BBA - Reviews on Cancer (v.1865, #2)
Editorial Board (i).
TGIF function in oncogenic Wnt signaling by Mohammed S. Razzaque; Azeddine Atfi (101-104).
Transforming growth-interacting factor (TGIF) has been implicated in the pathogenesis of many types of human cancer, but the underlying mechanisms remained mostly enigmatic. Our recent study has revealed that TGIF functions as a mediator of oncogenic Wnt/β-catenin signaling. We found that TGIF can interact with and sequesters Axin1 and Axin2 into the nucleus, thereby culminating in disassembly of the β-catenin-destruction complex and attendant accumulation of β-catenin in the nucleus, where it activates expression of Wnt target genes, including TGIF itself. We have provided proof-of-concept evidences that high levels of TGIF expression correlate with poor prognosis in patients with triple negative breast cancer (TNBC), and that TGIF empowers Wnt-driven mammary tumorigenesis in vivo. Here, we will briefly summarize how TGIF influences Wnt signaling to promote tumorigenesis.
Keywords: TGIF; Axin1; Axin2; β-Catenin; Mammary tumor;
HOX genes: Major actors in resistance to selective endocrine response modifiers by Kideok Jin; Saraswati Sukumar (105-110).
Long term treatment with therapies aimed at blocking the estrogen- (ER) or androgen receptor (AR) action often leads to the development of resistance to selective modulators of the estrogen receptor (SERMs) in ERα-positive breast cancer, or of the androgen receptor (SARMs) in AR-positive prostate cancer. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. Receptor tyrosine kinases (RTKs) such EGFR, ERBB2 and IGF1R are major mediators that can directly alter cellular response to the SERM, tamoxifen, but the mechanisms underlying increased expression of RTKs are not clear. A number of HOX genes and microRNAs and non-coding RNAs residing in the HOX cluster, have been identified as important independent predictors of endocrine resistant breast cancer. Recently, convincing evidence has accumulated that several members belonging to the four different HOX clusters contribute to endocrine therapy resistant breast cancer, but the mechanisms remain obscure. In this article, we have reviewed recent progress in understanding of the functioning of HOX genes and regulation of their expression by hormones. We also discuss, in particular, the contributions of several members of the HOX gene family to endocrine resistant breast cancer.
Keywords: HOX gene; Endocrine resistance; Non-coding RNA; Breast cancer;
New insights into perineural invasion of pancreatic cancer: More than pain by Dingkong Liang; Si Shi; Jin Xu; Bo Zhang; Yi Qin; Shunrong Ji; Wenyan Xu; Jiang Liu; Liang Liu; Chen Liu; Jiang Long; Quanxing Ni; Xianjun Yu (111-122).
Pancreatic cancer is one of the most malignant human tumors. Perineural invasion, whereby a cancer cell invades the perineural spaces surrounding nerves, is acknowledged as a gradual contributor to cancer aggressiveness. Furthermore, perineural invasion is considered one of the root causes of the recurrence and metastasis observed after pancreatic resection, and it is also an independent predictor of prognosis. Advanced research has demonstrated that the neural microenvironment is closely associated with perineural invasion in pancreatic cancer. Therapy targeting the molecular mechanism of perineural invasion may enable the durable clinical treatment of this formidable disease. This review provides an overview of the present status of perineural invasion, the relevant molecular mechanisms of perineural invasion, pain and hyperglycemia associated with perineural invasion in pancreatic cancer, and the targeted therapeutics based on these studies.Display Omitted
Keywords: Pancreatic cancer; Perineural invasion; Prognostic factor; Cancer microenvironment;
Pancreatic cancer: Current research and future directions by Marco Falasca; Minkyoung Kim; Ilaria Casari (123-132).
Despite the survival rate advancements in different types of cancer in the last 40 years, the perspective for pancreatic cancer patients has seen no substantial changes. Indeed, the five year survival rate remains around 5%. Nevertheless, in the last decade we have witnessed an increased interest in pancreatic cancer biology and this has produced a substantial increment in our knowledge on pancreatic cancer progression. The big challenge is now to translate this knowledge in better outcomes for patients. The aim of this review is to describe the latest discoveries and advancements in pancreatic cancer research and to discuss future directions.
Keywords: Pancreatic cancer; Cancer metabolism; Tumour stroma; MicroRNA; Exosomes;
Regulation of connexins by the ubiquitin system: Implications for intercellular communication and cancer by Edward Leithe (133-146).
The connexins constitute a family of integral membrane proteins that form intercellular channels, enabling adjacent cells to directly exchange ions and small molecules. The connexin channels assemble into distinct plasma membrane domains known as gap junctions. Intercellular communication via gap junctions has an important role in regulating cell growth and differentiation, as well as in maintaining tissue homeostasis. Connexin43 (Cx43), the most ubiquitously expressed connexin isoform in human tissues, has been shown to act as a tumor suppressor and is frequently downregulated during cancer development. Cx43 has a short half-life, and modulation of the Cx43 turnover rate represents an important mechanism by which the level of gap junctional intercellular communication is regulated under basal conditions. Moreover, many growth factors, oncogenes, and tumor promoters are potent inducers of Cx43 endocytosis and endolysosomal degradation, resulting in loss of gap junctions. Emerging evidence indicates that the ubiquitin system has a major role in these processes. Recent studies have shown that ubiquitination is also involved in the autophagy-mediated degradation of Cx43 in a process mediated by the proto-oncogenic E3 ubiquitin ligase NEDD4. Moreover, ubiquitination of connexins has been implicated in modulating the level of intercellular communication via gap junctions in response to oxidative stress. This review article provides an overview of our current understanding of the role of the ubiquitin system in the regulation of connexins and discusses how the malfunction of these processes may contribute to the loss of intercellular communication via gap junctions during carcinogenesis.
Keywords: Connexin; Ubiquitin; Gap junction; Intercellular communication; Cancer;
Do cell-autonomous and non-cell-autonomous effects drive the structure of tumor ecosystems? by Tazzio Tissot; Beata Ujvari; Eric Solary; Patrice Lassus; Benjamin Roche; Frédéric Thomas (147-154).
By definition, a driver mutation confers a growth advantage to the cancer cell in which it occurs, while a passenger mutation does not: the former is usually considered as the engine of cancer progression, while the latter is not. Actually, the effects of a given mutation depend on the genetic background of the cell in which it appears, thus can differ in the subclones that form a tumor. In addition to cell-autonomous effects generated by the mutations, non-cell-autonomous effects shape the phenotype of a cancer cell. Here, we review the evidence that a network of biological interactions between subclones drives cancer cell adaptation and amplifies intra-tumor heterogeneity. Integrating the role of mutations in tumor ecosystems generates innovative strategies targeting the tumor ecosystem's weaknesses to improve cancer treatment.
Keywords: Evolution; Ecology; Non-cell-autonomous effects; Mutations; Cancer;
Cellular senescence and tumor promotion: Is aging the key? by Natalia Loaiza; Marco Demaria (155-167).
The senescence response is a potent tumor suppressor mechanism characterized by an irreversible growth arrest in response to potentially oncogenic signals to prevent the proliferation of damaged cells. Late in life, some of the features of senescent cells seem to mediate the development of age-related pathologies, including cancer. In the present review, we present a summary of the current knowledge regarding the causes, effector pathways and cellular features of senescence. We also discuss how the senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. We argue that three age-related phenomena—senescence-associated secretory phenotype (SASP) dysregulation, decline in the immune system function and genomic instability—could contribute, independently or synergistically, to deteriorate the efficacy of the senescence response in stopping cancer. As a consequence, senescent cells could be considered premalignant cells, and targeting senescent cells could be a preventive and therapeutic strategy against cancer.
Keywords: Aging; Cancer; Cellular senescence; Premalignant; Pseudo-senescence; SASP;
The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation by Fernando Mendes; Cátia Domingues; Paulo Rodrigues-Santos; Ana Margarida Abrantes; Ana Cristina Gonçalves; Jéssica Estrela; João Encarnação; Ana Salomé Pires; Mafalda Laranjo; Vera Alves; Ricardo Teixo; Ana Bela Sarmento; Maria Filomena Botelho; Manuel Santos Rosa (168-175).
Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients.
Keywords: Cancer; Immune system; Regulator T cells; Innate; Acquire; Natural Killer cells;
Melatonin and the von Hippel–Lindau/HIF-1 oxygen sensing mechanism: A review by Jerry Vriend; Russel J. Reiter (176-183).
There are numerous reports that melatonin inhibits the hypoxia-inducible factor, HIF-1α, and the HIF-1α-inducible gene, VEGF, both in vivo and in vitro. Through the inhibition of the HIF-1-VEGF pathway, melatonin reduces hypoxia-induced angiogenesis. Herein we discuss the interaction of melatonin with HIF-1α and HIF-1α-inducible genes in terms of what is currently known concerning the HIF-1α hypoxia response element (HIF-1α-HRE) pathway.The von Hippel–Lindau protein (VHL), also known as the VHL tumor suppressor, functions as part of a ubiquitin ligase complex which recognizes HIF-1α as a substrate. As such, VHL is part of the oxygen sensing mechanism of the cell. Under conditions of hypoxia, HIF-1α stimulates the transcription of numerous HIF-1α-induced genes, including EPO, VEGF, and PFKFB3; the latter is an enzyme which regulates glycolysis. Data from several studies show that ROS generated in mitochondria under conditions of hypoxia stimulate HIF-1α. Since melatonin acts as an antioxidant and reduces ROS, these data suggest that the antioxidant action of melatonin could account for reduced HIF-1, less VEGF, and reduced glycolysis in cancer cells (Warburg effect). A direct or indirect inhibitory action (via the reduction in ROS) of melatonin on proteasome activity would account for much of the published data.Display Omitted
Keywords: Melatonin; Proteasome; Hypoxia; von Hippel–Lindau tumor suppressor; Hypoxia response element; Ubiquitin ligase; Warburg effect;
Mitochondrial dysfunction in DDR-related cancer predisposition syndromes by Alex Lyakhovich; Dmitry Graifer; Barbora Stefanovie; Lumir Krejci (184-189).
Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy.
Keywords: Mitochondrial dysfunction; DNA damage and repair; Cancer predisposition syndromes; Oxidative stress; ROS; Autophagy; Mitophagy;
PLK-1: Angel or devil for cell cycle progression by Shiv Kumar; Ashish Ranjan Sharma; Garima Sharma; Chiranjib Chakraborty; Jaebong Kim (190-203).
PLK-1 is a key player in the eukaryotic cell cycle. Cell cycle progression is precisely controlled by cell cycle regulatory kinases. PLK-1 is a mitotic kinase that actively regulates the G2/M transition, mitosis, mitotic exit, and cytokinesis. During cell cycle progression, PLK-1 controls various events related to the cell cycle maturation, directly and/or indirectly. On the contrary, aberrant expression of PLK-1 is strongly associated with tumorigenesis and its poor prognosis. The misexpression of PLK-1 causes the abnormalities including aneuploidy, mitotic defects, leading to tumorigenesis through inhibiting the p53 and pRB genes. Therefore, we reviewed the role of PLK-1 in the cell cycle progression and in the tumorigenesis either as a cell cycle regulator or on an attractive anti-cancer drug target.
Keywords: Cell cycle progression; Mitotic kinase; Mitosis; Polo-like kinase-1; Tumorigenesis;
Context-dependent roles for lymphotoxin-β receptor signaling in cancer development by Mónica T. Fernandes; Emmanuel Dejardin; Nuno R. dos Santos (204-219).
The LTα1β2 and LIGHT TNF superfamily cytokines exert pleiotropic physiological functions through the activation of their cognate lymphotoxin-β receptor (LTβR). Interestingly, since the discovery of these proteins, accumulating evidence has pinpointed a role for LTβR signaling in carcinogenesis. Early studies have shown a potential anti-tumoral role in a subset of solid cancers either by triggering apoptosis in malignant cells or by eliciting an anti-tumor immune response. However, more recent studies provided robust evidence that LTβR signaling is also involved in diverse cell-intrinsic and microenvironment-dependent pro-oncogenic mechanisms, affecting several solid and hematological malignancies. Consequently, the usefulness of LTβR signaling axis blockade has been investigated as a potential therapeutic approach for cancer. Considering the seemingly opposite roles of LTβR signaling in diverse cancer types and their key implications for therapy, we here extensively review the different mechanisms by which LTβR activation affects carcinogenesis, focusing on the diverse contexts and different models assessed.
Keywords: Lymphotoxin-β receptor; Cell signaling; Lymphotoxin; LIGHT; Oncogenesis; Tumor microenvironment;
Long story short: p53 mediates innate immunity by Jessica Miciak; Fred Bunz (220-227).
The story of p53 and how we came to understand it is punctuated by fundamental insights into the essence of cancer. In the decades since its discovery, p53 has been shown to be centrally involved in most, if not all, of the cellular processes that maintain tissue homeostasis. Extensive functional analyses of p53 and its tumor-associated mutants have illuminated many of the common defects shared by most cancer cells. As the central character in a tale that continues to unfold, p53 has become increasingly familiar and yet remains surprisingly inscrutable. New relationships periodically come to light, and surprising, novel activities continue to emerge, thereby revealing new dimensions and aspects of its function. What lies at the very core of this complex protagonist? What is its prime motivation? As every avid reader knows, the elements of character are profoundly shaped by adversity — originating from within and without. And so it is with p53. This review will briefly recap the coordinated responses of p53 to viral infection, and outline a hypothetical model that would explain how an abundance of seemingly unrelated phenotypic attributes may in the end reflect a singular function. All stories eventually draw to a conclusion. This epic tale may eventually leave us with the realization that p53, most simply described, is a protein that evolved to mediate immune surveillance.
Keywords: P53; Adenovirus; DNA damage; Interferon;
Necroptosis: an alternative cell death program defending against cancer by Dongshi Chen; Jian Yu; Lin Zhang (228-236).
One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL) protein. Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells.
Keywords: Necroptosis; Cancer; RIP1; RIP3; MLKL;
Histone demethylase JMJD3 at the intersection of cellular senescence and cancer by Patrick M. Perrigue; Joseph Najbauer; Jan Barciszewski (237-244).
Cellular senescence is defined by an irreversible growth arrest and is an important biological mechanism for suppression of tumor formation. Although deletion/mutation to DNA sequences is one mechanism by which cancer cells can escape senescence, little is known about the epigenetic factors contributing to this process. Histone modifications and chromatin remodeling related to the function of a histone demethylase, jumonji domain-containing protein 3 (JMJD3; also known as KDM6B), play an important role in development, tissue regeneration, stem cells, inflammation, and cellular senescence and aging. The role of JMJD3 in cancer is poorly understood and its function may be at the intersection of many pathways promoted in a dysfunctional manner such as activation of the senescence-associated secretory phenotype (SASP) observed in aging.
Keywords: Cancer; Senescence; Inflammation; Aging; Jumonji; JMJD3; SASP; H3K27;
The inflammatory inception of gallbladder cancer by Jaime A. Espinoza; Carolina Bizama; Patricia García; Catterina Ferreccio; Milind Javle; Juan F. Miquel; Jill Koshiol; Juan C. Roa (245-254).
Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia–dysplasia–carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.Display Omitted
Keywords: Gallbladder cancer; Gallstones; Chronic inflammation; Metaplasia; Salmonella Typhi; TP53;
Cytokines in cancer drug resistance: Cues to new therapeutic strategies by Valerie Sloane Jones; Ren-Yu Huang; Li-Pai Chen; Zhe-Sheng Chen; Liwu Fu; Ruo-Pan Huang (255-265).
The development of oncoprotein-targeted anticancer drugs is an invaluable weapon in the war against cancer. However, cancers do not give up without a fight. They may develop multiple mechanisms of drug resistance, including apoptosis inhibition, drug expulsion, and increased proliferation that reduce the effectiveness of the drug. The collective work of researchers has highlighted the role of cytokines in the mechanisms of cancer drug resistance, as well as in cancer cell progression. Furthermore, recent studies have described how specific cytokines secreted by cancer stromal cells confer resistance to chemotherapeutic treatments. In order to gain a better understanding of mechanism of cancer drug resistance and a prediction of treatment outcome, it is imperative that correlations are established between global cytokine profiles and cancer drug resistance. Here we discuss the recent discoveries in this field of research and discuss their implications for the future development of effective anti-cancer medicines.
Keywords: Cytokine; Cancer drug resistance; Stromal cells; Tumor microenvironment; Antibody array; Multiplex immunoassay;
Use of cell free DNA in breast oncology by Jenna VanLiere Canzoniero; Ben Ho Park (266-274).
Cell free DNA (cfDNA) are short fragments of nucleic acids present in circulation outside of cells. In patients with cancer, some portion of cfDNA is derived from tumor cells, termed circulating tumor DNA (ctDNA), and contains the same mutations and genetic changes as the cancer. The development of new, more effective methods to detect these changes has led to increased interest in developing ctDNA as a biomarker for cancer. Here we will review current literature on the use of ctDNA, with an emphasis on breast cancer, for cancer detection, prognosis, monitoring response to therapy, and tracking the rise of new mutant subclones.Display Omitted
Keywords: Breast cancer; Cell free DNA; Circulating tumor DNA; Mutation;
Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential by Anna Kazanets; Tatiana Shorstova; Khalid Hilmi; Maud Marques; Michael Witcher (275-288).
Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes.
Keywords: Epigenetics; Transcriptional silencing; DNA methylation; CTCF; Histone methylation; Therapeutics;