Open AccessReview
The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches
Cancers 2017, 9(6), 58; doi:10.3390/cancers9060058 (registering DOI) -
Abstract
The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor
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The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor progression, including HCC. Therefore, c-Met is now regarded as the most promising therapeutic target for the treatment of HCC. However, there are still concerns about resistance and the side effects of using conventional inhibitors of c-Met, such as tyrosine kinase inhibitors. Recently, many alternative strategies of c-Met targeting have been emerging. These include targeting the downstream effectors of c-Met, such as hydrogen peroxide-inducible clone 5 (Hic-5), to block the reactive oxygen species (ROS)-mediated signaling for HCC progression. Also, inhibition of endosomal regulators, such as PKCε and GGA3, may perturb the c-Met endosomal signaling for HCC cell migration. On the other hand, many herbal antagonists of c-Met-dependent signaling, such as saponin, resveratrol, and LZ-8, were identified. Taken together, it can be anticipated that more effective and safer c-Met targeting strategies for preventing HCC progression can be established in the future. Full article
Open AccessReview
Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma
Cancers 2017, 9(6), 57; doi:10.3390/cancers9060057 (registering DOI) -
Abstract
Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize
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Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients. Full article
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Open AccessFeature PaperReview
RGD-Binding Integrins in Head and Neck Cancers
Cancers 2017, 9(6), 56; doi:10.3390/cancers9060056 (registering DOI) -
Abstract
Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and β1 subunits has been
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Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and β1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors αvβ3 and αvβ5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as αvβ6, αvβ8, and β1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the arginine-glycine-aspartate (RGD)-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour-specific identification and therapy. Full article
Open AccessReview
Improving Outcomes in Patients with CRC: The Role of Patient Reported Outcomes—An ESDO Report
Cancers 2017, 9(6), 59; doi:10.3390/cancers9060059 (registering DOI) -
Abstract
Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying
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Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient’s health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer. Full article
Open AccessArticle
Self-Esteem and Academic Difficulties in Preadolescents and Adolescents Healed from Paediatric Leukaemia
Cancers 2017, 9(6), 55; doi:10.3390/cancers9060055 -
Abstract
Adolescents with cancer may demonstrate problems in their self-esteem and schooling. This study aims to screen the preadolescents and adolescents more at risk in their self-esteem perception and schooling difficulties post-five years from the end of therapy. Twenty-five paediatric ex-patients healed from leukaemia
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Adolescents with cancer may demonstrate problems in their self-esteem and schooling. This study aims to screen the preadolescents and adolescents more at risk in their self-esteem perception and schooling difficulties post-five years from the end of therapy. Twenty-five paediatric ex-patients healed from leukaemia were recruited at the Haematology-Oncologic Clinic (University of Padua). The mean age of the children was 13.64 years (Standard Deviation (SD)) = 3.08, range = 10–19 years), most were treated for acute lymphoblastic leukaemia (ALL) (84%) and relatively equally distributed by gender. They filled in the Multidimensional Self-Esteem Test, while parents completed a questionnaire on their child’s schooling. Global self-esteem was mostly below the 50 percentile (58.5%), especially regarding interpersonal relationships (75%). An independent sample t-test showed significant mean differences on the emotionality scale (t = 2.23; degree of freedom (df) = 24; p = 0.03) and in the bodily experience scale (t = 3.02; df = 24; p = 0.006) with survivors of Acute Myeloid Leukaemia (AML) having lower scores. An Analysis of Variance (ANOVA) showed significant mean differences in the bodily experience scale (F= 12.31; df = 2, p = 0.0001) depending on the survivors’ assigned risk band. The parent reports showed that 43.5% of children had difficulties at school. Childhood AML survivors with a high-risk treatment were more at risk in their self-esteem perceptions. Preventive interventions focusing on self-esteem and scholastic wellbeing are suggested in order to help their return to their normal schedules. Full article
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Open AccessReview
Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment
Cancers 2017, 9(6), 54; doi:10.3390/cancers9060054 -
Abstract
The tumor microenvironment, including cancer-associated fibroblasts (CAF), has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review
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The tumor microenvironment, including cancer-associated fibroblasts (CAF), has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell—tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment. Full article
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Open AccessReview
Physical Activity and Quality of Life in Cancer Survivors: A Meta-Synthesis of Qualitative Research
Cancers 2017, 9(5), 53; doi:10.3390/cancers9050053 -
Abstract
Qualitative research on the impact of physical activity on quality of life (QoL) in adults diagnosed with cancer is accumulating. However, the field of physical activity and cancer survivorship lack a synthesis of this research to reliably understand the implications for future research
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Qualitative research on the impact of physical activity on quality of life (QoL) in adults diagnosed with cancer is accumulating. However, the field of physical activity and cancer survivorship lack a synthesis of this research to reliably understand the implications for future research and practice. The aim of this meta-synthesis was to identify, appraise, and synthesize qualitative research on cancer survivors’ perspectives of the impact of physical activity on their QoL. Seven electronic databases were searched for original studies published in English, and reference lists of relevant studies were hand-searched to identify additional studies. Forty studies met eligibility criteria and were included in this meta-synthesis. Study characteristics and major findings were extracted, and findings were summarized, compared, and synthesized. Themes identified in this review revealed that physical activity positively impacted four dimensions of cancer survivors’ QoL: physical (e.g., managing the physical consequences of cancer and its treatment), psychological (e.g., evoking positive self-perceptions), social (e.g., feeling understood by others), and spiritual (e.g., redefining life purpose). This meta-synthesis corroborates conclusions from reviews of quantitative research and illustrates that physical activity can be used to improve QoL in adult cancer survivors, regardless of diagnosis (i.e., stage, cancer type) and treatment status. It also provides detailed insight into specific aspects within each dimension of QoL impacted by physical activity from cancer survivors’ perspectives, which is important for understanding the meaning and utility of physical activity for them. However, more research is needed to further develop the qualitative evidence base in order to better understand how physical activity impacts on QoL experiences in men, young adults, and adults diagnosed with less common types of cancer at different points along cancer trajectory (i.e., diagnosis, treatment, post-treatment, palliation). Full article
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Open AccessReview
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Cancers 2017, 9(5), 52; doi:10.3390/cancers9050052 -
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR
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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors. Full article
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Open AccessArticle
A Feasibility Study of Personalized Prescription Schemes for Glioblastoma Patients Using a Proliferation and Invasion Glioma Model
Cancers 2017, 9(5), 51; doi:10.3390/cancers9050051 -
Abstract
Purpose: This study investigates the feasibility of personalizing radiotherapy prescription schemes (treatment margins and fractional doses) for glioblastoma (GBM) patients and their potential benefits using a proliferation and invasion (PI) glioma model on phantoms. Methods and Materials: We propose a strategy to personalize
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Purpose: This study investigates the feasibility of personalizing radiotherapy prescription schemes (treatment margins and fractional doses) for glioblastoma (GBM) patients and their potential benefits using a proliferation and invasion (PI) glioma model on phantoms. Methods and Materials: We propose a strategy to personalize radiotherapy prescription schemes by simulating the proliferation and invasion of the tumor in 2D according to the PI glioma model. We demonstrate the strategy and its potential benefits by presenting virtual cases, where the standard and personalized prescriptions were applied to the tumor. Standard prescription was assumed to deliver 46 Gy in 23 fractions to the initial, gross tumor volume (GTV1) plus a 2 cm margin and an additional 14 Gy in 7 fractions to the boost GTV2 plus a 2 cm margin. The virtual cases include the tumors with a moving velocity of 0.029 (slow-move), 0.079 (average-move), and 0.13 (fast-move) mm/day for the gross tumor volume (GTV) with a radius of 1 (small) and 2 (large) cm. For each tumor size and velocity, the margin around GTV1 and GTV2 was varied between 0–6 cm and 1–3 cm, respectively. Equivalent uniform dose (EUD) to normal brain was constrained to the EUD value obtained by using the standard prescription. Various linear dose policies, where the fractional dose is linearly decreasing, constant, or increasing, were investigated to estimate the temporal effect of the radiation dose on tumor cell-kills. The goal was to find the combination of margins for GTV1 and GTV2 and a linear dose policy, which minimize the tumor cell-surviving fraction (SF) under a normal tissue constraint. The efficacy of a personalized prescription was evaluated by tumor EUD and the estimated survival time. Results: The personalized prescription for the slow-move tumors was to use 3.0–3.5 cm margins for GTV1, and a 1.5 cm margin for GTV2. For the average- and fast-move tumors, it was optimal to use a 6.0 cm margin for GTV1 and then 1.5–3.0 cm margins for GTV2, suggesting a course of whole brain therapy followed by a boost to a smaller volume. It was more effective to deliver the boost sequentially using a linearly decreasing fractional dose for all tumors. Personalized prescriptions led to surviving fractions of 0.001–0.465% compared to the standard prescription, and increased the tumor EUDs by 25.3–49.3% and estimated survival times by 7.6–22.2 months. Conclusions: Personalizing treatment margins based on the measured proliferative capacity of GBM tumor cells can potentially lead to significant improvements in tumor cell kill and related clinical outcomes. Full article
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Open AccessReview
Immunotherapy for Colorectal Cancer
Cancers 2017, 9(5), 50; doi:10.3390/cancers9050050 -
Abstract
The recent success of anti-PD1 drugs in metastatic colorectal cancer patients with mismatch repair deficiency generated overwhelming enthusiasm for immunotherapy in the disease. However, patients with mismatch repair deficient colorectal cancer represent only a small subset of the metastatic population. Current research focuses
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The recent success of anti-PD1 drugs in metastatic colorectal cancer patients with mismatch repair deficiency generated overwhelming enthusiasm for immunotherapy in the disease. However, patients with mismatch repair deficient colorectal cancer represent only a small subset of the metastatic population. Current research focuses on advancing immunotherapy to earlier stages of the disease including adjuvant and first-line metastatic settings, and on inducing sensitivity to immune checkpoint inhibitor therapy through a combinatorial approach. Here, we review the contemporary understanding of the immune and molecular landscape in colorectal cancer and discuss ongoing clinical trials evaluating novel combination regimens based on immune checkpoint inhibitors. Full article
Open AccessReview
Diagnostic and Therapeutic Potential of MicroRNAs in Lung Cancer
Cancers 2017, 9(5), 49; doi:10.3390/cancers9050049 -
Abstract
Lung cancer is the leading cause of deaths resulting from cancer owing to late diagnosis and limited treatment intervention. MicroRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally by translational repression or target messenger RNA degradation. Accumulating evidence suggests various roles
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Lung cancer is the leading cause of deaths resulting from cancer owing to late diagnosis and limited treatment intervention. MicroRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally by translational repression or target messenger RNA degradation. Accumulating evidence suggests various roles for microRNAs, including development and progression of lung cancers. Because microRNAs are degraded to a much lesser extent in formalin-fixed paraffin-embedded specimens and are present not only in tumor tissues but also in body fluids, there is an increased potential in microRNA analyses for cancer research. In this review, recent studies of microRNA are introduced and briefly summarized, with a focus on the association of microRNAs with histological subtypes, genetic driver alterations, therapeutically-targeted molecules, and carcinogens. The reported circulating microRNA signature for the early detection of lung cancer and the implications of microRNAs as the modulators of tumor immune response are also introduced. Full article
Open AccessReview
Targeting Intracellular Calcium Signaling ([Ca2+]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview
Cancers 2017, 9(5), 48; doi:10.3390/cancers9050048 -
Abstract
Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is
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Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. This mini-overview focuses on the interdependent relationship between intracellular calcium ([Ca2+]i) signaling and multidrug resistance of cancer cells, acquired upon treatment of tumors with anticancer drugs. We propose that [Ca2+]i signaling modulates gene expression of multidrug resistant (MDR) genes which in turn can be modulated by epigenetic factors which in turn leads to modified protein expression in drug resistant tumor cells. A precise knowledge of these mechanisms will help to develop new therapeutic strategies for drug resistant tumors and will improve current chemotherapy. Full article
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Open AccessArticle
Inhibition of Human Lung Cancer Cell Proliferation and Survival by Post-Exercise Serum Is Associated with the Inhibition of Akt, mTOR, p70 S6K, and Erk1/2
Cancers 2017, 9(5), 46; doi:10.3390/cancers9050046 -
Abstract
Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, and for the most cancer-related deaths. The survival pathway of Akt, its downstream effectors, the mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70 S6K), and the Ras-extracellular
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Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, and for the most cancer-related deaths. The survival pathway of Akt, its downstream effectors, the mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70 S6K), and the Ras-extracellular signal-regulated kinase (Erk1/2) pathways are activated in cancer leading to cell survival and growth. Thus, approaches that inhibit these signaling molecules may prove useful in the fight against lung cancer. Exercise is associated with health benefits and a limited number of studies indicate that serum from physically active individuals inhibit mammary and prostate cancer cell growth. In this study, we examined the effects of post exercise serum on proliferation, survival, and signaling cascades of human NSCLC cells. Blood was collected from male subjects prior to, 5 min, 1 h, and 24 h after a single bout of high intensity interval exercise on a cycle ergometer. Exposure of NSCLC cells to post exercise serum resulted in the inhibition of cell proliferation and survival, as well as significant reduction of phosphorylated/activated Akt, mTOR, p70 S6K, and Erk1/2 levels compared to cells treated with serum taken pre-exercise. Our data suggest that post exercise serum has anti-cancer properties in lung cancer and deserves further systematic investigation in animal models. Full article
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Open AccessReview
MTH1 as a Chemotherapeutic Target: The Elephant in the Room
Cancers 2017, 9(5), 47; doi:10.3390/cancers9050047 -
Abstract
Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated
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Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target. Full article
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Open AccessReview
Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies
Cancers 2017, 9(5), 45; doi:10.3390/cancers9050045 -
Abstract
Cancer cells display enhanced growth rates and a resistance to apoptosis. The ability of cancer cells to evade homeostasis and proliferate uncontrollably while avoiding programmed cell death/apoptosis is acquired through mutations to key signaling molecules, which regulate pathways involved in cell proliferation and
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Cancer cells display enhanced growth rates and a resistance to apoptosis. The ability of cancer cells to evade homeostasis and proliferate uncontrollably while avoiding programmed cell death/apoptosis is acquired through mutations to key signaling molecules, which regulate pathways involved in cell proliferation and survival and these mutations allow them to develop resistance to many chemotherapeutic agents, highlighting the need for development of new potent anti-cancer agents. Metformin has long been used as a treatment for type 2 diabetes and has recently attracted attention as a potential agent to be used in the treatment of cancer. The present review summarizes the existing in vitro and in vivo animal studies focusing on the anti-lung cancer effects of metformin and its effects on key proliferative and anti-apoptotic signaling pathways. Full article
Open AccessBrief Report
Androgen Receptor Could Be a Potential Therapeutic Target in Patients with Advanced Hepatocellular Carcinoma
Cancers 2017, 9(5), 43; doi:10.3390/cancers9050043 -
Abstract
Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC.
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Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. Here, we discuss the recent data on AR and HCC, and the combination of sorafenib and inhibitors of AR for advanced-HCC patients. Androgen-dependent and androgen-independent AR activation exist in human hepatocarcinogenesis. AR could directly control hepatocarcinogenesis and regulate the innate immune system to influence HCC progression. Combination of sorafenib with AR inhibitors might represent a potential treatment for patients with advanced HCC. Full article
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Open AccessReview
HGF/Met Signaling in Cancer Invasion: The Impact on Cytoskeleton Remodeling
Cancers 2017, 9(5), 44; doi:10.3390/cancers9050044 -
Abstract
The invasion of cancer cells into surrounding tissue and the vasculature is essential for tumor metastasis. Increasing evidence indicates that hepatocyte growth factor (HGF) induces cancer cell migration and invasion. A broad spectrum of mechanisms underlies cancer cell migration and invasion. Cytoskeletal reorganization
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The invasion of cancer cells into surrounding tissue and the vasculature is essential for tumor metastasis. Increasing evidence indicates that hepatocyte growth factor (HGF) induces cancer cell migration and invasion. A broad spectrum of mechanisms underlies cancer cell migration and invasion. Cytoskeletal reorganization is of central importance in the development of the phenotype of cancer cells with invasive behavior. Through their roles in cell mechanics, intracellular trafficking, and signaling, cytoskeleton proteins participate in all essential events leading to cell migration. HGF has been involved in cytoskeleton assembly and reorganization, and its role in regulating cytoskeleton dynamics is still expanding. This review summarizes our current understanding of the role of HGF in regulating cytoskeleton remodeling, distribution, and interactions. Full article
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Open AccessReview
KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer
Cancers 2017, 9(5), 42; doi:10.3390/cancers9050042 -
Abstract
Pancreatic cancer is a disease that has a very high fatality rate and one of the highest mortality ratios among all major cancers, remaining the fourth leading cause of cancer-related deaths in developed countries. The major treatment of pancreatic cancer is surgery; however,
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Pancreatic cancer is a disease that has a very high fatality rate and one of the highest mortality ratios among all major cancers, remaining the fourth leading cause of cancer-related deaths in developed countries. The major treatment of pancreatic cancer is surgery; however, only 15–20% of patients are candidates for it at the diagnosis of disease. On the other hand, survival in patients, who undergo surgery, is less than 30%. In most cancers, genome stability is disturbed and pancreatic cancer is not the exception. Approximately 97% of pancreatic cancers have gene derangements, defined by point mutations, amplifications, deletions, translocations, and inversions. This review describes the most frequent genetic alterations found in pancreatic cancer. Full article
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Open AccessReview
Targeting the ATR-CHK1 Axis in Cancer Therapy
Cancers 2017, 9(5), 41; doi:10.3390/cancers9050041 -
Abstract
Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article
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Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented. Full article
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Open AccessReview
HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance
Cancers 2017, 9(5), 40; doi:10.3390/cancers9050040 -
Abstract
HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60%
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HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab. Full article
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