Role of gut bacterial and non-bacterial microbiota in alcohol-associated liver disease: Molecular mechanisms, biomarkers, and therapeutic prospective.

Alcohol-associated liver disease (ALD) comprises a spectrum of liver diseases that include: steatosis to alcohol-associated hepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The pathophysiology and potential underlying mechanisms for alcohol-associated liver disease are unclear. Moreover, the treatment of ALD remains a challenge. Intestinal microbiota include bacteria, fungi, and viruses, that are now known to be important in the development of ALD. Alcohol consumption can change the gut microbiota and function leading to liver disease. Given the importance of interactions between intestinal microbiota, alcohol, and liver injury, the gut microbiota has emerged as a potential biomarker and therapeutic target. This review focuses on the potential mechanisms by which the gut microbiota may be involved in the pathogenesis of ALD and explains how this can be translated into clinical management. We discuss the potential of utilizing the gut microbiota signature as a biomarker in ALD patients. Additionally, we present an overview of the prospect of modulating the intestinal microbiota for the management of ALD.

The prognostic and therapeutic application of microRNAs in breast cancer: Tissue and circulating microRNAs.

Breast cancer is the second most common malignancy diagnosed in women, supporting the need for identification of novel prognostic and diagnostic biomarkers. Recently, microRNAs have emerged as molecular regulators that can have key roles in pathogenesis and progression of different malignancies, including breast cancer. Micro-RNAs can be circulated in body fluid, suggesting their values as non-invasive marker. There is growing body of evidence showing the aberrant activation of some known circulating miRNAs, for example let-151a, miR-21, miR-155, miR-,145 miR-18a, miR-16 as well as tissue specific-miRNAs, for example miR-182, miR-145, miR-21, miR-155/154, miR-203, miR-213, miR-7 in patients affected by breast cancer. In addition, there is growing body of evidences on the value of miRNAs to be associated with drug-resistance, suggesting their values as a potential approach to overcome chemo-resistance. Attuned with these facts, this review highlights recent preclinical and clinical investigation performed on tissue-specific miRNAs and circulating as novel promising biomarkers for detection of patients at early stages, prediction of prognosis, and monitoring of the patients in response to therapy.

Genetic variants as potential predictive biomarkers in advanced colorectal cancer patients treated with oxaliplatin-based chemotherapy.

Chemotherapy regimen containing oxaliplatin is often the first-line treatment for patient with advanced colorectal cancer. Oxaliplatin binds to DNA, leading to the formation of crosslinks and bulky adducts. Approximately 50% of patients with CRC benefit from treatment with oxaliplatin. It is possible that genetic variants in biological pathways involved in drug transportation, drug metabolism, DNA damage repair, and cell cycle modulation might affect the activity, or efficacy of oxaliplatin. Because oxaliplatin resistance may be related to these genetic variants and may therefore be an important reason for treatment failure, we have summarized the genetic variations that have been reported to be predictive markers of the response to oxaliplatin based therapy in patients with advanced CRC.

Therapeutic Potential of Targeting PI3K/AKT Pathway in Treatment of Colorectal Cancer: Rational and Progress.

PI3K/AKT/mTOR signaling pathway is one of the key dysregulated pathways in different tumor types, including colorectal cancer (CRC). Activation of this pathway is shown to be related with cellular transformation, tumor progression, cell survival, and drug resistance. There is growing body of data evaluating the value of PI3K/AKT/mTOR inhibitors in CRC (e.g., BEZ235, NVP-BEZ235, OSI-027, everolimus, MK-2206, KRX-0401, BYL719, and BKM120). This report summarizes the current knowledge about PI3K/AKT pathway and its cross talk with ERK/MAPK and mTOR pathways with particular emphasis on the value of targeting this pathway as a potential therapeutic target in treatment of colorectal cancer. J. Cell. Biochem. 119: 2460-2469, 2018. © 2017 Wiley Periodicals, Inc.

Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress.

Colorectal cancer (CC) is often diagnosed at a late stage when tumor metastasis may have already occurred. Current treatments are often ineffective in metastatic disease, and consequently late diagnosis is often associated with poor outcomes in CC. Alternative strategies are therefore urgently required. An interaction between epithelial cancer cells and their tissue microenvironment is a contributor to metastasis, and therefore recent studies are beginning to focus on the properties of the tumor microenvironment and the mechanism by which the metastatic cells exploit the tumor microenvironment for survival, immune evasion, and growth. We have reviewed the development of the combined therapeutic approaches that have focused on targeting the microenvironment of CC.

The Therapeutic Potential of Targeting Tumor Microenvironment in Breast Cancer: Rational Strategies and Recent Progress.

The tumor microenvironment (TME) is cellular environment in addition to harboring carcinoma cells, consists of different components (e.g., blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules, and the extracellular matrix) that have an essential role on drug activity and efficacy. There is growing body of evidence showing its involvement in the progression and metastasis of different cancers, including breast cancer (BC). These observations provide a proof of concept of targeting TME compartments as a novel potential therapeutic approach in treatment of this malignancy, which is the main interested for current review. J. Cell. Biochem. 119: 111-122, 2018. © 2017 Wiley Periodicals, Inc.

Genetic susceptibility in cervical cancer: From bench to bedside.

Cervical cancer (CC) is the third most common malignancy in women globally, and persistent infection with the oncogenic human papillomaviruses (HPV) is recognized as the major risk factor. The pathogenesis of CC relies on the interplay between the tumorigenic properties of the HPV and host factors. Host-related genetic factors, including the presence of susceptibility loci for cervix tumor is substantial importance. Preclinical and genome-wide association studies (GWAS) have reported the associations of genetic variations in several susceptibility loci for the development of cervical cancer. However, many of these reports are inconsistent. In this review, we discuss the findings to date of candidate gene association studies, and GWAS in cervical cancer. The associations between these genetic variations with response to chemotherapy are also discussed.

Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application.

Hirschsprung's disease (HSCR) is a congenital disorder, defined by partial or complete loss of the neuronal ganglion cells in the intestinal tract, which is caused by the failure of neural crest cells to migrate completely during intestinal development during fetal life. HSCR has a multifactorial etiology, and genetic factors play a key role in its pathogenesis; these include mutations within several gene loci. These have been identified by screening candidate genes, or by conducting genome wide association (GWAS) studies. However, only a small portion of them have been proposed as major genetic risk factors for the HSCR. In this review, we focus on those genes that have been identified as either low penetrant or high penetrant variants that determine the risk of Hirschsprung's disease. J. Cell. Biochem. 119: 28-33, 2018. © 2017 Wiley Periodicals, Inc.

The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress.

Breast cancer (BC) is the most commonly diagnosed cancer in women. The PI3K/AKT/mTOR pathway is among the most frequently dysregulated pathways in patients with BC. The activation of this pathway is associated with increased cell growth and clinical outcome, and its overexpression is associated with a poor prognosis. It has been proposed that it may be of importance as a potential therapeutic target in the treatment of BC. The aim of current review is to provide an overview of the potential utility of PI3K/Akt/mTOR inhibitors in patients with BC, with particular emphasis on recent preclinical and clinical studies. J. Cell. Biochem. 119: 213-222, 2018. © 2017 Wiley Periodicals, Inc.

Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer.

The V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is frequently dysregulated in colorectal cancer (CRC). It is involved in the modulation of several downstream effectors, that include: Raf/Mek/Erk, PI3K/Akt, RalGDS/p38MAPK, and Rac/Rho, and thereby influences tumorigenesis, the invasive behaviors of tumor cell, and resistance to therapy. There is growing evidence exploring the use of drugs that target these pathways in the treatment of CRC. Cetuximab has been approved for CRC patients without a KRAS mutation, or for EGFR-expressing metastatic CRC, although some of the patients have a mutation of KRAS and NRAS. This review summarizes the recent knowledge about the therapeutic potential of targeting RAS with particular emphasis on recent preclinical and clinical studies in treatment of CRC.

Genetic variation in the DNA repair pathway as a potential determinant of response to platinum-based chemotherapy in breast cancer.

Platinum-based chemotherapy is often used as a first-line treatment for patient with breast cancer. Platinum agents bind to DNA, forming adducts that contain intra and inter-strand crosslinks. It is possible that genetic variations of the DNA repair pathways may affect the activity, or efficacy of platinum, and hence resistance to platinum chemotherapy may be related to these genetic variants. We have summarized the known variants in the DNA repair pathway that have been reported to predict the response to platinum-based therapy in breast cancer.

Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer.

The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.

C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives.

Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis, and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK-rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy.

Therapeutic Potential of Targeting Wnt/ß-Catenin Pathway in Treatment of Colorectal Cancer: Rational and Progress.

Wnt/ß-catenin pathway is one of the main/frequent dysregulated pathways in several tumor types, including colon cancer. Aberrant activation of this pathway is associated with cell proliferation, invasive behaviors, and cell resistance, suggesting its potential value as a therapeutic target in treatment of CRC. Several agents have been developed for targeting of this pathway (e.g, natural agents: curcumin, 3,3-diindolylmethane, phytoestrogen; Synthetic/small Wnt inhibitors: Rofecoxib; PRI-724, CWP232291; and monoclonal antibody against frizzled receptors, Vanituctumab). This review summarizes the current knowledge about the therapeutic potential of targeting Wnt pathway with particular emphasis on preclinical/clinical studies in treatment of colorectal cancer. J. Cell. Biochem. 118: 1979-1983, 2017. © 2017 Wiley Periodicals, Inc.

Current Status and Perspectives Regarding the Therapeutic Potential of Targeting EGFR Pathway by Curcumin in Lung Cancer.

Lung cancer is among the leading causes of cancer-related-death. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. More than 70% of NSCLC patients have locally advanced or metastatic disease in diagnosis stage, which are then being treated with platinum-based chemotherapy or epidermal-growthfactor- receptor (EGFR) inhibitors. Several molecules which target multiple ErbB receptors and EGFR have been developed, including gefitinib and erlotinib. Identification of novel agents with less toxicity is warranted. Several interesting data have been reported about the antitumor activity of curcumin in several tumors, including lung, breast and colorectal cancers. In particular, a recent phase I trial evaluated the activity of curcumin in combination with FOLFOX chemotherapy in patients with inoperable colorectal cancer. They showed that curcumin added benefit in subsets of patients when administered with FOLFOX and was well-tolerated chemotherapy adjunct. Another ongoing trial is now investigating the beneficial effects of curcumin plus gefitinib or erlotinib for EGFRmutant NSCLC. Improved understanding of molecular mechanisms behind resistance to EGFR tyrosine kinase inhibitors suggests the importance of a genotype-guided approach to therapy and inhibition of parallel and downstream pathways, using agents which target heat-shock-protein-90, poly (ADP-ribose) polymerase and PI3K/mTOR pathway. The aim of the current review is to give an overview of the possible molecular mechanisms of curcumin in the preclinical and clinical investigations in solid tumors, with particular emphasis on its combination with other chemotherapeutic agents in lung cancers.

Phospho-Akt overexpression is prognostic and can be used to tailor the synergistic interaction of Akt inhibitors with gemcitabine in pancreatic cancer.

BACKGROUND: There is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine. METHODS: Phospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients (n = 100). Data were analyzed by Fisher and log-rank test. In vitro studies were performed in 14 PDAC cells, including seven primary cultures, characterized for their Akt1 mRNA and phospho-Akt/Akt levels by quantitative-RT-PCR and immunocytochemistry. Growth inhibitory effects of Akt inhibitors and gemcitabine were evaluated by SRB assay, whereas modulation of Akt and phospho-Akt was investigated by Western blotting and ELISA. Cell cycle perturbation, apoptosis-induction, and anti-migratory behaviors were studied by flow cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method. RESULTS: Immunohistochemistry of TMAs revealed a correlation between phospho-Akt expression and worse outcome, particularly in patients with the highest phospho-Akt levels, who had significantly shorter overall and progression-free-survival. Similar expression levels were detected in LPC028 primary cells, while LPC006 were characterized by low phospho-Akt. Remarkably, Akt inhibitors reduced cancer cell growth in monolayers and spheroids and synergistically enhanced the antiproliferative activity of gemcitabine in LPC028, while this combination was antagonistic in LPC006 cells. The synergistic effect was paralleled by a reduced expression of ribonucleotide reductase, potentially facilitating gemcitabine cytotoxicity. Inhibition of Akt decreased cell migration and invasion, which was additionally reduced by the combination with gemcitabine. This combination significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028, but not in LPC006 cells. However, targeting the key glucose transporter Glut1 resulted in similar apoptosis induction in LPC006 cells. CONCLUSIONS: These data support the analysis of phospho-Akt expression as both a prognostic and a predictive biomarker, for the rational development of new combination therapies targeting the Akt pathway in PDAC. Finally, inhibition of Glut1 might overcome resistance to these therapies and warrants further studies.

Therapeutic Potential of Curcumin in Treatment of Pancreatic Cancer: Current Status and Future Perspectives.

Pancreatic cancer is among the leading cause of deaths due to cancer with extremely poor prognosis. Gemcitabine is being used in the treatment of patient with pancreatic ductal adenocarcinoma (PDAC), although, the response rate is bellow 12%. A recent phase III trial revealed that FOLFIRINOX could be an option for the treatment of metastatic PDAC patients, although it is associated with increased toxicity. Therefore, identification of novel agents that either improves gemcitabine activity, within novel combinatorial approaches, or with a better efficacy than gemcitabine is warranted. The antitumor activity of curcumin in several tumors, including prostate, breast and colorectal cancers have investigated. A recent phase II trial explored the effects of curcumin in advanced pancreatic cancer patient. They found that oral curcumin was well tolerated. Another trial showed the activity of 8,000 mg of curcumin in combination with gemcitabine in patients with advanced pancreatic cancer. This review summarizes the current knowledge about possible molecular mechanisms of curcumin in PDAC with particular emphasis on preclinical/clinical studies in pancreatic cancer treatment. J. Cell. Biochem. 118: 1634-1638, 2017. © 2017 Wiley Periodicals, Inc.

Targeting stroma in pancreatic cancer: Promises and failures of targeted therapies.

Desmoplasia or abundant fibrotic stroma is a typical property of most malignancies, which has a great effect on tumorigenesis, angiogenesis, and resistance to therapy. The activated stroma cells comprises several cell types including endothelial cells, nerve cells, inflammatory/macrophages cells, stellate cells, and extracellular matrix. In other word, the interactions of cancer-stroma modulate tumorigenesis, therapy resistance, and poor delivery of drugs. Therefore, targeting the tumor stroma in combination with conventional chemotherapeutic agents could provide a promising approach in the treatment of pancreatic cancer. This review summarizes the current knowledge about pancreatic stellate cells, targeting stroma compartments with particular emphasis on preclinical, and clinical trials on targeting of stroma as an option in pancreatic cancer treatment.

Exosome-Encapsulated microRNAs as Potential Circulating Biomarkers in Colon Cancer.

Exosome-encapsulated microRNAs are being suggested as a new class novel biomarker as diagnostic and predictive markers in colorectal cancer. These particles are released from many cell types into the extracellular space upon fusion of multivesicular bodies (MVB) with the plasma membrane. They contain a wide variety of information, including proteins, lipids, RNAs, non-transcribed RNAs, microRNAs, which can be circulated in various body fluids (e.g., blood, salvia, ascites, urine). Exosomes can be taken up by neighboring or distant cells and thereby modulate the functional of recipient cells and play a key role in disease progression or facilitate metastasis in cancers. The aim of current review is to give an overview about origin and trafficking of exosomes between cells, techniques to isolate exosomal microRNAs as well as the potential applications of exosomeencapsulated microRNAs as diagnostic markers in clinical settings in colorectal cancer. There is growing body of evidence showing the prognostic and diagnostic value of some exosomal microRNAs in colon cancer (e.g., miR- 150, miR-21, miR-192, let-7a, miR-223, and miR-23a). These findings provide a new insight on novel application of these markers as being novel non-invasive biomarkers for early detection and risk assessment of patients with colorectal cancer, although further investigations in larger population are required to explore the clinical utility of exosomal microRNAs in colorectal cancer patients.

Circulating microRNAs as Potential Diagnostic Biomarkers and Therapeutic Targets in Gastric Cancer: Current Status and Future Perspectives.

Gastric cancer is among the leading causes of cancer related death worldwide. Patients with gastric cancer are typically asymptomatic, and diagnosed at late stages, supporting the need for the identification of novel prognostic and diagnostic biomarkers. Recently, microRNAs have emerged as molecular regulators that can play key roles in pathogenesis and progression of different malignancies, including gastric cancer. There is a growing body of evidence showing the aberrant activation of some known circulating miRNAs, e.g. let-7a, miR-21, miR-16, miR-93, miR- 103, miR-192a s well as tissue specific-miRNAs, e.g. miR-18a, miR-10b, miR-544, miR-195, miR-378, miR-34a, miR-145 in patients affected by gastric cancer, which involved with modulation of gastric-cancer-associated genes. In addition, there are mounting evidences on the value of miRNAs which are detected to be associated with drug-resistance mechanisms; suggesting their modulation as a potential approach to overcome chemo-resistance. Attuned with these facts, in this review we highlight several recent preclinical and clinical studies performed on circulating and tissue-specific miRNAs as promising biomarkers for detection of patients at early stages, prediction of prognosis, and monitoring of the patients in response to therapy.