer-free survival in TNM-stage I-II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II-III colon tumour. CONCLUSION: In colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

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Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

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Liver cancer is the second most frequent cause of cancer death in men and the sixth leading cause of cancer death in women. Hepatocellular carcinoma (HCC) represents the major subtype in liver cancer and its five-year survival rate remains very poor. Sorafenib, a molecular targeted therapeutic agent, was the first drug approved for the treatment of patients with HCC. However, the clinical response of sorafenib was seriously limited by drug resistance. Autophagy is an evolutionarily conserved mechanism among all eukaryotes. Recently, many studies have indicated that autophagy can be activated as a cellular protective mechanism in many tumour cells. Thus, we hypothesized that autophagy may play an important role in resistance to sorafenib in hepatocellular carcinoma. Although the exact role of autophagy in the sorafenib resistance of HCC is still complex and further studies are needed to be proven, at least it suggests that autophagy may be a new therapeutic target for the sorafenib resistance of HCC.

El cáncer de hígado es la segunda causa de muerte más frecuente por cáncer en los hombres y la sexta causa de muerte por cáncer en las mujeres. El carcinoma hepatocelular (CHC) representa el subtipo principal en el cáncer de hígado, y su tasa de supervivencia de cinco años sigue siendo muy pobre. El sorafenib, un agente terapéutico dirigido selectivamente a moléculas especificas, fue el primer medicamento aprobado para el tratamiento de pacientes con CHC. Sin embargo, la respuesta clínica de sorafenib estaba seriamente limitada por la resistencia al medicamento. La autofagia es un mecanismo evolutivamente conservado entre todos las eucariotas. Recientemente, muchos estudios han indicado que la autofagia puede activarse como mecanismo de protección celular en muchas células tumorales. Por consiguiente, postulamos la hipótesis de que la autofagia puede desempeñar un papel importante en la resistencia del carcinoma hepatocelular al sorafenib. Aunque el papel exacto de la autofagia en la resistencia al sorafenib del CHC es aún complejo y se necesitan estudios adicionales para ser probado, al menos se sugiere que la autofagia puede ser una nueva meta terapéutica frente a la resistencia del sorafenib en el CHC.

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and its five-year survival rate remains low. Autophagy is a catabolic process conserved among all eukaryotes ranging from yeast to mammals. Recently, many studies show that tumour cells can utilize autophagy as a cellular defence mechanism when facing metabolic stress. Thus, we hypothesize that autophagy may play an important role in the resistance of hepatocellular carcinomas to therapy. Although the exact role of autophagy on tumour cells is still complex and further studies are needed to prove the impact of autophagy on HCC, it suggests that autophagy may be a new therapeutic target for the resistance to therapy of HCC.

El carcinoma hepatocelular (CHC) es uno de los tumores malignos más comunes, y su tasa de super-vivencia a los cinco años sigue siendo baja. La autofagia es un proceso catabólico conservado en todos los eucariotas, que abarca desde las levaduras hasta los mamíferos. Recientemente, numerosos estudios han demostrado que las células tumorales pueden utilizar la autofagia como un mecanismo celular de defensa frente al estrés metabólico. De este modo, sostenemos la hipótesis de que la autofagia puede desempeñar un papel importante en la resistencia de los carcinomas hepatocelulares a la terapia. Aunque el papel exacto de la autofagia en las celulares tumorales sigue siendo complejo, y se requieren más estudios a fin de probar el impacto de la autofagia en el CHC, hay indicios de que la autofagia puede ser un nuevo objetivo terapéutico para la resistencia a la terapia del CHC.

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