BBA - Reviews on Cancer (v.1826, #2)

Molecular and cellular biology of neuroendocrine lung tumors: Evidence for separate biological entities by Dorian R.A. Swarts; Frans C.S. Ramaekers; Ernst-Jan M. Speel (255-271).
Pulmonary neuroendocrine tumors (NETs) are traditionally described as comprising a spectrum of neoplasms, ranging from low grade typical carcinoids (TCs) via the intermediate grade atypical carcinoids (ACs) to the highly malignant small cell lung cancers (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). Recent data, however, suggests that two categories can be distinguished on basis of molecular and clinical data, i.e. the high grade neuroendocrine (NE) carcinomas and the carcinoid tumors.Bronchial carcinoids and SCLCs may originate from the same pulmonary NE precursor cells, but a precursor lesion has only been observed in association with carcinoids, termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. The occurrence of mixed tumors exclusively comprising high grade NE carcinomas also supports a different carcinogenesis for these two groups. Histopathologically, high grade NE lung tumors are characterized by high mitotic and proliferative indices, while carcinoids are defined by maximally 10 mitoses per 2 mm2 (10 high-power fields) and rarely have Ki67-proliferative indices over 10%. High grade NE carcinomas are chemosensitive tumors, although they usually relapse. Surgery is often not an option due to extensive disease at presentation and early metastasis, especially in SCLC. Conversely, carcinoids are often insensitive to chemo- and radiation therapy, but cure can usually be achieved by surgery.A meta-analysis of comparative genomic hybridization studies performed for this review, as well as gene expression profiling data indicates separate clustering of carcinoids and carcinomas. Chromosomal aberrations are much more frequent in carcinomas, except for deletion of 11q, which is involved in the whole spectrum of NE lung tumors. Deletions of chromosome 3p are rare in carcinoids but are a hallmark of the high grade pulmonary NE carcinomas. On the contrary, mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are restricted to carcinoid tumors.Many of the differences between carcinoids and high grade lung NETs can be ascribed to tobacco consumption, which is strongly linked to the occurrence of high grade NE carcinomas. Smoking causes p53 mutations, very frequently present in SCLCs and LCNECs, but rarely in carcinoids. It further results in other early genetic events in SCLCs and LCNECs, such as 3p and 17p deletions. Smoking induces downregulation of E-cadherin and associated epithelial to mesenchymal transition. Also, high grade lung NETs display higher frequencies of aberrations of the Rb pathway, and of the intrinsic and extrinsic apoptotic routes. Carcinoid biology on the other hand is not depending on cigarette smoke intake but rather characterized by aberrations of other specific genetic events, probably including Menin or its targets and interaction partners. This results in a gradual evolution, most likely from proliferating pulmonary NE cells via hyperplasia and tumorlets towards classical carcinoid tumors.We conclude that carcinoids and high grade NE lung carcinomas are separate biological entities and do not comprise one spectrum of pulmonary NETs. This implies the need to reconsider both diagnostic as well as therapeutic approaches for these different groups of malignancies.
Keywords: Neuroendocrine lung tumors; Carcinoids; Small cell lung cancer; Large cell neuroendocrine carcinoma; Carcinogenesis; Tumor biology;

The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness by Bin Bao; Asfar S. Azmi; Shadan Ali; Aamir Ahmad; Yiwei Li; Sanjeev Banerjee; Dejuan Kong; Fazlul H. Sarkar (272-296).
Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. It has been well recognized that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotypic cells are associated with therapeutic resistance and contribute to aggressive tumor growth, invasion, metastasis and believed to be the cause of tumor recurrence. Interestingly, hypoxia and HIF signaling pathway are known to play an important role in the regulation and sustenance of CSCs and EMT phenotype. However, the molecular relationship between HIF signaling pathway with the biology of CSCs and EMT remains unclear although NF-κB, PI3K/Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT. In this article, we will discuss the state of our knowledge on the role of HIF-hypoxia signaling pathway and its kinship with CSCs and EMT within the tumor microenvironment. We will also discuss the potential role of hypoxia-induced microRNAs (miRNAs) in tumor development and aggressiveness, and finally discuss the potential effects of nutraceuticals on the biology of CSCs and EMT in the context of tumor hypoxia.
Keywords: Hypoxia; HIF; CSC; EMT; miRNAs;

Epithelial E- and P-cadherins: Role and clinical significance in cancer by Joana Paredes; Joana Figueiredo; André Albergaria; Patrícia Oliveira; Joana Carvalho; Ana Sofia Ribeiro; Joana Caldeira; Ângela Margarida Costa; Joana Simões-Correia; Maria José Oliveira; Hugo Pinheiro; Salomé S. Pinho; Rita Mateus; Celso A. Reis; Marina Leite; Maria Sofia Fernandes; Fernando Schmitt; Fátima Carneiro; Céu Figueiredo; Carla Oliveira; Raquel Seruca (297-311).
E-cadherin and P-cadherin are major contributors to cell–cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes during development, and in maintaining integrity and homeostasis in adult tissues. It is now generally accepted that alterations in these two molecules are observed during tumour progression of most carcinomas. Genetic or epigenetic alterations in E- and P-cadherin-encoding genes (CDH1 and CDH3, respectively), or alterations in their proteins expression, often result in tissue disorder, cellular de-differentiation, increased invasiveness of tumour cells and ultimately in metastasis. In this review, we will discuss the major properties of E- and P-cadherin molecules, its regulation in normal tissue, and their alterations and role in cancer, with a specific focus on gastric and breast cancer models.
Keywords: E-cadherin; P-cadherin; Cancer; Gastric; Breast; Hereditary diffuse gastric cancer;

Using mice to unveil the genetics of cancer resistance by Louise van der Weyden; David J. Adams (312-330).
In the UK, four in ten people will develop some form of cancer during their lifetime, with an individual's relative risk depending on many factors, including age, lifestyle and genetic make-up. Much research has gone into identifying the genes that are mutated in tumorigenesis with the over-whelming majority of genetically-modified (GM) mice in cancer research showing accelerated tumorigenesis or recapitulating key aspects of the tumorigenic process. Yet if six out of ten people will not develop some form of cancer during their lifetime, together with the fact that some cancer patients experience spontaneous regression/remission, it suggests there are ways of ‘resisting’ cancer. Indeed, there are wildtype, spontaneously-arising mutants and GM mice that show some form of ‘resistance’ to cancer. Identification of mice with increased resistance to cancer is a novel aspect of cancer research that is important in terms of providing both chemopreventative and therapeutic options. In this review we describe the different mouse lines that display a ‘cancer resistance’ phenotype and discuss the molecular basis of their resistance.
Keywords: Cancer; Resistance; Tumorigenesis; Mouse;

Normal to cancer microbiome transformation and its implication in cancer diagnosis by Abdul Arif Khan; Abhinav Shrivastava; Mohsin Khurshid (331-337).
Microbial communities coexisting with humans are collectively known as microbiome. It influences almost every aspect of an individual's body function. Microbiome is idiosyncratic for body condition and its alteration is indicative for several abnormalities. This article discusses about recent ideas for developing microbiology based cancer indicators using alterations in microbiome. It is noteworthy that large exploratory studies are required to identify cancer indicator microorganisms from complex and diverse microbiome constituents. This complexity also warrants that these markers should be used in conjunction with other routine cancer indicators. The present article concludes that such studies can spur development of novel microbiome based cancer diagnostics.
Keywords: Normal microbiome; Cancer microbiome; Cancer diagnosis; TLR; Estrobolome;

Glioblastoma: Therapeutic challenges, what lies ahead by Flavia R.S. Lima; Suzana Assad Kahn; Rossana C. Soletti; Deborah Biasoli; Tercia Alves; Anna Carolina C. da Fonseca; Celina Garcia; Luciana Romão; José Brito; Rosenilde Holanda-Afonso; Jane Faria; Helena Borges; Vivaldo Moura-Neto (338-349).
Glioblastoma (GBM) is one of the most aggressive human cancers. Despite current advances in multimodality therapies, such as surgery, radiotherapy and chemotherapy, the outcome for patients with high grade glioma remains fatal. The knowledge of how glioma cells develop and depend on the tumor environment might open opportunities for new therapies. There is now a growing awareness that the main limitations in understanding and successfully treating GBM might be bypassed by the identification of a distinct cell type that has defining properties of somatic stem cells, as well as cancer-initiating capacity — brain tumor stem cells, which could represent a therapeutic target. In addition, experimental studies have demonstrated that the combination of antiangiogenic therapy, based on the disruption of tumor blood vessels, with conventional chemotherapy generates encouraging results. Emerging reports have also shown that microglial cells can be used as therapeutic vectors to transport genes and/or substances to the tumor site, which opens up new perspectives for the development of GBM therapies targeting microglial cells. Finally, recent studies have shown that natural toxins can be conjugated to drugs that bind to overexpressed receptors in cancer cells, generating targeted-toxins to selectively kill cancer cells. These targeted-toxins are highly effective against radiation- and chemotherapy-resistant cancer cells, making them good candidates for clinical trials in GBM patients. In this review, we discuss recent studies that reveal new possibilities of GBM treatment taking into account cancer stem cells, angiogenesis, microglial cells and drug delivery in the development of new targeted-therapies.Display Omitted
Keywords: High-grade glioma; Cancer therapy; Cancer stem cell; Microglia; Angiogenesis; Cytolysins;

Circulating tumor cells in the diagnosis and management of pancreatic cancer by Putao Cen; Xiaoling Ni; Jingxuan Yang; David Y. Graham; Min Li (350-356).
Pancreatic cancers are typically resistant to chemo and radiation therapy and are predisposed to distant metastases. Circulating tumor cells (CTCs) are tumor cells disseminated from primary and metastatic sites and can be isolated from peripheral blood. CTC may overcome the limitation of the current available tumor markers, CA19-9. As a surrogate for ‘real-time biopsy’, CTCs allow recurrent assessment of a tumor's biological activity. We review the current methodologies for CTC extraction and characterization including antibody-based immunological assays, PCR-based assays, and novel technologies based on the physical or biological characteristics of CTCs. CTCs also provide an accessible link to the existence of epithelial to mesenchymal transition, tumor stem cell markers, and ongoing clonal mutations and epigenetic changes in the tumor. We also explore the potential of using CTC profiling in diagnosis, selection of neoadjuvant and adjuvant therapy, detection of recurrent disease, examination of pharmacodynamic biomarkers, as well as in gene therapy and immunotherapy for pancreatic cancer. Ongoing CTC characterization not only has the potential to represent all cells shed from primary pancreatic tumor and each metastatic site, but also allows dynamic sampling at multiple time points during the clinical course to identify the subpopulations of CTCs and the specific molecules driving metastasis and chemo resistance. We predict that CTC genotyping and phenotyping will play an increasing role in personalized therapy and in identification of novel therapeutic targets as well as monitoring the course and status of the disease.
Keywords: Circulating tumor cells; Pancreatic cancer;

Regulators of mammalian Hippo pathway in cancer by Angela M. Liu; Kwong-Fai Wong; Xiaoou Jiang; Yiting Qiao; John M. Luk (357-364).
Hippo pathway, originally discovered in Drosophila, is responsible for organ size control. The pathway is conserved in mammals and has a significant role in restraining cancer development. Regulating the Hippo pathway thus represents a potential therapeutic approach to treat cancer, which however requires deep understanding of the targeted pathway. Despite our limited knowledge on the pathway, there are increasing discoveries of new molecules that regulate and modulate the Hippo downstream signaling particularly in various solid malignancies, from extracellular stimuli or via pathway crosstalk. Herein, we discuss the roles of newly identified and key regulators that connect with core components (MST1/2, LATS1/2, SAV1, and MOB1) and downstream effector (YAP) in the Hippo pathway having an important role in cancer development and progression. Understanding of the mammalian Hippo pathway regulation may shed new insights to allow us selecting the right oncogenic targets and designing effective drugs for cancer treatments.
Keywords: Solid cancer; Hippo signaling; LATS1/2; MST1/2; Regulators; YAP;

Role of BAG3 protein in leukemia cell survival and response to therapy by Alessandra Rosati; Anna Basile; Antonia Falco; Morena d'Avenia; Michelina Festa; Vincenzo Graziano; Vincenzo De Laurenzi; Claudio Arra; Maria Pascale; Maria Caterina Turco (365-369).
The ability of BAG3, a member of the BAG family of heat shock protein (Hsp) 70 — cochaperones, to sustain the survival of human primary B-CLL and ALL cells was recognized about nine years ago. Since then, the anti-apoptotic activity of BAG3 has been confirmed in other tumor types, where it has been shown to regulate the intracellular concentration and localization of apoptosis-regulating factors, including NF-κB‐activating (IKKγ) and Bcl2-family (Bax) proteins. Furthermore, growing evidences support its role in lymphoid and myeloid leukemia response to therapy. Moreover in the last years, the contribution of BAG3 to autophagy, a process known to be involved in the pathogenesis and response to therapy of leukemia cells, has been disclosed, opening a new avenue for the interpretation of the role of this protein in leukemias' biology.
Keywords: BAG3; Cancer; Apoptosis; Leukemia; Autophagy;

A common set of functional characteristics of cancer cells is that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even in the presence of oxygen compared to that of normal cells (Warburg's Effects). In addition, cancer cells exhibit substantial alterations in several energy metabolism pathways including glucose transport, tricarboxylic acid (TCA) cycle, glutaminolysis, mitochondrial respiratory chain oxidative phosphorylation and pentose phosphate pathway (PPP). In the present work, we focused on reviewing the current knowledge about the dysregulation of the proteins/enzymes involved in the key regulatory steps of glucose transport, glycolysis, TCA cycle and glutaminolysis by several oncogenes including c-Myc and hypoxia inducible factor-1 (HIF-1) and tumor suppressor, p53, in cancer cells. The dysregulation of glucose transport and energy metabolism pathways by oncogenes and lost functions of the tumor suppressors have been implicated as important biomarkers for cancer detection and as valuable targets for the development of new anticancer therapies.
Keywords: p53; c-Myc; Glucose transporter; Glycolysis; TCA cycle; Glutaminolysis;

Targeting pancreatic cancer stem cells for cancer therapy by Jun Xia; Changjie Chen; Zhiwen Chen; Lucio Miele; Fazlul H. Sarkar; Zhiwei Wang (385-399).
Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.
Keywords: Pancreatic cancer; Stem cell; Natural agents; Cancer therapy;

Neurofibromatosis type 2 (NF2), characterized by tumors of the nervous system, is a result of functional loss of the NF2 gene. The NF2 gene encodes Merlin (moesin–ezrin–radixin-like protein), an ERM (Ezrin, Radixin, Moesin) protein family member. Merlin functions as a tumor suppressor through impacting mechanisms related to proliferation, apoptosis, survival, motility, adhesion, and invasion. Several studies have summarized the tumor intrinsic mutations in Merlin. Given the fact that tumor cells are not in isolation, but rather in an intricate, mutually sustaining synergy with their surrounding stroma, the dialog between the tumor cells and the stroma can potentially impact the molecular homeostasis and promote evolution of the malignant phenotype. This review summarizes the epigenetic modifications, transcript stability, and post-translational modifications that impact Merlin. We have reviewed the role of extrinsic factors originating from the tumor milieu that influence the availability of Merlin inside the cell. Information regarding Merlin regulation could lead to novel therapeutics by stabilizing Merlin protein in tumors that have reduced Merlin protein expression without displaying any NF2 genetic alterations.
Keywords: Merlin; NF2; Neurofibromatosis; Stability; Tumor microenvironment;

Plasmacytoids dendritic cells are a therapeutic target in anticancer immunity by Giuseppe Palma; Vincenzo De Laurenzi; Margot De Marco; Antonio Barbieri; Antonella Petrillo; Maria Caterina Turco; Claudio Arra (407-414).
Dendritic cells (DCs) are immunological sentinels of the organism acting as antigen-presenting cells (APC) and are critical for induction of innate and adaptive immunity. Traditionally they are divided in myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), a rare population of circulating cells that selectively express Toll-like receptors (TLR) 7 and TLR9 and have the capacity to produce large amounts of type I interferons (IFNs) in response to pathogenic agents or danger signals. It has been demonstrated that pDCs can coordinate events during the course of viral infections, allergic and autoimmune diseases and cancer. Through the production of type I IFNs, pDCs initiate protective immunity by activating classical DCs, T cells, natural killer cells and B cells. Upon activation, pDCs also differentiate into mature DCs and may contribute to the contraction of T-cell response. Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7; LILRA4), which couples with a signaling adapter to activate a prominent immune-receptor tyrosine-based activation motif (ITAM)-mediated signaling pathway. The interaction between ILT7 and bone marrow stromal cell antigen 2 (BST2, CD317) assures an appropriate TLR response by pDCs during viral infections and likely participates in pDCs tumor crosstalk. Moreover these cells seem to play a crucial role in the initiation of the pathological process of autoimmune diseases such as lupus or psoriasis. Despite the fact that their function within a tumor context is still controversial they represent an attractive target for therapeutic manipulation of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies.
Keywords: Plasmacytoid dendritic cells; Cancer; Immunology; Clinical trial;

New pieces of a puzzle: The current biological picture of MPN by Maria Kleppe; Ross L. Levine (415-422).
Over the last years, we have witnessed significant improvement in our ability to elucidate the genetic events, which contribute to the pathogenesis of acute and chronic leukemias, and also in patients with myeloproliferative neoplasms (MPN). However, despite significant insight into the role of specific mutations, including the JAK2V617F mutation, in MPN pathogenesis, the precise mechanisms by which specific disease alleles contribute to leukemic transformation in MPN remain elusive. Here we review recent studies aimed at understanding the role of downstream signaling pathways in MPN initiation and phenotype, and discuss how these studies have begun to lead to novel insights with biologic, clinical, and therapeutic relevance.
Keywords: MPN; JAK2; Signaling; Epigenetics; STAT3; Leukemia;

Cancer cells increase glucose uptake and reject lactic acid even in the presence of oxygen (Warburg effect). This metabolism reorients glucose towards the pentose phosphate pathway for ribose synthesis and consumes great amounts of glutamine to sustain nucleotide and fatty acid synthesis. Oxygenated and hypoxic cells cooperate and use their environment in a manner that promotes their development. Coenzymes (NAD+, NADPH,H+) are required in abundance, whereas continuous consumption of ATP and citrate precludes the negative feedback of these molecules on glycolysis, a regulation supporting the Pasteur effect. Understanding the metabolism of cancer cells may help to develop new anti-cancer treatments.
Keywords: Energetic metabolism; Biochemical pathways; Citrate; Phosphofructokinase;

The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis by Liliana Endo-Munoz; Andreas Evdokiou; Nicholas A. Saunders (434-442).
Osteosarcoma (OS) is the most common primary bone tumour in the paediatric age group. Treatment-refractory pulmonary metastasis continues to be the major complication of OS, reducing the 5-year survival rate for these patients to 10–20%. The mechanisms underlying the metastatic process in OS are still unclear, but undoubtedly, a greater understanding of the factors and interactions involved in its regulation will open new and much needed opportunities for therapeutic intervention. Recent published data have identified a new role for bone-specific macrophages (osteoclasts) and tumour-associated macrophages (TAMs), in OS metastasis. In this review we discuss the contribution of TAMs and osteoclasts in the establishment and maintenance of secondary metastatic lesions, and their novel role in the prevention of metastatic disease in a primary bone cancer such as osteosarcoma.
Keywords: Osteosarcoma; Metastasis; Osteoclast; Tumour-associated macrophage; Microenvironment;

Ascorbic acid: Chemistry, biology and the treatment of cancer by Juan Du; Joseph J. Cullen; Garry R. Buettner (443-457).
Since the discovery of vitamin C, the number of its known biological functions is continually expanding. Both the names ascorbic acid and vitamin C reflect its antiscorbutic properties due to its role in the synthesis of collagen in connective tissues. Ascorbate acts as an electron-donor keeping iron in the ferrous state thereby maintaining the full activity of collagen hydroxylases; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, as well as via the epigenetic landscape of cells and tissues. In fact, all known physiological and biochemical functions of ascorbate are due to its action as an electron donor. The ability to donate one or two electrons makes AscH an excellent reducing agent and antioxidant. Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H2O2). In the presence of catalytic metals this oxidation is accelerated. In this review, we show that the chemical and biochemical nature of ascorbate contribute to its antioxidant as well as its prooxidant properties. Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H2O2 to tumors. This new knowledge has rekindled interest and spurred new research into the clinical potential of pharmacological ascorbate. Knowledge and understanding of the mechanisms of action of pharmacological ascorbate bring a rationale to its use to treat disease especially the use of i.v. delivery of pharmacological ascorbate as an adjuvant in the treatment of cancer.
Keywords: Ascorbate; Oxidative stress; Hydrogen peroxide; Cancer; Pharmacology; Nutrition;