Javier Martinez-Useros

PP2A Inhibition Is a Common Event in Colorectal Cancer and Its Restoration Using FTY720 Shows Promising Therapeutic Potential

Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. Mol Cancer Ther; 13(4); 938–47. ©2014 AACR.

Obesity and colorectal cancer: molecular features of adipose tissue

The huge part of population in developed countries is overweight or obese. Obesity is often determined by body mass index (BMI) but new accurate methods and ratios have recently appeared to measure body fat or fat located in the intestines. Early diagnosis of obesity is crucial since it is considered an increasing colorectal cancer risk factor. On the one hand, colorectal cancer has been strongly associated with lifestyle factors. A diet rich in red and processed meats may increase colorectal cancer risk; however, high-fiber diets (grains, cereals and fruits) have been associated with a decreased risk of colorectal cancer. Other life-style factors associated with obesity that also increase colorectal cancer risk are physical inactivity, smoking and high alcohol intake. Cutting-edge studies reported that high-risk transformation ability of adipose tissue is due to production of different pro-inflammatory cytokines like IL-8, IL-6 or IL-2 and other enzymes like lactate dehydrogenase (LDH) and tumour necrosis factor alpha (TNFα). Furthermore, oxidative stress produces fatty-acid peroxidation whose metabolites possess very high toxicities and mutagenic properties. 4-hydroxy-2-nonenal (4-HNE) is an active compounds that upregulates prostaglandin E2 which is directly associated with high proliferative colorectal cancer. Moreover, 4-HNE deregulates cell proliferation, cell survival, differentiation, autophagy, senescence, apoptosis and necrosis via mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PIK3CA)—AKT and protein kinase C pathways. Other product of lipid peroxidation is malondialdehyde (MDA) being able to regulate insulin through WNT-pathway as well as having demonstrated its mutagenic capability. Accumulation of point mutation enables genomic evolution of colorectal cancer described in the model of Fearon and Vogelstein. In this review, we will summarize different determination methods and techniques to assess a truthfully diagnosis and we will explain some of the capabilities that performs adipocytes as the largest endocrine organ.

Oxidative Stress: A New Target for Pancreatic Cancer Prognosis and Treatment

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumors, and its incidence is rising worldwide. Survival can be improved when tumors are detected at an early stage; however, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. Several risk factors are associated to this disease. Chronic pancreatitis, diabetes, and some infectious disease are the most relevant risk factors. Incidence of PDAC has increased in the last decades. It is hypothesized it could be due to other acquired risk habits, like smoking, high alcohol intake, and obesity. Indeed, adipose tissue is a dynamic endocrine organ that secretes different pro-inflammatory cytokines, enzymes, and other factors that activate oxidative stress. Reactive oxygen species caused by oxidative stress, damage DNA, proteins, and lipids, and produce several toxic and high mutagenic metabolites that could modify tumor behavior, turning it into a malignant phenotype. Anti-oxidant compounds, like vitamins, are considered protective factors against cancer. Here, we review the literature on oxidative stress, the molecular pathways that activate or counteract oxidative stress, and potential treatment strategies that target reactive oxygen species suitable for this kind of cancer.

The challenge of blocking a wider family members of EGFR against head and neck squamous cell carcinomas

Head and neck squamous cell carcinoma (HNSCC) represent 95% of head and neck cancer with an incidence of over half a million people globally. The prognosis for patients with recurrent or metastatic HNSCC is generally poor with low 5-year survival rates despite treatment advances over the past few decades. Consequently, it is essential to search for new biomarkers and effective therapy options to optimize HNSCC treatment. Epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of tumours. EGFR has become one of most common targets for new therapies being investigated in HNSCC. In this way, multiple therapies targeting EGFR in HNSCC have been tested but response rates are still low especially in the recurrent or metastatic setting. This has been attributed to mechanisms of resistance to EGFR-targeted therapies. Afatinib, an oral small molecule ErbB Family Blocker that irreversibly binds to ErbB1 (EGFR), ErbB2 (HER2) and ErbB4 (HER4), is being investigated in HNSCC treatment with encouraging phase II results and several ongoing phase III trials. Results of these trials will help to understand the place of afatinib in the HNSCC treatment armamentarium.

Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer

KRAS mutation is often present in many hard-to-treat tumors such as colon and pancreatic cancer and it is tightly linked to serious alterations in the normal cell metabolism and clinical resistance to chemotherapy. In 1931, the winner of the Nobel Prize in Medicine, Otto Warburg, stated that cancer was primarily caused by altered metabolism interfering with energy processing in the normal cell. Increased cell glycolytic rates even in the presence of oxygen is fully recognized as a hallmark in cancer and known as the Warburg effect. In the late 1970′s, Linus Pauling and Ewan Cameron reported that vitamin C may have positive effects in cancer treatment, although deep mechanistic knowledge about this activity is still scarce. We describe a novel antitumoral mechanism of vitamin C in KRAS mutant colorectal cancer that involves the Warburg metabolic disruption through downregulation of key metabolic checkpoints in KRAS mutant cancer cells and tumors without killing human immortalized colonocytes. Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation. As a consequence of this activity, strong downregulation of the glucose transporter (GLUT-1) and pyruvate kinase M2 (PKM2)-PTB dependent protein expression are observed causing a major blockage of the Warburg effect and therefore energetic stress. We propose a combination of conventional chemotherapy with metabolic strategies, including vitamin C and/or other molecules targeting pivotal key players involved in the Warburg effect which may constitute a new horizon in anti-cancer therapies.

Can Molecular Biomarkers Change the Paradigm of Pancreatic Cancer Prognosis

Pancreatic ductal adenocarcinoma is one of the most lethal types of tumour, and its incidence is rising worldwide. Although survival can be improved when these tumours are detected at an early stage, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. The only prognostic biomarker approved by the FDA to date is carbohydrate antigen 19-9 (CA19-9); however, the specificity of this biomarker has been called into question, and diagnosis is usually based on clinical parameters. Tumour size, degree of differentiation, lymph node status, presence of distant metastasis at diagnosis, protein levels of KI-67 or C-reactive protein, and mutational status of P53, KRAS, or BRCA2 are the most useful biomarkers in clinical practice. In addition to these, recent translational research has provided evidence of new biomarkers based on different molecules involved in endoplasmic reticulum stress, epithelial-to-mesenchymal transition, and noncoding RNA panels, especially microRNAs and long noncoding RNAs. These new prospects open new paths to tumour detection using minimally or noninvasive techniques such as liquid biopsies. To find sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.

The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients.

Decreased PLK1 expression denotes therapy resistance and unfavourable disease-free survival in rectal cancer patients receiving neoadjuvant chemoradiotherapy

AIM Polo-like kinase 1 (Plk1) plays a key role in mitotic cell division and DNA damage repair. It has been observed that either up-regulated or down-regulated Plk1 could induce mitotic defects that results in aneuploidy and tumorigenesis, probably depending on the context. Few previous reports have associated Plk1 expression with prognosis and response to radiotherapy in rectal carcinomas. The aim of this study is to investigate the prognostic impact of Plk1 expression and its role in predicting response to neoadjuvant cheomoradiotherapy in rectal cancer. METHODS AND RESULTS Immunohistochemical analysis of Plk1 expression was performed in the pre-treatment tumour specimens from 75 rectal cancer patients. We analysed the assocation between Plk1 expression and clinicopathological parameters, pathologic response and outcome. Opposed to previous reports on this issue, low expression of Plk1 was significantly associated with a high grade of differentiation (P=0.0007) and higher rate of distant metastasis (P=0.014). More importantly, decreased levels of Plk1 were associated with absence of response after neoadjuvant therapy (P=0.049). Moreover, low Plk1 expression emerged as an unfavourable prognostic factor for disease-free survival in the non-responder group of patients (P=0.037). CONCLUSIONS Decreased Plk1 expression was associated with poor pathologic response and worse disease-free survival in rectal cancer patients receiving neoadjuvant chemoradiotherapy, suggesting Plk1 as a clinically relevant marker to predict chemoradiotherapy response and outcome.

UNR/CDSE1 expression as prognosis biomarker in resectable pancreatic ductal adenocarcinoma patients: A proof-of-concept

Pancreatic ductal adenocarcinoma is an aggressive form of pancreatic cancer and the fourth leading cause of cancer-related death. When possible, curative approaches are based on surgical resection, though not every patient is a candidate for surgery. There are clinical guidelines for the management of these patients that offer different treatment options depending on the clinical and pathologic characteristics. However, the survival rates seen in this kind of patients are still low. The CDSE1 gene is located upstream of NRAS and encodes an RNA-binding protein termed UNR. The aim of this study was to analyze UNR expression and its correlation with outcome in patients with resectable pancreatic ductal adenocarcinoma (PDAC). For this, samples from resectable PDAC patients who underwent duodenopancreatectomy were used to evaluate UNR protein expression by immunohistochemistry using a tissue microarray. Here, we observed that low UNR expression was significantly associated with shorter progression-free survival after surgery (P = 0.010). Moreover, this prognostic marker remained significant after Cox proportional hazards model (P = 0.036). We further studied the role of CDSE1 expression in patient’s prognosis using data from public repositories (GEO and TGCA), confirming our results. Interestingly, CDSE1 expression correlated with that of genes characteristic of an immunogenic molecular subtype of pancreatic cancer. Based on these findings, UNR may be considered a potential prognostic biomarker for resectable PDAC and may serve to guide subsequent adjuvant treatment decisions.

Identification of Poor-outcome Biliopancreatic Carcinoma Patients With Two-marker Signature Based on ATF6α and p-p38 "STARD Compliant".

AbstractBiliopancreatic cancer is one of the most aggressive solid neoplasms, and incidence is rising worldwide. It is known that ATF6&agr; is one of the transmembrane proteins that acts crucially in endoplasmic reticulum stress response, and knockdown induces apoptosis of pancreatic cells. Apart from this, p-p38 has been previously correlated with better outcome in pancreatic cancer. Interestingly, ATF6&agr; knockdown pancreatic cells showed increased p-p38. The aim of this study was to evaluate the expression of these 2 proteins, p-p38 and ATF6&agr;, and their correlation with the outcome of biliopancreatic adenocarcinoma patients.Samples from patients with biliopancreatic adenocarcinoma that underwent pancreaticoduodenectomy from 2007 to 2013 were used to construct a tissue microarray to evaluate p-p38 and ATF6&agr; proteins by immunohistochemistry.We observed that both markers showed a tendency to impact in the time to recurrence; then a combination of these 2 proteins was analyzed. Combination of ATF6&agr;high and p-p38low was strongly associated with a higher risk of recurrence (hazard ratio 2.918, P = 0.013). This 2-protein model remained significant after multivariate adjustment.We proposed a 2-protein signature based on ATF6&agr;high and p-p38low as a potential biomarker of risk of recurrence in resected biliopancreatic adenocarcinoma patients.