BBA - Reviews on Cancer (v.1846, #2)

The unfolded protein response as a target for cancer therapy by Anika Nagelkerke; Johan Bussink; Fred C.G.J. Sweep; Paul N. Span (277-284).
Various physiological and pathological conditions generate an accumulation of misfolded proteins in the endoplasmic reticulum (ER). This results in ER stress followed by a cellular response to cope with this stress and restore homeostasis: the unfolded protein response (UPR). Overall, the UPR leads to general translational arrest and the induction of specific factors to ensure cell survival or to mediate cell death if the stress is too severe. In multiple cancers, components of the UPR are overexpressed, indicating increased dependence on the UPR. In addition, the UPR can confer resistance to anti-cancer treatment. Therefore, modification of the UPR should be explored for its anti-cancer properties. This review discusses factors associated with the UPR that represent potential therapeutic targets.
Keywords: Unfolded protein response; Cancer; Therapy; Endoplasmic reticulum stress; Autophagy;

The multifaceted regulation and functions of PKM2 in tumor progression by Zongwei Li; Peng Yang; Zhuoyu Li (285-296).
Tumor cells undergo metabolic rewiring from oxidative phosphorylation towards aerobic glycolysis to maintain the increased anabolic requirements for cell proliferation. It is widely accepted that specific expression of the M2 type pyruvate kinase (PKM2) in tumor cells contributes to this aerobic glycolysis phenotype. To date, researchers have uncovered myriad forms of functional regulation for PKM2, which confers a growth advantage on the tumor cells to enable them to adapt to various microenvironmental signals. Here the richness of our understanding on the modulations and functions of PKM2 in tumor progression is reviewed, and some new insights into the paradoxical expression and functional differences of PKM2 in distinct cancer types are offered.
Keywords: Pyruvate kinase M2; Aerobic glycolysis; Tetramer; Dimer; Tumor progression;

NFAT as cancer target: Mission possible? by Jiang-Jiang Qin; Subhasree Nag; Wei Wang; Jianwei Zhou; Wei-Dong Zhang; Hui Wang; Ruiwen Zhang (297-311).
The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calcium sensor, integrating calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates diverse cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer development and progression. Though the NFAT family has been conclusively proved to be pivotal in cancer progression, the different isoforms play distinct roles in different cellular contexts. In this review, our discussion is focused on the mechanisms that drive the activation of various NFAT isoforms in cancer. Additionally, we analyze the potential of NFAT as a valid target for cancer prevention and therapy.
Keywords: NFAT; Calcineurin–NFAT signaling; NFAT regulation; Cancer development and progression; Drug target; Small molecule inhibitor;

Deconstructing breast cancer cell biology and the mechanisms of multidrug resistance by Mafalda Videira; Rita Leones Reis; Maria Alexandra Brito (312-325).
Cancer complexity constantly challenges the way that clinicians manage breast cancer therapy. Tumor heterogeneity and intratumoral stroma characteristics allow cells with different phenotypes and deregulated apoptotic, proliferative and migration abilities to co-exist contributing to a disappointing therapeutic response. While new approaches are being associated with conventional chemotherapy, such as hormonal therapy or target monoclonal antibodies, recurrence and metastasization are still observed. Membrane transporters are the cell's first line of contact with anticancer drugs having a major role in multidrug resistance events. This structural-based activity enables the cell to be drug-resistant by decreasing drug intracellular concentration through an efflux-transport mechanism, mainly associated with overexpression of ATP-binding cassette (ABC) proteins. This review focuses on some of the important structural and biological properties of the malignant cell and tumor microenvironment, addressing the role of the membrane ABC transporters in therapeutic outcomes, and highlighting related molecular pathways that may represent meaningful target therapies.
Keywords: Cancer biology; Chemoresistance; Efflux transporters; Epithelial-mesenchymal transition; Multidrug resistance proteins; Tumor microenvironment;

The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation by Remco J. Molenaar; Tomas Radivoyevitch; Jaroslaw P. Maciejewski; Cornelis J.F. van Noorden; Fonnet E. Bleeker (326-341).
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key events in the development of glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (ICC), and angioimmunoblastic T-cell lymphoma. They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes. IDH1/2 mutations are associated with prolonged survival in glioma and in ICC, but not in AML. The reason for this is unknown. In their wild-type forms, IDH1 and IDH2 convert isocitrate and NADP+ to α-ketoglutarate (αKG) and NADPH. Missense mutations in the active sites of these enzymes induce a neo-enzymatic reaction wherein NADPH reduces αKG to D-2-hydroxyglutarate (D-2HG). The resulting D-2HG accumulation leads to hypoxia-inducible factor 1α degradation, and changes in epigenetics and extracellular matrix homeostasis. Such mutations also imply less NADPH production capacity. Each of these effects could play a role in cancer formation. Here, we provide an overview of the literature and discuss which downstream molecular effects are likely to be the drivers of the oncogenic and survival-prolonging properties of IDH1/2 mutations. We discuss interactions between mutant IDH1/2 inhibitors and conventional therapies. Understanding of the biochemical consequences of IDH1/2 mutations in oncogenesis and survival prolongation will yield valuable information for rational therapy design: it will tell us which oncogenic processes should be blocked and which “survivalogenic” effects should be retained.Display Omitted
Keywords: IDH1; IDH2; Glioma; Acute myeloid leukemia; D-2-hydroxyglutarate; NADPH;

The links between AKT and two intracellular proteolytic cascades: Ubiquitination and autophagy by Masayuki Noguchi; Noriyuki Hirata; Futoshi Suizu (342-352).
The serine threonine kinase AKT plays a central role in the regulation of cell survival in a variety of human neoplastic diseases. A series of studies have revealed a connection between AKT signaling and two important protein degradation pathways in mammalian cells: the ubiquitin–proteasome system and autophagy. Two distinct ubiquitination systems have been reported to regulate AKT signaling: K63-linked ubiquitination, which promotes the oncogenic activation of AKT, and K48-linked ubiquitination, which triggers the proteasomal degradation of phosphorylated AKT. Autophagy is an evolutionarily conserved mechanism for the gross disposal and recycling of intracellular proteins in mammalian cells. AKT signaling may play a regulatory role in autophagy; however, the underlying mechanisms have not been fully clarified. Recently, AKT was shown to phosphorylate key molecules involved in the regulation of autophagy. Furthermore, lysosomal co-localization of the AKT–Phafin2 complex is reportedly critical for the induction of autophagy. In this review, we will discuss the connection between AKT, a core intracellular survival regulator, and two major intracellular proteolytic signaling pathways in mammalian cells.Display Omitted
Keywords: AKT; Autophagy; Ubiquitination;

Personalized drug combinations to overcome trastuzumab resistance in HER2-positive breast cancer by Thuy Vu; Mark X. Sliwkowski; Francois X. Claret (353-365).
HER2-positive (HER2 +) breast cancer accounts for 18%–20% of all breast cancer cases and has the second poorest prognosis among breast cancer subtypes. Trastuzumab, the first Food and Drug Administration-approved targeted therapy for breast cancer, established the era of personalized treatment for HER2 + metastatic disease. It is well tolerated and improves overall survival and time-to-disease progression; with chemotherapy, it is part of the standard of care for patients with HER2 + metastatic disease. However, many patients do not benefit from it because of resistance. Substantial research has been performed to understand the mechanism of trastuzumab resistance and develop combination strategies to overcome the resistance. In this review, we provide insight into the current pipeline of drugs used in combination with trastuzumab and the degree to which these combinations have been evaluated, especially in patients who have experienced disease progression on trastuzumab. We conclude with a discussion of the current challenges and future therapeutic approaches to trastuzumab-based combination therapy.
Keywords: Targeted therapy; Combination approaches; HER2-positive breast cancer; Trastuzumab resistance;

Role of somatic cancer mutations in human protein lysine methyltransferases by Srikanth Kudithipudi; Albert Jeltsch (366-379).
Methylation of lysine residues is an important post-translational modification of histone and non-histone proteins, which is introduced by protein lysine methyltransferases (PKMTs). An increasing number of reports demonstrate that aberrant lysine methylation plays a central role in carcinogenesis that is often correlated with abnormal expression of PKMTs. Recent whole genome and whole transcriptome sequencing projects have also discovered several somatic mutations in PKMTs that frequently appear in various tumors. These include chromosomal translocations that lead to aberrant expression or mistargeting of PKMTs and nonsense or frameshift mutations, which cause the loss of the protein function. Another type of mutations are missense mutations which may lead to the loss of enzyme activity, but may also alter the properties of PKMTs either by changing the product or substrate specificity or by increasing the enzymatic activity finally leading to a gain-of-function phenotype. In this review, we provide an overview of the roles of EZH2, SETD2, NSD family, SMYD family, MLL family and DOT1L PKMTs in cancer focusing on the effects of somatic cancer mutations in these enzymes. Investigation of the effect of somatic cancer mutations in PKMTs is pivotal to understand the general role of this important class of enzymes in carcinogenesis and to improve and develop more individualized cancer therapies.Display Omitted
Keywords: Histone methylation; Lysine methylation; Protein lysine methyltransferase; Somatic cancer mutations; Enzyme mechanism;

T-box transcription factors in cancer biology by Sabina Wansleben; Jade Peres; Shannagh Hare; Colin R. Goding; Sharon Prince (380-391).
Keywords: T-box factors; TBX2; Cancer; Transcription factors; Cancer therapy;

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models by M. Binsfeld; K. Fostier; J. Muller; F. Baron; R. Schots; Y. Beguin; R. Heusschen; J. Caers (392-404).
The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models.Display Omitted
Keywords: Multiple myeloma; Mouse models; Immunotherapy; Transplantation; Adoptive transfer; Vaccination;

Phenethyl isothiocyanate: A comprehensive review of anti-cancer mechanisms by Parul Gupta; Stephen E. Wright; Sung-Hoon Kim; Sanjay K. Srivastava (405-424).
The epidemiological evidence suggests a strong inverse relationship between dietary intake of cruciferous vegetables and the incidence of cancer. Among other constituents of cruciferous vegetables, isothiocyanates (ITC) are the main bioactive chemicals present. Phenethyl isothiocyanate (PEITC) is present as gluconasturtiin in many cruciferous vegetables with remarkable anti-cancer effects. PEITC is known to not only prevent the initiation phase of carcinogenesis process but also to inhibit the progression of tumorigenesis. PEITC targets multiple proteins to suppress various cancer-promoting mechanisms such as cell proliferation, progression and metastasis. Pre-clinical evidence suggests that combination of PEITC with conventional anti-cancer agents is also highly effective in improving overall efficacy. Based on accumulating evidence, PEITC appears to be a promising agent for cancer therapy and is already under clinical trials for leukemia and lung cancer. This is the first review which provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of PEITC as a future anti-cancer agent.
Keywords: Cruciferous vegetables; Isothiocyanates; PEITC; Reactive oxygen species; Chemoprevention;

Bone metastases are characterized by increased osteoblastic and/or osteolytic processes depending on the tumor type. The altogether destructive effect of metastasis formation promoted by increased metabolic activity raises the release of components from the osseous metabolism into the blood stream. These components are either enzymes directly involved in the alteration processes, metabolites/proteins that develop during this or bone matrix proteins released during this. These biomarkers are categorized in relation to their involvement in the bone formation or resorption as bone formation and resorption markers. Based on a PubMed literature search, a critical appraisal of the various biomarkers for diagnostic, prognostic, and monitoring purposes is given for patients with skeletal metastases caused by breast, prostate, lung, or renal cell carcinomas.
Keywords: Bone markers; Cancer; Osseous metastasis; Diagnostic biomarker; Prognostic biomarker;

Multipotent mesenchymal stromal cells in liver cancer: Implications for tumor biology and therapy by Pratika Y. Hernanda; Alexander Pedroza-Gonzalez; Dave Sprengers; Maikel P. Peppelenbosch; Qiuwei Pan (439-445).
Remodeling of tumor microenvironment is a hallmark in the pathogenesis of liver cancer. Being a pivotal part of tumor stroma, multipotent mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells (MSCs), are recruited and enriched in liver tumors. Owing to their tumor tropism, MSCs are now emerging as vehicles for anticancer drug/gene delivery against liver cancer. However, the exact impact of MSCs on liver cancer remains elusive, as a variety of effects of these cells that have been reported included a plethora of tumor-promoting effects and anti-oncogenic properties. This review aims to dissect the mechanistic insight regarding this observed discrepancy in different experimental settings of liver cancer. Furthermore, we call for caution using MSCs to treat liver cancer or even premalignant liver diseases, before conclusive evidence for safety and efficacy having been obtained.
Keywords: Multipotent mesenchymal stromal cells; Liver cancer; Dual role;

Genetic variation: effect on prostate cancer by Tristan M. Sissung; Douglas K. Price; Marzia Del Re; Ariel M. Ley; Elisa Giovannetti; William D. Figg; Romano Danesi (446-456).
The crucial role of androgens in the development of prostate cancer is well established. The aim of this review is to examine the role of constitutional (germline) and tumor-specific (somatic) polymorphisms within important regulatory genes of prostate cancer. These include genes encoding enzymes of the androgen biosynthetic pathway, the androgen receptor gene, genes that encode proteins of the signal transduction pathways that may have a role in disease progression and survival, and genes involved in prostate cancer angiogenesis. Characterization of deregulated pathways critical to cancer cell growth have lead to the development of new treatments, including the CYP17 inhibitor abiraterone and clinical trials using novel drugs that are ongoing or recently completed [1]. The pharmacogenetics of the drugs used to treat prostate cancer will also be addressed. This review will define how germline polymorphisms are known affect a multitude of pathways, and therefore phenotypes, in prostate cancer etiology, progression, and treatment.
Keywords: Pharmacogenomics; Prostate cancer; Androgen deprivation therapy; Chemotherapy; Steroid;

MYC deregulation in lymphoid tumors: molecular mechanisms, clinical consequences and therapeutic implications by Tomasz Sewastianik; Monika Prochorec-Sobieszek; Bjoern Chapuy; Przemysław Juszczyński (457-467).
MYC is one of the most frequently deregulated oncogenes in human malignancies. It encodes a leucine zipper transcription factor that modulates a broad spectrum of cellular genes responsible for enhancing cell proliferation, cellular metabolism, growth, angiogenesis, metastasis, genomic instability, stem cell self-renewal and reduced differentiation. MYC functions predominantly as an amplifier of expression of already active genes, potentiating the pre-existing transcriptional program, although it can also repress certain transcriptional targets. In mouse models, MYC induces lymphomas, but requires cooperation with other lesions, including inactivation of the p53 pathway, structural alterations of BCL2 family members, or increased PI3K activity. In human B-cell tumors, MYC rearrangements involving the 8q24 region and immunoglobulin heavy or light genes are a hallmark of Burkitt lymphoma (BL), but can also occur in other lymphoid malignancies, that include diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU), plasma cell myeloma (PCM), mantle cell lymphoma (MCL) and plasmablastic lymphoma. For non-BL lymphoid malignancies, MYC fusions represent secondary genetic events and exist in the context of complex karyotypes. Regardless of the mechanism deregulating MYC, lymphomas over-expressing MYC are addicted to this oncogene, highlighting the potential clinical utility of MYC targeting strategies. Several promising approaches for pharmaceutical intervention have been suggested which are now in preclinical or clinical development. Herein, we therefore review the molecular pathogenetic mechanisms associated with MYC deregulation in human B-cell lymphomas and their implications for therapies targeting MYC.
Keywords: MYC; Burkitt lymphoma; Diffuse large B-cell lymphoma; Double hit lymphoma; Targeted therapy;

Familial nonmedullary thyroid cancer: Screening, clinical, molecular and genetic findings by Diana Navas-Carrillo; Antonio Ríos; José Manuel Rodríguez; Pascual Parrilla; Esteban Orenes-Piñero (468-476).
Thyroid cancer, the commonest of endocrine malignancies, continues increasing in incidence being the 5th more prevalent cancer among women in the United States in 2012. Familial thyroid cancer has become a well-recognized, unique, clinical entity in patients with thyroid cancer originating from follicular cells, that is, nonmedullary thyroid carcinoma. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]).Although there is some controversy, some epidemiologic and clinical kindred studies have shown that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumours, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. This way, preventing screening will allow earlier detection, more timely intervention, and hopefully improved outcomes for patients and their families. On the other hand, in the last years, an important number of genetic studies on FNMTC have been published, trying to determine its genetic contribution. However, the genetic inheritance of FNMTC remains unclear; but it is believed to be autosomal dominant with incomplete penetrance and variable expressivity. This paper provides an extensive overview of FNMTC from several points of view. Firstly, the impact of early detection on prognosis, secondly, the management and follow-up of FNMTC patients, and finally, the role of susceptibility loci, microRNAs (miRNAs) and telomerases in recently identified isolated cases of FNMTC.
Keywords: Familial nonmedullary thyroid cancer; Screening; Susceptibility loci; Telomerase; miRNA;

Epigenetic diversity in hematopoietic neoplasms by Rita Shaknovich; Subhajyoti De; Franziska Michor (477-484).
Tumor cell populations display a remarkable extent of variability in non-genetic characteristics such as DNA methylation, histone modification patterns, and differentiation levels of individual cells. It remains to be elucidated whether non-genetic heterogeneity is simply a byproduct of tumor evolution or instead a manifestation of a higher-order tissue organization that is maintained within the neoplasm to establish a differentiation hierarchy, a favorable microenvironment, or a buffer against changing selection pressures during tumorigenesis. Here, we review recent findings on epigenetic diversity, particularly heterogeneity in DNA methylation patterns in hematologic malignancies. We also address the implications of epigenetic heterogeneity for the clonal evolution of tumors and discuss its effects on gene expression and other genome functions in cancer.
Keywords: Epigenetics; Heterogeneity; Cancer; Lymphoma;

Semaphorin 5A mediated cellular navigation: Connecting nervous system and cancer by Abhilasha Purohit; Anguraj Sadanandam; Pavan Myneni; Rakesh K. Singh (485-493).
The ultraprecise wiring of neurons banks on the instructions provided by guidance cue proteins that steer them to their appropriate target tissue during neuronal development. Semaphorins are one such family of proteins. Semaphorins are known to play major physiological roles during the development of various organs including the nervous, cardiovascular, and immune systems. Their role in different pathologies including cancer remains an intense area of investigation. This review focuses on a novel member of this family of proteins, semaphorin 5A, which is much less explored in comparison to its other affiliates. Recent reports suggest that semaphorins play important roles in the pathology of cancer by affecting angiogenesis, tumor growth and metastasis. We will firstly give a general overview of the semaphorin family and its receptors. Next, we discuss their roles in cellular movements and how that makes them a connecting link between the nervous system and cancer. Finally, we focus our discussion on semaphorin 5A to summarize the prevailing knowledge for this molecule in developmental biology and carcinogenesis.
Keywords: Semaphorin; Semaphorin 5A; Developmental biology; Cancer; Plexins; Neuropilins;

Nrf2, the master redox switch: The Achilles' heel of ovarian cancer? by Monique G.P. van der Wijst; Robert Brown; Marianne G. Rots (494-509).
Ovarian cancer is the most lethal gynecological tumor type in the world due to late stage detection, and resistance to chemotherapy. Therefore, alternative additional therapies are required. The etiology of ovarian cancer remains largely unknown, but risk factors point toward an important role for oxidative stress. Both healthy and tumor cells can cope with oxidative stress by activating the transcription factor Nrf2 (also known as Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most ovarian cancers, aberrant activation of Nrf2 is observed, which is often associated with a copy number loss within the Nrf2-inhibitory complex KEAP1CUL3RBX1. A key role for Nrf2 in ovarian carcinogenesis has been validated by siRNA studies. However, to exploit the Nrf2 pathway for therapeutic interventions, potential side-effects should be minimized. In this review, we explore ovarian cancer specific factors with links to aberrant activity of Nrf2, to be exploited in future combination strategies, synergistic with direct Nrf2 inhibitory drugs. Particularly, we propose to stratify patients based on common ovarian cancer mutations (KRAS, BRAF, ERBB2, BRCA1 and its link with estradiol, TP53) for future NRF2 targeting strategies.
Keywords: Reactive oxygen species; Oxidative stress; Nrf2; Ovarian cancer; Cancer therapy; Mutations;

Local tumour ablative therapies: Opportunities for maximising immune engagement and activation by Morgan A. O'Brien; Derek G. Power; A. James P. Clover; Brian Bird; Declan M. Soden; Patrick F. Forde (510-523).
The relationship between cancer and the immune system is a complex one. The immune system can prevent tumour growth by eliminating cancer cells but this editing process ultimately results in poorly immunogenic cells remaining allowing for unchallenged tumour growth. In light of this, the focus of cancer treatment should be to maximise cancer elimination and the prevention of escape mechanisms. In this review we will examine current and emerging ablative treatment modalities that induce Immunogenic Cell Death (ICD), a special type of cell death that allows for immune cell involvement and the generation of an anti-tumour specific immune response. When paired with immune modulating agents, capable of potentiating the immune response and reversing the immune-suppressive environment created by tumours, we may be looking at the future of anti-cancer therapy.
Keywords: Immuno-editing; Tumour ablation; Immunogenic cell death; DAMPs; Immune blockade; Immune stimulation;

Histone deacetylase 2 controls p53 and is a critical factor in tumorigenesis by Tobias Wagner; Peter Brand; Thorsten Heinzel; Oliver H. Krämer (524-538).
Histone deacetylase 2 (HDAC2) regulates biological processes by deacetylation of histones and non-histone proteins. HDAC2 is overexpressed in numerous cancer types, suggesting general cancer-relevant functions of HDAC2. In human tumors the TP53 gene encoding p53 is frequently mutated and wild-type p53 is often disarmed. Molecular pathways inactivating wild-type p53 often remain to be defined and understood. Remarkably, current data link HDAC2 to the regulation of the tumor suppressor p53 by deacetylation and to the maintenance of genomic stability. Here, we summarize recent findings on HDAC2 overexpression in solid and hematopoietic cancers with a focus on mechanisms connecting HDAC2 and p53 in vitro and in vivo. In addition, we present an evidence-based model that integrates molecular pathways and feedback loops by which p53 and further transcription factors govern the expression and the ubiquitin-dependent proteasomal degradation of HDAC2 and of p53 itself. Understanding the interactions between p53 and HDAC2 might aid in the development of new therapeutic approaches against cancer.
Keywords: Cancer; HDAC inhibitors; HDAC2; p53; RLIM; Sumoylation;

Liquid biopsies in lung cancer: The new ambrosia of researchers by Christian Rolfo; Marta Castiglia; David Hong; Riccardo Alessandro; Inge Mertens; Geert Baggerman; Karen Zwaenepoel; Ignacio Gil-Bazo; Francesco Passiglia; Anna P. Carreca; Simona Taverna; Renza Vento; Marc Peeters; Antonio Russo; Patrick Pauwels (539-546).
In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a “one-fits-all” strategy to the “personalized medicine” based on the molecular characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery. More precisely in the last years the scientific community has started to use the term “liquid biopsy”. A liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) and, as well as a tissue biopsy, a representative of the tissue from which it is spread. In this review we will focus our attention on circulating tumor cells, circulating tumor DNA, exosomes and secretomes with the aim to underlie their usefulness and potential application in a clinical setting for lung cancer patient management.
Keywords: Circulating tumor cells; Exosomes; Circulating tumor DNA; Lung cancer; Biomarkers;

Targeting protein kinase C in sarcoma by J. Martin-Liberal; A.J. Cameron; J. Claus; I.R. Judson; P.J. Parker; M. Linch (547-559).
Protein kinase C (PKC) is a family of serine/threonine tyrosine kinases that regulate many cellular processes including division, proliferation, survival, anoikis and polarity. PKC is abundant in many human cancers and aberrant PKC signalling has been demonstrated in cancer models. On this basis, PKC has become an attractive target for small molecule inhibition within oncology drug development programmes. Sarcoma is a heterogeneous group of mesenchymal malignancies. Due to their relative insensitivity to conventional chemotherapies and the increasing recognition of the driving molecular events of sarcomagenesis, sarcoma provides an excellent platform to test novel therapeutics. In this review we provide a structure–function overview of the PKC family, the rationale for targeting these kinases in sarcoma and the state of play with regard to PKC inhibition in the clinic.
Keywords: Kinases; Protein kinase C; Sarcoma; Therapeutics;

Mechanisms of intimate and long-distance cross-talk between glioma and myeloid cells: How to break a vicious cycle by Thomas Wurdinger; Katrin Deumelandt; Hans J. van der Vliet; Pieter Wesseling; Tanja D. de Gruijl (560-575).
Glioma-associated microglia and macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs) condition the glioma microenvironment to generate an immunosuppressed niche for tumour expansion. This immunosuppressive microenvironment is considered to be shaped through a complex multi-step interactive process between glioma cells, GAMs and MDSCs. Glioma cells recruit GAMs and MDSCs to the tumour site and block their maturation. Glioma cell-derived factors subsequently skew these cells towards an immunosuppressive, tumour-promoting phenotype. Finally, GAMs and MDSCs enhance immune suppression in the glioma microenvironment and promote glioma growth, invasiveness, and neovascularization. The local and distant cross-talk between glioma cells and GAMs and MDSCs is regulated by a plethora of soluble proteins and cell surface-bound factors, and possibly via extracellular vesicles and platelets. Importantly, GAMs and MDSCs have been reported to impair the efficacy of glioma therapy, in particular immunotherapeutic approaches. Therefore, advancing our understanding of the function of GAMs and MDSCs in brain tumours and targeted intervention of their immunosuppressive function may benefit the treatment of glioma.
Keywords: Glioblastoma; Cross-talk; Immune response; Monocytes; Glioma-associated macrophages and microglia; Myeloid-derived suppressor cells;

Human leukocyte antigen (HLA)-G and cervical cancer immunoediting: A candidate molecule for therapeutic intervention and prognostic biomarker? by Fabrícia Gimenes; Jorge Juarez Vieira Teixeira; André Luelsdorf Pimenta de Abreu; Raquel Pantarotto Souza; Monalisa Wolski Pereira; Vânia Ramos Sela da Silva; Cinthia Gandolfi Bôer; Silvya Stuchi Maria-Engler; Marcelo Gialluisi Bonini; Sueli Donizete Borelli; Márcia Edilaine Lopes Consolaro (576-589).
While persistent infection with oncogenic types of human Papillomavirus (HPV) is required for cervical epithelial cell transformation and cervical carcinogenesis, HPV infection alone is not sufficient to induce tumorigenesis. Only a minor fraction of HPV infections produce high-grade lesions and cervical cancer, suggesting complex host–virus interactions. Based on its pronounced immunoinhibitory properties, human leukocyte antigen (HLA)-G has been proposed as a possible prognostic biomarker and therapeutic target relevant in a wide variety of cancers and viral infections, but to date remains underexplored in cervical cancer. Given the possible influence of HLA-G on the clinical course of HPV infection, cervical lesions and cancer progression, a better understanding of HLA-G involvement in cervical carcinogenesis might contribute to two aspects of fundamental importance: 1. Characterization of a novel diagnostic/prognostic biomarker to identify cervical cancer and to monitor disease stage, critical for patient screening; 2. Identification of HLA-G-driven immune mechanisms involved in lesion development and cancer progression, leading to the development of strategies for modulating HLA-G expression for treatment purposes. Thus, this systematic review explores the potential involvement of HLA-G protein expression and polymorphisms in cervical carcinogenesis.
Keywords: Cervical cancer; HLA-G; HPV; Cancer immunoediting; Therapeutic intervention; Prognostic biomarker;

PINK1 signalling in cancer biology by Ciara H. O'Flanagan; Cora O'Neill (590-598).
PTEN-induced kinase 1 (PINK1) was identified initially in cancer cells as a gene up‐regulated by overexpression of the major tumor suppressor, PTEN. Loss‐of‐function mutations in PINK1 were discovered subsequently to cause autosomal recessive Parkinson's disease. Substantial work during the past decade has revealed that PINK1 regulates several primary cellular processes of significance in cancer cell biology, including cell survival, stress resistance, mitochondrial homeostasis and the cell cycle. Mechanistically, PINK1 has been shown to interact on a number of levels with the pivotal oncogenic PI3-kinase/Akt/mTOR signalling axis and to control critical mitochondrial and metabolic functions that regulate cancer survival, growth, stress resistance and the cell cycle. A cytoprotective and chemoresistant function for PINK1 has been highlighted by some studies, supporting PINK1 as a target in cancer therapeutics. This article reviews the function of PINK1 in cancer cell biology, with an emphasis on the mechanisms by which PINK1 interacts with PI3-kinase/Akt signalling, mitochondrial homeostasis, and the potential context-dependent pro- and anti-tumorigenic functions of PINK1.
Keywords: PINK1; Cancer; Mitochondrial homeostasis; PI3-kinase/Akt; Chemoresistance; Cell cycle;

Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate filament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo efficacy, suggesting that cytoskeletal filaments may be exploited to supplement chemotherapeutic approaches currently used in the clinical setting. Therefore, this review is intended to expose academics and clinicians to the tremendous variety of cytoskeletal filament-directed agents that are currently available for further chemotherapeutic evaluation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage malignant cells are discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents.
Keywords: Actin; Microfilaments; Intermediate filaments; Drug synergy; Chemotherapy;

Dichloroacetate and cancer: New home for an orphan drug? by Shyam Kankotia; Peter W. Stacpoole (617-629).
We reviewed the anti-cancer effects of DCA, an orphan drug long used as an investigational treatment for various acquired and congenital disorders of mitochondrial intermediary metabolism. Inhibition by DCA of mitochondrial pyruvate dehydrogenase kinases and subsequent reactivation of the pyruvate dehydrogenase complex and oxidative phosphorylation is the common mechanism accounting for the drug's anti-neoplastic effects. At least two fundamental changes in tumor metabolism are induced by DCA that antagonize tumor growth, metastases and survival: the first is the redirection of glucose metabolism from glycolysis to oxidation (reversal of the Warburg effect), leading to inhibition of proliferation and induction of caspase-mediated apoptosis. These effects have been replicated in both human cancer cell lines and in tumor implants of diverse germ line origin. The second fundamental change is the oxidative removal of lactate, via pyruvate, and the co-incident buffering of hydrogen ions by dehydrogenases located in the mitochondrial matrix. Preclinical studies demonstrate that DCA has additive or synergistic effects when used in combination with standard agents designed to modify tumor oxidative stress, vascular remodeling, DNA integrity or immunity. These findings and limited clinical results suggest that potentially fruitful areas for additional clinical trials include 1) adult and pediatric high grade astrocytomas; 2) BRAF-mutant cancers, such as melanoma, perhaps combined with other pro-oxidants; 3) tumors in which resistance to standard platinum-class drugs alone may be overcome with combination therapy; and 4) tumors of endodermal origin, in which extensive experimental research has demonstrated significant anti-proliferative, pro-apoptotic effects of DCA, leading to improved host survival.
Keywords: Dichloroacetate; Cancer; Mitochondria; Pyruvate dehydrogenase complex; Hypoxia inducible factor-1 alpha; Warburg effect;

Neuroendocrine differentiation in prostate cancer: Novel morphological insights and future therapeutic perspectives by Matteo Santoni; Alessandro Conti; Luciano Burattini; Rossana Berardi; Marina Scarpelli; Liang Cheng; Antonio Lopez-Beltran; Stefano Cascinu; Rodolfo Montironi (630-637).
Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer (CRPC) The detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor targeted therapies.The poor molecular characterization of NEPC accounts in part for the lack of disease specific therapeutics. Several mechanisms are involved in NE differentiation, including inflammation and autophagy, and may actually represent future therapeutic targets for advanced NEPC patients. Furthermore, a growing body of evidence suggests a potential role of circulating tumor cells in the early diagnosis and treatment of NEPC.Here we summarize the recent findings on NEPC pathogenesis and we discuss the ongoing clinical trials and future perspectives for the treatment of NEPC patients.
Keywords: Androgen deprivation therapy; Carcinoid; Drug resistance; Large cell neuroendocrine carcinoma; Neuroendocrine prostate cancer; Small cell carcinoma;

mTOR signaling in tumorigenesis by Kai Xu; Pengda Liu; Wenyi Wei (638-654).
mTOR (the mechanistic target of rapamycin) is an atypical serine/threonine kinase involved in regulating major cellular functions including growth and proliferation. Deregulation of the mTOR signaling pathway is one of the most commonly observed pathological alterations in human cancers. To this end, oncogenic activation of the mTOR signaling pathway contributes to cancer cell growth, proliferation and survival, highlighting the potential for targeting the oncogenic mTOR pathway members as an effective anti-cancer strategy. In order to do so, a thorough understanding of the physiological roles of key mTOR signaling pathway components and upstream regulators would guide future targeted therapies. Thus, in this review, we summarize available genetic mouse models for mTORC1 and mTORC2 components, as well as characterized mTOR upstream regulators and downstream targets, and assign a potential oncogenic or tumor suppressive role for each evaluated molecule. Together, our work will not only facilitate the current understanding of mTOR biology and possible future research directions, but more importantly, provide a molecular basis for targeted therapies aiming at key oncogenic members along the mTOR signaling pathway.
Keywords: mTORC2; mTORC1; mTOR pathway; Mouse model; Tumorigenesis;

Chordoma: the entity by Youssef Yakkioui; Jacobus J. van Overbeeke; Remco Santegoeds; Manon van Engeland; Yasin Temel (655-669).
Chordomas are malignant tumors of the axial skeleton, characterized by their locally invasive and slow but aggressive growth. These neoplasms are presumed to be derived from notochordal remnants with a molecular alteration preceding their malignant transformation. As these tumors are most frequently observed on the skull base and sacrum, patients suffering from a chordoma present with debilitating neurological disease, and have an overall 5-year survival rate of 65%. Surgical resection with adjuvant radiotherapy is the first-choice treatment modality in these patients, since chordomas are resistant to conventional chemotherapy. Even so, management of chordomas can be challenging, as chordoma patients often present with recurrent disease. Recent advances in the understanding of the molecular events that contribute to the development of chordomas are promising; the most novel finding being the identification of brachyury in the disease process. Here we present an overview of the current paradigms and summarize relevant research findings.
Keywords: Chordoma; Etiology; Epigenetics; Notochord; Tumor biology; Pathophysiology;