Showing papers in "Cancer and Metastasis Reviews in 2015"

HER2 expression status in diverse cancers: review of results from 37,992 patients

Abstract: Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/− amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.

Metastatic breast cancer: the potential of miRNA for diagnosis and treatment monitoring

Abstract: Breast cancer affects approximately 12 % women worldwide and results in 14 % of all cancer-related fatalities. Breast cancer is commonly categorized into one of four main subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) positive and basal), indicating molecular characteristics and informing treatment regimes. The most severe form of breast cancer is metastasis, when the tumour spreads from the breast tissue to other parts of the body. Significantly, the primary tumour subtype affects rates and sites of metastasis. Currently, up to 5 % of patients present with incurable metastasis, with an additional 10–15 % of patients going on to develop metastasis within 3 years of diagnosis. MicroRNAs (miRNAs) are short 21–25 long nucleotides that have been shown to significantly affect gene expression. Currently, >2000 miRNAs have been identified and significantly, specific miRNAs have been found associated with diseases states. Importantly, miRNAs are found circulating in the blood, presenting an opportunity to use these circulating disease-related miRNAs as biomarkers. Clearly, the identification of circulating miRNA specific to metastatic breast cancer presents a unique opportunity for early disease identification and for monitoring disease burden. Currently however, few groups have identified miRNA associated with metastatic breast cancer. Here, we review the literature surrounding the identification of metastatic miRNA in breast cancer patients, highlighting key areas where miRNA biomarker discovery could be beneficial, identifying key concepts, recognizing critical areas requiring further research and discussing potential problems.

Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies

Abstract: Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors.

Neutrophils: important contributors to tumor progression and metastasis

Abstract: The presence of neutrophils in tumors has traditionally been considered to be indicative of a failed immune response against cancers. However, there is now evidence showing that neutrophils can promote tumor growth, and increasingly, the data support an active role for neutrophils in tumor progression to distant metastasis. Neutrophils have been implicated in promoting metastasis in cancer patients, where neutrophil numbers and neutrophil-related factors and functions have been associated with progressive disease. Nevertheless, the role of neutrophils in tumors, both at the primary and secondary sites, remains controversial, with some studies reporting their anti-tumor functions. This review will focus on the data demonstrating a role for neutrophils in both tumor growth and metastasis and will attempt to clarify the discrepancies in the literature.

The challenge of targeting metastasis.

Abstract: Metastases that are resistant to conventional therapy are the major cause of death from cancer. In most patients, metastasis has already occurred by the time of diagnosis. Thus, the prevention of metastasis is unlikely to be of therapeutic benefit. The biological heterogeneity of metastases presents a major obstacle to treatment. However, the growth and survival of metastases depend on interactions between tumor cells and host homeostatic mechanisms. Targeting these interactions, in addition to the tumor cells, can produce synergistic therapeutic effects against existing metastases.

Epigenetics in lung cancer diagnosis and therapy

Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. The initiation and progression of lung cancer is the result of the interaction between permanent genetic and dynamic epigenetic alterations. DNA methylation is the best studied epigenetic mark in human cancers. Altered DNA methylation in cancer was identified in 1983. Within 30 years of this discovery, DNA methylation inhibitors are used clinically to treat a variety of cancers, highlighting the importance of the epigenetic basis of cancer. In addition, histone modifications, nucleosome remodeling, and micro RNA (miRNA)-mediated gene regulation are also fundamental to tumor genesis. Distinct chromatin alterations occur in all stages of lung cancer, including initiation, growth, and metastasis. Therefore, stage-specific epigenetic changes can be used as powerful and reliable tools for early diagnosis of lung cancer and to monitor patient prognosis. Moreover, since epigenetic changes are dynamic and reversible, chromatin modifiers are promising targets for the development of more effective therapeutic strategies against cancer. This review summarizes the chromatin alterations in lung cancer, focusing on the diagnostic and therapeutic approaches targeting epigenetic modifications that could help to reduce the high case-fatality rate of this dreadful disease.

Omega-3 polyunsaturated fatty acids and cancer: lessons learned from clinical trials

Abstract: Over the past decades, extensive studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 FAs) against different human diseases such as cardiovascular and neurodegenerative diseases, cancer, etc. A growing body of scientific research shows the pharmacokinetic information and safety of these natural occurring substances. Moreover, during recent years, a plethora of studies has demonstrated that omega-3 FAs possess therapeutic role against certain types of cancer. It is also known that omega-3 FAs can improve efficacy and tolerability of chemotherapy. Previous reports showed that suppression of nuclear factor-κB, activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins, are the main mechanisms of antineoplastic effect of omega-3 FAs. In this review, we have collected the available clinical data on the therapeutic role of omega-3 FAs against breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, lung cancer, head and neck cancer, as well as cancer cachexia. We also discussed the chemistry, dietary source, and bioavailability of omega-3 FAs, and the potential molecular mechanisms of anticancer and adverse effects.

Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications.

Abstract: Folate can be transported into the cell by the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), or the folate receptor (FR), of which various isoforms exist. While the RFC and PCFT are expressed by many normal cells, the FR is present only in a small proportion of normal tissues. In these tissues, the FR expression level is often low and restricted to the apical surface of polarized epithelial cells. In contrast, FR is expressed on the blood-accessible basal and lateral membranes of many types of epithelial cancer. Considering that FR is expressed in few nonmalignant cell types on luminal membranes generally not accessible for molecules transported in the blood, FR is considered a promising antitumor target. As FR expression seems associated with tumor progression and prognosis, anticancer therapies targeting FR are currently being developed, such as farletuzumab (Morphotek, Exton, PA, USA), IMGN853 (ImmunoGen, Waltham, MA, USA), vintafolide, and EC1456 (both Endocyte Inc., West Lafayette, IN, USA). FR expression could be used as a response-predictive biomarker for these treatments. The ability to identify patients and treat them with an effective therapy based on the known expression of the tumor marker would, indeed, be the next step in predictive medicine for these patients. This review summarizes the role of FR in ovarian cancer and the value of FR as a prognostic biomarker for ovarian cancer and a response-predictive biomarker for folate-targeted therapeutics.

Protease-activated receptors (PARs)--biology and role in cancer invasion and metastasis.

Abstract: Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.

Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications

Abstract: Fibroblast growth factors (FGFs) and their receptors (FGFRs) are transmembrane growth factor receptors with wide tissue distribution. FGF/FGFR signaling is involved in neoplastic behavior and also development, differentiation, growth, and survival. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers. FGF/FGFR aberrations reported in cancers are mainly thought to be gain-of-function changes, and several cancers have high frequencies of FGFR alterations, including breast, bladder, or squamous cell carcinomas (lung and head and neck). FGF ligand aberrations (predominantly gene amplifications) are also frequently seen in cancers, in contrast to hereditary syndromes. There are several pharmacologic agents that have been or are being developed for inhibition of FGFR/FGF signaling. These include both highly selective inhibitors as well as multi-kinase inhibitors. Of note, only four agents (ponatinib, pazopanib, regorafenib, and recently lenvatinib) are FDA-approved for use in cancer, although the approval was not based on their activity against FGFR. Perturbations in the FGFR/FGF signaling are present in both inherited and malignant diseases. The development of potent inhibitors targeting FGF/FGFR may provide new tools against disorders caused by FGF/FGFR alterations.

Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment

Abstract: Colorectal cancer is still a major health problem worldwide. Based on the most recent released data by the World Health Organization GLOBOCAN in 2012, colorectal cancer is the third most prevalent type of cancer in males and the second in females. In 1999, it was published the first report showing evidence of a strong correlation between diet and cancer incidence, being its positive or negative impact intimately linked to dietary patterns. A diet rich in fiber is associated with a low risk of developing colorectal cancer. The fermentation of the dietary fiber by intestinal microflora results in production of butyrate, which plays a plurifunctional role on the colonocytes, and it has also been reported as a chemopreventive agent. However, there are limited studies focusing its anti-cancer potential. Here, we review the recent new insights that focus butyrate and its role in colorectal cancer prevention and treatment, from its synthesis, metabolism, and transport, through its involvement on several cancer-related signaling pathways, to the novel existing approaches for its clinical use.

Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?

Abstract: Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

The conflicting roles of tumor stroma in pancreatic cancer and their contribution to the failure of clinical trials: a systematic review and critical appraisal

Abstract: A nearly universal feature of pancreatic ductal adenocarcinoma (PDAC) is an extensive presence of activated stroma. This stroma is thought to aid in various tumor-promoting processes and hampers response to therapy. Here, we aim to evaluate the evidence that supports this role of the stroma in PDAC with functional experiments in relevant models, discuss the clinical trials that have aimed to target the stroma in this disease, and examine recent work that explains why these clinical trials based on stroma-targeting strategies have thus far not achieved the expected success. We systematically searched PubMed through August 2014 with no restrictions to identify published peer-reviewed research articles assessing the effect of targeting the stroma on tumor growth or metastases in preclinical animal models. Five hundred and thirty articles were extracted of which 31 were included in the analysis. Unfortunately, due to the large variety in models and outcome measures, we could not perform a meta-analysis of our data. We find that despite an abundance of positive outcomes reported in previous studies on stroma targeting, a strong discrepancy exists with the outcomes of clinical trials and the more recent preclinical work that is in line with these trials. We explain the incongruities by the duration of stroma targeting and propose that chronic stroma targeting treatment is possibly detrimental in the treatment of this disease.

Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches

Abstract: Resistance to chemotherapy is among the most important issues in the management of ovarian cancer Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment In addition, hypoxia induced by anti-angiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies

Lung cancer and metastasis: new opportunities and challenges

Abstract: Lung cancer continues to attract special attention since the real number of lung cancer mortality and incidence in 2014 was definitely higher than those estimated numbers according to the report from World Health Organization. The present special issue highly focuses on advanced discovery and development of lung cancer and metastasis and discusses about potential opportunities and challenges to be faced. The present issue explores clinical applications of cancer immunotherapies, gene therapies, radiotherapies, or target-oriented therapies. A new and novel methodology can be used to identify differential interactions of driver genes, cancer-predictive genes, subtype-specific genes, or disease-exclusive genes or gene pairs from imbalanced or heterogeneous datasets. We also demonstrate the importance of lung cancer-specific gene mutations, epigenetics, gene sequencing, heterogeneity, or biomarker discovery. Clinical bioinformatics is emphasized as a critical tool and merging science. Novel therapies are designed and expected on basis of oncogenic molecular aberrations in lung cancer.

New advances in ovarian autotransplantation to restore fertility in cancer patients.

Abstract: Human ovary autotransplantation is a promising option for fertility preservation of young women and girls undergoing gonadotoxic treatments for cancer or some autoimmune diseases. Although experimental, it resulted in at least 42 healthy babies worldwide. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review was performed for all relevant full-text articles published in English from 1 January 2000 to 01 October 2015 in PubMed to explore the latest clinical and research advances of human ovary autotransplantation. Human ovary autotransplantation involves ovarian tissue extraction, freezing/thawing, and transplantation back into the same patient. Three major forms of human ovary autotransplantation exist including (a) transplantation of cortical ovarian tissue, (b) transplantation of whole ovary, and (c) transplantation of ovarian follicles (artificial ovary). According to the recent guidelines, human ovary autotransplantation is still considered experimental; however, it has unique advantages in comparison to other options of female fertility preservation. Human ovary autotransplantation (i) does not need prior ovarian stimulation, (ii) allows immediate initiation of cancer therapy, (iii) can restore both endocrine and reproductive ovarian functions, and (iv) may be the only fertility preservation option suitable for prepubertal girls or for young women with estrogen-sensitive malignancies. As any other fertility preservation option, human ovary autotransplantation has both advantages and disadvantages and may not be feasible for all cases. The major challenges facing this option are how to avoid the risk of reintroducing malignant cells and how to prolong the lifespan of ovarian transplant as well as how to improve artificial ovary results.

Immunotherapy of melanoma: Present options and future promises

Abstract: Metastatic melanoma is notorious for its immune evasion and resistance to conventional chemotherapy. The recent success of ipilimumab, a human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), in increasing the median survival time and stabilizing the disease progression renewed, hopes in treatment for melanoma. Currently, ipilimumab and high-dose interleukin-2 (IL-2; Aldesleukin) are approved as monotherapies for the treatment of patients with unresectable advanced melanoma, and pegylated interferon-α2b (p-IFN-α2b) is approved as an adjuvant for the treatment of patients with surgically resected high-risk melanoma. The present review describes the currently approved immune-modulators and the promising immune-based interventions that are currently in clinical trials. We present the four commonly used strategies to boost immune responses against the tumors; monoclonal antibodies, cytokines, cancer vaccines, and adoptive T cell transfer. The corresponding lists of ongoing clinical trials include details of the trial phase, target patients, intervention details, status of the study, and expected date of completion. Further, our review discusses the challenges faced by immunotherapy and the various strategies adopted to overcome them.

Proteomics of ovarian cancer: functional insights and clinical applications.

Abstract: In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. We propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.

Contribution of very late antigen-4 (VLA-4) integrin to cancer progression and metastasis

Abstract: The integrin "very late antigen-4" (VLA-4) is expressed by numerous cells of hematopoietic origin and possesses a key function in the cellular immune response, e.g., by mediating leukocyte tethering, rolling, binding, and finally transmigration of the vascular wall at inflammatory sites. Thus, VLA-4 is a valuable target in medical sciences to interfere with pathological inflammations. In addition, leukemic cells and different solid tumors, which express VLA-4, make use of these adhesive functions and confer VLA-4 a progressive role in the metastatic spread. With a growing insight into the molecular mechanisms for creating a tumor-friendly microenvironment at metastatic sites and various tumor host interactions, the multiple functions of VLA-4 became evident recently, e.g., in leukocyte recruitment to micrometastases, the protection of tumors from immune surveillance, or contribution to a chemoresistance. Nevertheless, despite accumulating evidence for several functions of VLA-4 in tumorigenicity, a therapeutic interference with VLA-4 in cancer sciences has not been developed yet to the clinical level, undoubtedly by a marked impact on the physiological immune response. This review gives an up to date insight into the multiple functional role of VLA-4 in cancer and introduces this integrin as a promising target worthwhile to attract attention in biomedical cancer research.

Nanomedicine as an emerging platform for metastatic lung cancer therapy.

Abstract: Metastatic lung cancer is one of the most common cancers leading to mortality worldwide. Current treatment includes chemo- and pathway-dependent therapy aiming at blocking the spread and proliferation of these metastatic lesions. Nanomedicine is an emerging multidisciplinary field that offers unprecedented access to living cells and promises the state of the art in cancer detection and treatment. Development of nanomedicines as drug carriers (nanocarriers) that target cancer for therapy draws upon principles in the fields of chemistry, medicine, physics, biology, and engineering. Given the zealous activity in the field as demonstrated by more than 30 nanocarriers already approved for clinical use and given the promise of recent clinical results in various studies, nanocarrier-based strategies are anticipated to soon have a profound impact on cancer medicine and human health. Herein, we will detail the latest innovations in therapeutic nanomedicine with examples from lipid-based nanoparticles and polymer-based approaches, which are engineered to deliver anticancer drugs to metastatic lung cells. Emphasis will be placed on the latest and most attractive delivery platforms, which are developed specifically to target lung metastatic tumors. These novel nanomedicines may open new avenues for therapeutic intervention carrying new class of drugs such as RNAi and mRNA and the ability to edit the genome using the CRISPER/Cas9 system. Ultimately, these strategies might become a new therapeutic modality for advanced-stage lung cancer.

Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer

Abstract: Urothelial carcinoma is a highly heterogeneous disease that develops along two distinct biological tracks as evident by candidate gene analysis and genome-wide screening and therefore, offers different challenges for clinical management. Tumors representing the truly distinct molecular entities express molecular markers characteristic of a developmental process and a major mechanism of cancer metastasis, known as epithelial-to-mesenchymal transition (EMT). Recently identified subset of cells known as urothelial cancer stem cells (UroCSCs) in urothelial cell carcinoma (UCC) have self-renewal properties, ability to generate cellular tumor heterogeneity via differentiation and are ultimately responsible for tumor growth and viability. In this review paper, PubMed and Google Scholar electronic databases were searched for original research papers and review articles to extract relevant information on the molecular mechanisms delineating the relationship between EMT and cancer stemness and their clinical implications for different subsets of urothelial cell carcinomas. Experimental and clinical studies over the past few years in bladder cancer cell lines and tumor tissues of different cancer subtypes provide evidences and new insights for mechanistic complexity for induction of EMT, tumorigenicity, and cancer stemness in malignant transformation of urothelial cell carcinomas. Differentiation and elimination therapies targeting EMT-cancer stemness pathway have been proposed as cynosure in the molecular biology of urothelial cell carcinomas and could prove to be clinically beneficial in an ability to reverse the EMT phenotype of tumor cells, suppress the properties of UroCSCs, inhibit bladder cancer progression and tumor relapse, and provide rationale in the treatment and clinical management of urothelial cancer.

Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer

Abstract: The present study aimed at investigating genetic variations, specific signal pathways, or biological processes of chromosome 1 genes between subtypes and stages of lung cancer and prediction of selected targeting genes for patient survival rate. About 537 patients with lung adenocarcinoma (ADC), 140 with lung squamous carcinoma (SCC), 9 with lung large-cell carcinoma (LCC), 56 with small-cell lung cancer (SCLC), and 590 without caner were integrated from 16 databases and analyzed in the present study. Three (ASPM, CDC20, KIAA1799) or 28 genes significantly up- or down-expressed in four subtypes of lung cancer. The activated cell division and down-regulated immune responses were identified in patients with lung cancer. Keratinocyte development associated genes S100 and SPRR families dominantly up-expressed in SCC and AKT3 and NRAS in SCLC. Subtype-specific genes of ADC, SCC, LCC, or SCLC were also identified. C1orf106, CAPN8, CDC20, COL11A1, CRABP2, and NBPF9 up-expressed at four stages of ADC. Fifty six related with keratinocytes or potassium channels up-expressed in three stages of SCC. CDC20, IL10, ECM1, GABPB2, CRABP2, and COL11A1 significantly predicted the poor overall survival of ADC patients and S100A2 and TIMM17A in SCC patients. Our data indicate that a number of altered chromosome 1 genes have the subtype and stage specificities of lung cancer and can be considered as diagnostic and prognosis biomarkers.

Optimal first-line chemotherapeutic treatment in patients with locally advanced or metastatic esophagogastric carcinoma: triplet versus doublet chemotherapy: a systematic literature review and meta-analysis

Abstract: There is a debate whether triplet or doublet chemotherapy should be used as a first-line treatment in patients with advanced or metastatic esophagogastric cancer. Therefore, here we will review the available literature to assess the efficacy and safety of triplet versus doublet chemotherapy as a first-line treatment in patients with advanced esophagogastric cancer. We searched MEDLINE, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) between 1980 and March 2015 for randomized controlled phase II and III trials comparing triplet with doublet chemotherapy and abstracts of major oncology meetings from 1990 to 2014. Twenty-one studies with a total of 3475 participants were included in the meta-analysis for overall survival. An improvement in overall survival (OS) (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.83-0.97) and progression-free survival (PFS) (HR 0.80, 95% CI 0.69-0.93) was observed in favor of triplet. In addition, the use of triplet was associated with better objective response rate (ORR) (risk ratio 1.25, 95% CI 1.09-1.44) compared to doublet. The risks of grade 3-4 thrombocytopenia (6.2 vs 3.8%), infection (10.2 vs 6.4%), and mucositis (9.7 vs 4.7%) were statistically significantly increased with triplet compared to doublet. This review shows that first-line triplet therapy is superior to doublet therapy in patients with advanced esophagogastric cancer. However, the survival benefit is limited and the risks of grade 3-4 thrombocytopenia, infection, and mucositis are increased.

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

Abstract: Inflammatory cells and mediators are essential components in tumor microenvironment and play decisive roles in the initiation, proliferation, survival, promotion, invasion, or metastasis of lung cancer. Clinical and epidemiologic studies suggested a strong association between inflammation and lung cancer and an influence of immune surveillances and tumor responses to chemotherapeutic drugs, although roles of inflammation in lung cancer remain unclear. The present review outlined roles of inflammation in lung cancer, with particular focus on inflammatory components, types, biomarkers, or principal mechanisms by which the inflammation contributes to the development of lung cancer. The cancer-associated inflammatory cells (CICs) should be furthermore defined and include cancer-specific and interacted cells with inflammatory or inflammation-like characteristics, e.g., innate or adaptive immune cells and cancer tissue cells. We also discuss targeting potentials of inflammation in the prevention and treatment of lung cancer. The diversity of cancer-related inflammatory microenvironment is instrumental to design novel therapeutic approaches for lung cancer.

Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors

Abstract: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients' well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess changes in HRQoL in this population.

Five critical elements to ensure the precision medicine.

Abstract: The precision medicine as a new emerging area and therapeutic strategy has occurred and was practiced in the individual and brought unexpected successes, and gained high attentions from professional and social aspects as a new path to improve the treatment and prognosis of patients. There will be a number of new components to appear or be discovered, of which clinical bioinformatics integrates clinical phenotypes and informatics with bioinformatics, computational science, mathematics, and systems biology. In addition to those tools, precision medicine calls more accurate and repeatable methodologies for the identification and validation of gene discovery. Precision medicine will bring more new therapeutic strategies, drug discovery and development, and gene-oriented treatment. There is an urgent need to identify and validate disease-specific, mechanism-based, or epigenetics-dependent biomarkers to monitor precision medicine, and develop “precision” regulations to guard the application of precision medicine.

EPLIN: a fundamental actin regulator in cancer metastasis?

Abstract: Treatment of malignant disease is of paramount importance in modern medicine. In 2012, it was estimated that 162,000 people died from cancer in the UK which illustrates a fundamental problem. Traditional treatments for cancer have various drawbacks, and this creates a considerable need for specific, molecular targets to overcome cancer spread. Epithelial protein lost in neoplasm (EPLIN) is an actin-associated molecule which has been implicated in the development and progression of various cancers including breast, prostate, oesophageal and lung where EPLIN expression is frequently lost as the cancer progresses. EPLIN is important in the regulation of actin dynamics and has multiple associations at epithelial cells junctions. Thus, EPLIN loss in cancer may have significant effects on cancer cell migration and invasion, increasing metastatic potential. Overexpression of EPLIN has proved to be an effective tool for manipulating cancerous traits such as reducing cell growth and cell motility and rendering cells less invasive illustrating the therapeutic potential of EPLIN. Here, we review the current state of knowledge of EPLIN, highlighting EPLIN involvement in regulating cytoskeletal dynamics, signalling pathways and implications in cancer and metastasis.

Imaging approaches to assess the therapeutic response of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current perspectives and future trends of an exciting field in development.

Abstract: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of neoplasms with a complex spectrum of clinical behavior. Although generally more indolent than carcinomas, once they progress beyond surgical resectability, they are essentially incurable. Systemic treatment options have substantially expanded in recent years for the management of advanced disease. Imaging plays a major role in new drug development, as it is the main tool used to objectively evaluate response to novel agents. However, current standard response criteria have proven suboptimal for the assessment of the antiproliferative effect of many targeted agents, particularly in the context of slow-growing tumors such as well-differentiated NETs. The aims of this article are to discuss the advantages and limitations of conventional radiological techniques and standard response assessment criteria and to review novel imaging modalities in development as well as alternative cancer- and therapy-specific criteria to assess drug efficacy in the field of GEP-NETs.

The origin of prostate metastases: emerging insights

Abstract: The outcome of patients with prostate cancer (PCa) is mainly dependent on the presence or absence of distant metastases. Although several advances have been made in understanding the biological basis of this tumor, the mechanisms underlying PCa metastatic spread are not fully clear. The lack of a clear origin for PCa metastasis may be partially due to the evidence of PCa heterogeneity between primary tumor and metastases and among different metastatic sites. Cross-metastatic seeding and the de novo monoclonal seeding of daughter metastases have been proposed as crucial events during metastasis. This process requires the contribution of tumor environment, which modulates cancer cell homing and growth, and involves several components including cancer stem cells (CSCs), tumor secreted microvesicles, circulating tumor cells (CTCs), and immune cells. In this review, we have focused on the recent findings on the origin of prostate metastasis, showing the contribution of tumor microenvironment to this evolutionary process.

Integrin αvβ6 sets the stage for colorectal cancer metastasis

Abstract: The β6 subunit of the αvβ6 integrin heterodimer has long been an enigma in cancer biology though recent research has provided many new insights into its biology. Collectively, these findings include discovery of the transcriptional, translational and cell biological mechanisms by which β6 acts, the identification of the cellular influences β6 exerts upon the cell proteome, the characterisation of multiple β6-centric pro-metastatic signalling systems and the search for pharmacological therapies (industry and academia) targeted against β6. Once expressional restriction is overcome in early colorectal cancer (CRC), epithelial cell surface restricted αvβ6 can physically interact with, and activate, known oncoproteins, and has the potential to enable the cross-talk through non-canonical signal transduction pathways, resulting in the adoption of an invasive/metastatic phenotype. This recent research has identified numerous interconnections and potential feedback loops, highlighting the fact that the expression of the β6 subunit may initiate a cascade of downstream effects on the CRC cell rather than acting through a single mechanism. We here review these recent studies and postulate that the existence of a cell surface uPAR/αvβ6/TGFβ "metastasome" interactome in/on a proportion of colorectal cancer cells, where β6 expression sequesters and activates multiple systems at the invasive front of tumour lesions, promoting cancer metastasis and hence explaining why β6 has been correlated with reduced patient survival in CRC.