BBA - Reviews on Cancer (v.1846, #1)
Editorial Board (i).
Vascular-homing peptides for targeted drug delivery and molecular imaging: Meeting the clinical challenges by Nunzia D'Onofrio; Michele Caraglia; Anna Grimaldi; Raffaele Marfella; Luigi Servillo; Giuseppe Paolisso; Maria Luisa Balestrieri (1-12).
The vasculature of each organ expresses distinct molecular signatures critically influenced by the pathological status. The heterogeneous profile of the vascular beds has been successfully unveiled by the in vivo phage display, a high-throughput tool for mapping normal, diseased, and tumor vasculature. Specific challenges of this growing field are targeted therapies against cancer and cardiovascular diseases, as well as novel bioimaging diagnostic tools. Tumor vasculature-homing peptides have been extensively evaluated in several preclinical and clinical studies both as targeted-therapy and diagnosis. To date, results from several Phase I and II trials have been reported and many other trials are currently ongoing or recruiting patients. In this review, advances in the identification of novel peptide ligands and their corresponding receptors on tumor endothelium through the in vivo phage display technology are discussed. Emphasis is given to recent findings in the clinical setting of vascular-homing peptides selected by in vivo phage display for the treatment of advanced malignancies and their altered vascular beds.
Keywords: Phage display; Peptides; Endothelium; Cancer;
Protein mislocalization: Mechanisms, functions and clinical applications in cancer by Xiaohong Wang; Shulin Li (13-25).
The changes from normal cells to cancer cells are primarily regulated by genome instability, which foster hallmark functions of cancer through multiple mechanisms including protein mislocalization. Mislocalization of these proteins, including oncoproteins, tumor suppressors, and other cancer-related proteins, can interfere with normal cellular function and cooperatively drive tumor development and metastasis. This review describes the cancer-related effects of protein subcellular mislocalization, the related mislocalization mechanisms, and the potential application of this knowledge to cancer diagnosis, prognosis, and therapy.
Keywords: Subcellular localization; Cancer; Oncogene; Tumor suppressor;
Role of endothelial progenitor cells in cancer progression by Michele Moschetta; Yuji Mishima; Ilyas Sahin; Salomon Manier; Siobhan Glavey; Angelo Vacca; Aldo M. Roccaro; Irene M. Ghobrial (26-39).
Tumor-associated neovasculature is a critical therapeutic target; however, despite significant progress made in the clinical efficacy of anti-vessel drugs, the effect of these agents remains transient: over time, most patients develop resistance, which inevitably leads to tumor progression. To develop more effective treatments, it is imperative that we better understand the mechanisms involved in tumor vessel formation, how they participate to the tumor progression and metastasis, and the best way to target them.Several mechanisms contribute to the formation of tumor-associated vasculature: i) neoangiogenesis; ii) vascular co-option; iii) mosaicism; iv) vasculogenic mimicry, and v) postnatal vasculogenesis. These mechanisms can also play a role in the development of resistance to anti-angiogenic drugs, and could serve as targets for designing new anti-vascular molecules to treat solid as well as hematological malignancies. Bone marrow-derived endothelial progenitor cell (EPC)-mediated vasculogenesis represents an important new target, especially at the early stage of tumor growth (when EPCs are critical for promoting the “angiogenic switch”), and during metastasis, when EPCs promote the transition from micro- to macro-metastases. In hematologic malignancies, the EPC population could be related to the neoplastic clone, and both may share a common ontogeny. Thus, characterization of tumor-associated EPCs in blood cancers may provide clues for more specific anti-vascular therapy that has both direct and indirect anti-tumor effects. Here, we review the role of vasculogenesis, mediated by bone marrow-derived EPCs, in the progression of cancer, with a particular focus on the role of these cells in promoting progression of hematological malignancies.
Keywords: Endothelial progenitor cells; Cancers; Hematological malignancies; Vasculogenesis;
PLA2R1: Expression and function in cancer by David Bernard; David Vindrieux (40-44).
The phospholipase A2 receptor 1 (PLA2R1 or PLA2R) was isolated twenty years ago for its ability to bind several secretory phospholipase A2 proteins (sPLA2). Since its identification, it has attracted only a limited interest, mainly in the sPLA2 biology field, as it is viewed uniquely as a regulator of sPLA2 activities. Recent discoveries outline novel important functions of this gene in cancer biology. Indeed, PLA2R1 gain or loss of function experiments in vitro and in vivo shows that this receptor promotes several tumor suppressive responses including senescence, apoptosis and inhibition of transformation. Supporting a tumor suppressive role of PLA2R1, its expression decreases in numerous cancers, and known oncogenes such as HIF2α and c-MYC repress its expression. PLA2R1 promoter methylation, a classical way to repress tumor suppressive gene expression in cancer cells, is observed in leukemia, in kidney and in breast cancer cells. Mechanistically, PLA2R1 activates the kinase JAK2 and orients its activity towards a tumor suppressive one. PLA2R1 also promotes accumulation of reactive oxygen species which induce cell death and senescence. This review compiles recent data demonstrating an unexpected tumor suppressive role of PLA2R1 and outlines the future work needed to improve our knowledge of the functions of this gene in cancer.
Keywords: Cancer; PLA2R1; Senescence; Apoptosis; Methylation; c-MYC;
Opportunities for translation: Targeting DNA repair pathways in pancreatic cancer by Elaina N. Maginn; Camila H. de Sousa; Harpreet S. Wasan; Euan A. Stronach (45-54).
Pancreatic ductal adenocarcinoma (PDAC) remains one of the poorest prognosis neoplasms. It is typified by high levels of genomic aberrations and copy-number variation, intra-tumoural heterogeneity and resistance to conventional chemotherapy. Improved therapeutic options, ideally targeted against cancer-specific biological mechanisms, are urgently needed. Although induction of DNA damage and/or modulation of DNA damage response pathways are associated with the activity of a number of conventional PDAC chemotherapies, the effectiveness of this approach in the treatment of PDAC has not been comprehensively reviewed. Here, we review chemotherapeutic agents that have shown anti-cancer activity in PDAC and whose mechanisms of action involve modulation of DNA repair pathways. In addition, we highlight novel potential targets within these pathways based on the emerging understanding of PDAC biology and their exploitation as targets in other cancers.
Keywords: Pancreatic ductal adenocarcinoma; DNA damage response and repair; DNA damaging agents; Chemoresistance;
Signaling pathways involved in MDSC regulation by Prashant Trikha; William E. Carson (55-65).
The immune system has evolved mechanisms to protect the host from the deleterious effects of inflammation. The generation of immune suppressive cells like myeloid derived suppressor cells (MDSCs) that can counteract T cell responses represents one such strategy. There is an accumulation of immature myeloid cells or MDSCs in bone marrow (BM) and lymphoid organs under pathological conditions such as cancer. MDSCs represent a population of heterogeneous myeloid cells comprising of macrophages, granulocytes and dendritic cells that are at early stages of development. Although, the precise signaling pathways and molecular mechanisms that lead to MDSC generation and expansion in cancer remains to be elucidated. It is widely believed that perturbation of signaling pathways involved during normal hematopoietic and myeloid development under pathological conditions such as tumorogenesis contributes to the development of suppressive myeloid cells. In this review we discuss the role played by key signaling pathways such as PI3K, Ras, Jak/Stat and TGFb during myeloid development and how their deregulation under pathological conditions can lead to the generation of suppressive myeloid cells or MDSCs. Targeting these pathways should help in elucidating mechanisms that lead to the expansion of MDSCs in cancer and point to methods for eliminating these cells from the tumor microenvironment.
Keywords: Myeloid derived suppressor cells (MDSC); PI3K; TGFβ; Ras; Jak/Stat; Tumor microenvironment;
Glutamate as chemotactic fuel for diffuse glioma cells: Are they glutamate suckers? by Sanne A.M. van Lith; Anna C. Navis; Kiek Verrijp; Simone P. Niclou; Rolf Bjerkvig; Pieter Wesseling; Bastiaan Tops; Remco Molenaar; Cornelis J.F. van Noorden; William P.J. Leenders (66-74).
Diffuse gliomas comprise a group of primary brain tumors that originate from glial (precursor) cells and present as a variety of malignancy grades which have in common that they grow by diffuse infiltration. This phenotype complicates treatment enormously as it precludes curative surgery and radiotherapy. Furthermore, diffusely infiltrating glioma cells often hide behind a functional blood–brain barrier, hampering delivery of systemically administered therapeutic and diagnostic compounds to the tumor cells. The present review addresses the biological mechanisms that underlie the diffuse infiltrative phenotype, knowledge of which may improve treatment strategies for this disastrous tumor type. The invasive phenotype is specific for glioma: most other brain tumor types, both primary and metastatic, grow as delineated lesions. Differences between the genetic make-up of glioma and that of other tumor types may therefore help to unravel molecular pathways, involved in diffuse infiltrative growth. One such difference concerns mutations in the NADP+-dependent isocitrate dehydrogenase (IDH1 and IDH2) genes, which occur in > 80% of cases of low grade glioma and secondary glioblastoma. In this review we present a novel hypothesis which links IDH1 and IDH2 mutations to glutamate metabolism, possibly explaining the specific biological behavior of diffuse glioma.
Keywords: Glioma; Isocitrate dehydrogenase; 2-Hydroxyglutarate; Metabolism; Glutamate; Diffuse infiltration;
A comprehensive overview of exosomes as drug delivery vehicles — Endogenous nanocarriers for targeted cancer therapy by Kasper Bendix Johnsen; Johann Mar Gudbergsson; Martin Najbjerg Skov; Linda Pilgaard; Torben Moos; Meg Duroux (75-87).
Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale.Display Omitted
Keywords: Exosome; Drug delivery; Cancer; Loading; Targeted therapy; Chemotherapy;
Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor by Sakthivel Muniyan; Matthew A. Ingersoll; Surinder K. Batra; Ming-Fong Lin (88-98).
The inactivation of tumor suppressor genes (TSGs) plays a vital role in the progression of human cancers. Nevertheless, those ubiquitous TSGs have been shown with limited roles in various stages of diverse carcinogenesis. Investigation on identifying unique TSG, especially for early stage of carcinogenesis, is imperative. As such, the search for organ-specific TSGs has emerged as a major strategy in cancer research. Prostate cancer (PCa) has the highest incidence in solid tumors in US males. Cellular prostatic acid phosphatase (cPAcP) is a prostate-specific differentiation antigen. Despite intensive studies over the past several decades on PAcP as a PCa biomarker, the role of cPAcP as a PCa-specific tumor suppressor has only recently been emerged and validated. The mechanism underlying the pivotal role of cPAcP as a prostate-specific TSG is, in part, due to its function as a protein tyrosine phosphatase (PTP) as well as a phosphoinositide phosphatase (PIP), an apparent functional homologue to phosphatase and tensin homolog (PTEN) in PCa cells. This review is focused on discussing the function of this authentic prostate-specific tumor suppressor and the mechanism behind the loss of cPAcP expression leading to prostate carcinogenesis. We review other phosphatases' roles as TSGs which regulate oncogenic PI3K signaling in PCa and discuss the functional similarity between cPAcP and PTEN in prostate carcinogenesis.
Keywords: cPAcP; Tumor suppressor; Prostate cancer; Protein tyrosine phosphatase; ErbB-2; Phosphoinositide phosphatase;
Prostate-specific antigen and other serum and urine markers in prostate cancer by Carsten Stephan; Bernhard Ralla; Klaus Jung (99-112).
Prostate-specific antigen (PSA) is one of the most widely used tumor markers, and strongly correlates with the risk of harboring from prostate cancer (PCa). This risk is visible already several years in advance but PSA has severe limitations for PCa detection with its low specificity and low negative predictive value. There is an urgent need for new biomarkers especially to detect clinically significant and aggressive PCa. From all PSA-based markers, the FDA-approved Prostate Health Index (phi) shows improved specificity over percent free and total PSA. Other serum kallikreins or sarcosine in serum or urine show more diverging data. In urine, the FDA-approved prostate cancer gene 3 (PCA3) has also proven its utility in the detection and management of early PCa. However, some aspects on its correlation with aggressiveness and the low sensitivity at very high values have to be re-examined. The detection of a fusion of the androgen regulated TMPRSS2 gene with the ERG oncogene (from the ETS family), which acts as transcription factor gene, in tissue of ~ 50% of all PCa patients was one milestone in PCa research. When combining the urinary assays for TMPRSS2:ERG and PCA3, an improved accuracy for PCa detection is visible. PCA3 and phi as the best available PCa biomarkers show an equal performance in direct comparisons.
Keywords: PSA; Prostate cancer; Prostate health index; PCA3; TMPRSS2; Biomarkers;
The emerging role of MMP14 in brain tumorigenesis and future therapeutics by Ilya Ulasov; Ruiyang Yi; Donna Guo; Purvaba Sarvaiya; Charles Cobbs (113-120).
Glioblastoma is a malignant brain tumor of glial origin. These tumors are thought to be derived from astrocytic cells that undergo malignant transformation. A growing body of evidence suggests that upregulation of MMP expression plays a significant role in promoting glioma pathogenesis. Elevated expression of MMP14 not only promotes glioma invasion and tumor cell proliferation but also plays a role in angiogenesis. Despite the fact that levels of MMP14 correlate with breast cancer progression, the controversial role of MMP14 in gliomagenesis needs to be elucidated. In the present review, we discuss the role of MMP14 in glioma progression as well as the mechanisms of MMP14 regulation in the context of future therapeutic manipulations.
Keywords: MMP14; Invasion; Angiogenesis; Brain; Tumor; Glioblastoma;
Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells by Daniel Heylmann; Franz Rödel; Thomas Kindler; Bernd Kaina (121-129).
Immunodeficiency is a severe side effect of radiation therapy, notably at high radiation doses. It may also impact healthy individuals exposed to environmental ionizing radiation. Although it is believed to result from cytotoxicity of bone marrow cells and of immunocompetent cells in the peripheral blood, the response of distinct bone marrow and blood cell subpopulations following exposure to ionizing radiation is not yet fully explored. In this review, we aim to compile the knowledge on radiation sensitivity of immunocompetent cells and to summarize data from bone marrow and peripheral blood cells derived from mouse and human origin. In addition, we address the radiation response of blood stem and progenitor cells. The data indicate that stem cells, T helper cells, cytotoxic T cells, monocytes, neutrophils and, at a high degree, B cells display a radiation sensitive phenotype while regulatory T cells, macrophages, dendritic cells and natural killer cells appear to be more radioresistant. No conclusive data are available for basophil and eosinophil granulocytes. Erythrocytes and thrombocytes, but not their precursors, seem to be highly radioresistant. Overall, the data indicate considerable differences in radiosensitivity of bone marrow and blood normal and malignant cell populations, which are discussed in the light of differential radiation responses resulting in hematotoxicity and related clinical implications.
Keywords: Radiation; Cancer therapy; DNA repair; Lymphocytes; Monocytes; Stem cells;
The CD95/CD95L signaling pathway: A role in carcinogenesis by Amélie Fouqué; Laure Debure; Patrick Legembre (130-141).
Apoptosis is a fundamental process that contributes to tissue homeostasis, immune responses, and development. The receptor CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance, and various lineages of malignant cells exhibit loss-of-function mutations in this pathway; therefore, CD95 was initially classified as a tumor suppressor gene. However, more recent data indicate that in different pathophysiological contexts, this receptor can transmit non-apoptotic signals, promote inflammation, and contribute to carcinogenesis. A comparison with the initial molecular events of the TNF-R signaling pathway leading to non-apoptotic, apoptotic, and necrotic pathways reveals that CD95 is probably using different molecular mechanisms to transmit its non-apoptotic signals (NF-κB, MAPK, and PI3K). As discussed in this review, the molecular process by which the receptor switches from an apoptotic function to an inflammatory role is unknown. More importantly, the biological functions of these signals remain elusive.Display Omitted
Keywords: Fas; Apoptosis; Cytokine; Inflammation; Carcinogenesis;
Mucins and tumor resistance to chemotherapeutic drugs by Nicolas Jonckheere; Nicolas Skrypek; Isabelle Van Seuningen (142-151).
Epithelial cancer patients not considered eligible for surgical resection frequently benefit from chemotherapy. Chemotherapy is the treatment of cancer with one or combination of cytotoxic or cytostatic drugs. Recent advances in chemotherapy allowed a great number of cancer patients to receive treatment with significant results. Unfortunately, resistance to chemotherapeutic drug treatment is a major challenge for clinicians in the majority of epithelial cancers because it is responsible for the inefficiency of therapies.Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Implications of mucins have been described in relation to cancer cell behavior and cell signaling pathways associated with epithelial tumorigenesis. Because of the frequent alteration of the pattern of mucin expression in cancers as well as their structural and functional characteristics, mucins are thought to also be involved in response to therapies. In this report, we review the roles of mucins in chemoresistance and the associated underlying molecular mechanisms (physical barrier, resistance to apoptosis, drug metabolism, cell stemness, epithelial–mesenchymal transition) and discuss the therapeutic tools/strategies and/or prognosis biomarkers for personalized chemotherapy that could be proposed from these studies.
Keywords: Mucin; Cancer; Resistance; Chemotherapeutic drug; Apoptosis; Prognosis biomarker;
Molecular mechanisms of oncogene-induced inflammation and inflammation-sustained oncogene activation in gastrointestinal tumors: An underappreciated symbiotic relationship by Denada Dibra; Lopa Mishra; Shulin Li (152-160).
Inflammation plays an integral part in tumor initiation. Specifically, patients with colitis, pancreatitis, or hepatitis have an increased susceptibility to cancer. The activation, mutation, and overexpression of oncogenes have been well documented in cell proliferation and transformation. Recently, oncogenes were found to also regulate the inflammatory milieu in tumors. Similarly, the inflammatory milieu can promote oncogene activation.In this review, we summarize advances of the symbiotic relationship oncogene activation and inflammation in gastrointestinal tumors such as colorectal, hepatic, and pancreatic tumors. NF-κB and STAT3 are the two most common pathways that are deregulated via these oncogenes. Understanding these interactions may yield effective therapeutic strategies for tumor prevention and treatment.
Keywords: Oncogene-induced inflammation; p53; K-RAS; WNT; NF-kappaB; STAT3;
Angiogenic factors as potential drug target: Efficacy and limitations of anti-angiogenic therapy by Rajesh N. Gacche; Rohan J. Meshram (161-179).
Formation of new blood vessels (angiogenesis) has been demonstrated to be a basic prerequisite for sustainable growth and proliferation of tumor. Several growth factors, cytokines, small peptides and enzymes support tumor growth either independently or in synergy. Decoding the crucial mechanisms of angiogenesis in physiological and pathological state has remained a subject of intense interest during the past three decades. Currently, the most widely preferred approach for arresting tumor angiogenesis is the blockade of vascular endothelial growth factor (VEGF) pathway; however, the clinical usage of this modality is still limited by several factors such as adverse effects, toxicity, acquired drug resistance, and non-availability of valid biomarkers. Nevertheless, angiogenesis, being a normal physiological process imposes limitations in maneuvering it as therapeutic target for tumor angiogenesis. The present review offers an updated relevant literature describing the role of well-characterized angiogenic factors, such as VEGF, basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), placenta growth factor (PLGF), hepatocyte growth factor/scatter factor (HGF/SF) and angiopoetins (ANGs) in regulating tumor angiogenesis. We have also attempted to discuss tumor angiogenesis with a perspective of ‘an attractive target with emerging challenges’, along with the limitations and present status of anti-angiogenic therapy in the current state-of-the-art.Display Omitted
Keywords: Tumor angiogenesis; Pro-angiogenic cytokines; Anti-angiogenic therapy;
The development of Wilms tumor: From WT1 and microRNA to animal models by Fang Tian; Gregory Yourek; Xiaolei Shi; Yili Yang (180-187).
Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3′–5′ exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor.
Keywords: Wilms tumor; WT1; Epigenetics; miRNA; Kidney development; STAT1;
WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies by C. Marcelo Aldaz; Brent W. Ferguson; Martin C. Abba (188-200).
WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers and uterine and gastric adenocarcinomas.Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer.Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism.Finally, very recently the first human pedigrees with probands carrying homozygous germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation.In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions.
Keywords: WWOX; FRA16D; TGFβ; WNT; Lipid metabolism; Epilepsy;
Inhibition of poly(ADP-ribosyl)ation in cancer: Old and new paradigms revisited by Barbara Lupo; Livio Trusolino (201-215).
Inhibitors of poly(ADP-ribose) polymerases actualized the biological concept of synthetic lethality in the clinical practice, yielding a paradigmatic example of translational medicine. The profound sensitivity of tumors with germline BRCA mutations to PARP1/2 blockade owes to inherent defects of the BRCA-dependent homologous recombination machinery, which are unleashed by interruption of PARP DNA repair activity and lead to DNA damage overload and cell death. Conversely, aspirant BRCA-like tumors harboring somatic DNA repair dysfunctions (a vast entity of genetic and epigenetic defects known as “BRCAness”) not always align with the familial counterpart and appear not to be equally sensitive to PARP inhibition. The acquisition of secondary resistance in initially responsive patients and the lack of standardized biomarkers to identify “BRCAness” pose serious threats to the clinical advance of PARP inhibitors; a feeling is also emerging that a BRCA-centered perspective might have missed the influence of additional, not negligible and DNA repair-independent PARP contributions onto therapy outcome. While regulatory approval for PARP1/2 inhibitors is still pending, novel therapeutic opportunities are sprouting from different branches of the PARP family, although they remain immature for clinical extrapolation. This review is an endeavor to provide a comprehensive appraisal of the multifaceted biology of PARPs and their evolving impact on cancer therapeutics.
Keywords: Poly(ADP-ribose) polymerase; BRCAness; Tankyrase; DNA repair; Synthetic lethality; Targeted cancer therapies;
The metabolic cooperation between cells in solid cancer tumors by Philippe Icard; Perrine Kafara; Jean-Marc Steyaert; Laurent Schwartz; Hubert Lincet (216-225).
Cancer cells cooperate with stromal cells and use their environment to promote tumor growth. Energy production depends on nutrient availability and O2 concentration. Well-oxygenated cells are highly proliferative and reorient the glucose metabolism towards biosynthesis, whereas glutamine oxidation replenishes the TCA cycle coupled with OXPHOS-ATP production. Glucose, glutamine and alanine transformations sustain nucleotide and fatty acid synthesis. In contrast, hypoxic cells slow down their proliferation, enhance glycolysis to produce ATP and reject lactate which is recycled as fuel by normoxic cells. Thus, glucose is spared for biosynthesis and/or for hypoxic cell function. Environmental cells, such as fibroblasts and adipocytes, serve as food donors for cancer cells, which reject waste products (CO2, H+, ammoniac, polyamines…) promoting EMT, invasion, angiogenesis and proliferation. This metabolic-coupling can be considered as a form of commensalism whereby non-malignant cells support the growth of cancer cells. Understanding these cellular cooperations within tumors may be a source of inspiration to develop new anti-cancer agents.
Keywords: Tumoral microenvironment; Warburg effect; Tumoral metabolism; Autophagy; Waste products;
Viral infection-oxidative stress/DNA damage-aberrant DNA methylation: separate or interrelated events responsible for genetic instability and childhood ALL development? by Ryszard Olinski; Jan Styczynski; Elwira Olinska; Daniel Gackowski (226-231).
Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates in a single B- or T-lymphocyte progenitor and is characterized by a range of numeric and structural chromosomal aberrations. Although, so far no clear cause can be found for ALL the most commonly recognized and strongest causal factor is infection. However, an interesting question is how viral infection may be responsible for genetic changes that lead to lymphoid cell transformation. A plausible mechanism by which infection might impact the process of leukemogenesis via genetic alteration is through: oxidative stress/DNA damage which is closely linked with inflammation, aberrant expression of AID/ABOBEC family enzymes which may be responsible for massive mutation introduction and alteration of DNA methylation, leading to changes in the expression of hematopoietic genes. In this review we propose several specific molecular mechanisms which link infection with all the above-mentioned processes. The most likely event which links common virus infection with ALL pathogenesis is aberrant expression of AID/APOBEC. This event may be directly responsible for the introduction of point mutations (as the result of cytosine or 5-methylcytosine deamination and formation of G:U or G:T misspairs) as well as changes in DNA methylation status.
Keywords: Acute lymphoblastic leukemia; 5-Methylcytosine; Deaminases; Oxidative stress; Viral infection; Epigenetics;
Targeted therapy for gastric cancer: Molecular pathways and ongoing investigations by Wei Yang; Alexander Raufi; Samuel J. Klempner (232-237).
Gastric cancer is currently the second leading cause of worldwide cancer mortality. Ongoing collaborative sequencing efforts have highlighted recurrent somatic genomic aberrations in gastric cancer, however, despite advances in characterizing the genomic landscape, there have been few advances in patient outcomes. Prognosis remains poor with a median overall survival of 12 months for advanced disease. The improved survival with trastuzumab, and more recently ramucirumab, underscore the promise of targeted and biologic therapies and the importance of molecular tumor characterization in gastric cancer. Here we review the most frequent actionable alterations in gastric cancer and highlight ongoing clinical investigations attempting to translate biologic understanding into improved clinical outcomes.
Keywords: Targeted therapy; Gastric; Cancer; Mutation; Proteomics; Sequencing;
Sweet escape: Sialic acids in tumor immune evasion by Christian Büll; Martijn H. den Brok; Gosse J. Adema (238-246).
Sialic acids represent a family of sugar molecules derived from neuraminic acid that frequently terminate glycan chains and contribute to many biological processes. Already five decades ago, aberrantly high expression of sialic acids has been proposed to protect cancer cells from recognition and eradication by the immune system. Today, increased understanding at the molecular level demonstrates the broad immunomodulatory capacity of tumor-derived sialic acids that is, at least in part, mediated through interactions with immunoinhibitory Siglec receptors. Here we will review current studies from a sialic acid sugar perspective showing that tumor-derived sialic acids disable major killing mechanisms of effector immune cells, trigger production of immune suppressive cytokines and dampen activation of antigen-presenting cells and subsequent induction of anti-tumor immune responses. Furthermore, strategies to modulate sialic acid expression in cancer cells to improve cancer immunotherapy will be discussed.
Keywords: Sialic acids; Sialoglycans; Siglecs; Immune evasion; Cancer; Tumor microenvironment;
Neem components as potential agents for cancer prevention and treatment by Fang Hao; Sandeep Kumar; Neelu Yadav; Dhyan Chandra (247-257).
Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment.
Keywords: Neem; Mitochondria and apoptosis; Cancer cell death and proliferation; Tumor microenvironment and metabolism; Angiogenesis; Azadirachtin and nimbolide;
Racial/ethnic disparities in human DNA methylation by Yin-yin Xia; Yu-bing Ding; Xue-qing Liu; Xue-mei Chen; Shu-qun Cheng; Lian-bing Li; Ming-fu Ma; Jun-lin He; Ying-xiong Wang (258-262).
The racial/ethnic disparities in DNA methylation patterns indicate that molecular markers may play a role in determining the individual susceptibility to diseases in different ethnic groups. Racial disparities in DNA methylation patterns have been identified in prostate cancer, breast cancer and colorectal cancer and are related to racial differences in cancer prognosis and survival.
Keywords: DNA methylation; Racial/ethnic disparities; Individual susceptibility; Cancer;
PALB2: The hub of a network of tumor suppressors involved in DNA damage responses by Jung-Young Park; Fan Zhang; Paul R. Andreassen (263-275).
PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.Display Omitted
Keywords: PALB2; Tumor suppressor; DNA repair; Homologous recombination; Genome stability; Breast cancer;