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BBA - Reviews on Cancer (v.1825, #2)
The NF-Y/p53 liaison: Well beyond repression by Carol Imbriano; Nerina Gnesutta; Roberto Mantovani (pp. 131-139).
NF-Y is a sequence-specific transcription factor – TF – targeting the common CCAAT promoter element. p53 is a master TF controlling the response to stress signals endangering genome integrity, often mutated in human cancers. The NF-Y/p53 – and p63, p73 – interaction results in transcriptional repression of a subset of genes within the vast NF-Y regulome under DNA-damage conditions. Recent data shows that NF-Y is also involved in pro-apoptotic activities, either directly, by mediating p53 transcriptional activation, or indirectly, by being targeted by a non coding RNA, PANDA. The picture is subverted in cells carrying Gain-of-function mutant p53, through interactions with TopBP1, a protein also involved in DNA repair and replication. In summary, the connection between p53 and NF-Y is crucial in determining cell survival or death.
Keywords: NF-Y; p53; Repression; Apoptosis
Progress of molecular targeted therapies for prostate cancers by Weihua Fu; Elena Madan; Marla Yee; Hongtao Zhang (pp. 140-152).
Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.
Keywords: Prostate cancer; EGFR; IGF-1R; VEGFR; Androgen; Hormone resistant
The landscape of mitochondrial DNA variation in human colorectal cancer on the background of phylogenetic knowledge by Katarzyna Skonieczna; Boris A. Malyarchuk; Tomasz Grzybowski (pp. 153-159).
Recently, an increasing number of studies indicate that mutations in mitochondrial genome may contribute to cancer development or metastasis. Hence, it is important to determine whether the mitochondrial DNA might be a good, clinically applicable marker of cancer. This review describes hereditary as well as somatic mutations reported in mitochondrial DNA of colorectal cancer cells. We showed here that the entire mitochondrial genome mutational spectra are different in colorectal cancer and non-tumor cells. We also placed the described mutations on the phylogenetic context, which highlighted the recurrent problem of data quality. Therefore, the most important rules for adequately assessing the quality of mitochondrial DNA sequence analysis in cancer have been summarized. As follows from this review, neither the reliable spectrum of mtDNA somatic mutations nor the association between hereditary mutations and colorectal cancer risk have been resolved. This indicates that only high resolution studies on mtDNA variability, followed by a proper data interpretation employing phylogenetic knowledge may finally verify the utility of mtDNA sequence (if any) in clinical practice.
Keywords: Colorectal cancer; Mitochondrial DNA haplogroup; Mitochondrial DNA hereditary mutations; Human mitochondrial phylogeny; Mitochondrial DNA somatic mutations; Mitochondrial D310 mutations
The immunological contribution of NF-κB within the tumor microenvironment: A potential protective role of zinc as an anti-tumor agent by Bin Bao; Archana Thakur; Yiwei Li; Aamir Ahmad; Asfar S. Azmi; Sanjeev Banerjee; Dejuan Kong; Shadan Ali; Lawrence G. Lum; Fazlul H. Sarkar (pp. 160-172).
Over decades, cancer treatment has been mainly focused on targeting cancer cells and not much attention to host tumor microenvironment. Recent advances suggest that the tumor microenvironment requires in-depth investigation for understanding the interactions between tumor cell biology and immunobiology in order to optimize therapeutic approaches. Tumor microenvironment consists of cancer cells and tumor associated reactive fibroblasts, infiltrating non-cancer cells, secreted soluble factors or molecules, and non-cellular support materials. Tumor associated host immune cells such as Th1, Th2, Th17, regulatory cells, dendritic cells, macrophages, and myeloid-derived suppressor cells are major components of the tumor microenvironment. Accumulating evidence suggests that these tumor associated immune cells may play important roles in cancer development and progression. However, the exact functions of these cells in the tumor microenvironment are poorly understood. In the tumor microenvironment, NF-κB plays an important role in cancer development and progression because this is a major transcription factor which regulates immune functions within the tumor microenvironment. In this review, we will focus our discussion on the immunological contribution of NF-κB in tumor associated host immune cells within the tumor microenvironment. We will also discuss the potential protective role of zinc, a well-known immune response mediator, in the regulation of these immune cells and cancer cells in the tumor microenvironment especially because zinc could be useful for conditioning the tumor microenvironment toward innovative cancer therapy.
Keywords: Tumor microenvironment; T helper cells; Tregs; MDSCs; DCs; TAMs
TET2, a tumor suppressor in hematological disorders by Thomas Mercher; Cyril Quivoron; Couronne Lucile Couronné; Christian Bastard; William Vainchenker; Olivier A. Bernard (pp. 173-177).
The TET family of proteins has been described a few years ago. Only recently, their roles in DNA modification, through the oxidation of methyl-cytosine, and in normal and malignant development, through the description of TET2 as a tumor suppressor have been documented. The conjunction of these findings has prompted large efforts to understand the biology of these novel entities. Here, we summarize the recent results implicating TET2 in hematological malignancies suggesting that further studies are required to fully understand the role of DNA methylation alterations during transformation.
Keywords: Hematology; Oncology; Tumor suppressor; Mouse models; Epigenetics
Lost in disruption: Role of proteases in glioma invasion and progression by Rolf Mentlein; Kirsten Hattermann; Janka Held-Feindt (pp. 178-185).
A characteristic feature of malignant glial tumors (gliomas) is their tendency to diffusely infiltrate the nervous system preventing their complete surgical resection. Proteases play a decisive role in this malignant process, either by degradation of brain extracellular matrix (ECM) components, adhesion molecules, or by regulating the activity of growth and chemotactic factors. Secreted matrix metalloproteinases (MMPs) and ADAMTS proteases (ADAMs withthrombospondin motifs) cleave different ECM components like the proteoglycans (lecticans) aggrecan, versican, neurocan and brevican with selective preferences; they are further regulated by endogenous inhibitors and activating metallo- and serine proteases. Cell surface proteases of the ADAM family (A Disintegrin And Metalloproteinase), but also serine proteases regulate the activity of growth factors and chemokines that act as autocrine / paracrine stimulators within gliomas. Thus, proteases play a decisive role for the spread and growth of gliomas and are prominent targets for their therapy.
Keywords: Abbreviations; ADAM; a disintegrin and metalloproteinase; ADAMTS; ADAMs with thrombospondin motifs; bFGF; basic fibroblast growth factor; ECM; extracellular matrix; EGF; epidermal growth factor; FAP; fibroblast activation protein; GAG; glycosaminoglycan; GFAP; glial fibrillary acidic protein; GIM; glioma-infiltrating microglia cell/macrophage; HA; hyaluronic acid; MMP; matrix metalloproteinase; IL; interleukin; MT-MMP; membrane-type MMP; PAI; plasminogen activator inhibitor; uPA; urokinase-type plasminogen activator; tPA; tissue-type plasminogen activator; TGF; transforming growth factor; TIMP; tissue inhibitor of MMP; TNF; tumor necrosis factor; WHO; World Health OrganizationAstrocytoma; Invasion; Protease; Extracellular matrix; Growth factors; Chemokines
Interrogating genomic and epigenomic data to understand prostate cancer by Jung Kim; Jindan Yu (pp. 186-196).
Major breakthroughs at the beginning of this century in high-throughput technologies have profoundly transformed biological research. Significant knowledge has been gained regarding our biological system and its disease such as malignant transformation. In this review, we summarize leading discoveries in prostate cancer research derived from the use of high-throughput approaches powered by microarrays and massively parallel next-generation sequencing (NGS). These include the seminal discovery of chromosomal translocations such as TMPRSS2-ERG gene fusions as well as the identification of critical oncogenes exemplified by the polycomb group protein EZH2. We then demonstrate the power of interrogating genomic and epigenomic data in understanding the plethora of mechanisms of transcriptional regulation. As an example, we review how androgen receptor (AR) binding events are mediated at multiple levels through protein–DNA interaction, histone and DNA modifications, as well as high-order chromatin structural changes.
Keywords: Integrative genomics; FoxA1; EZH2; Androgen receptor; Nucleosome positioning; Transcriptional regulation; Gene fusion
Taxane resistance in breast cancer: A closed HER2 circuit? by Joep P.J. de Hoon; Jürgen Veeck; Birgit E.P.J. Vriens; Tim G.A. Calon; Manon van Engeland; Vivianne C.G. Tjan-Heijnen (pp. 197-206).
Microtubule inhibitors, such as the taxanes docetaxel and paclitaxel, are commonly used drugs for the treatment of breast cancer. Although highly active in a large fraction of individuals a considerable number of patients show poor response due to either intrinsic or acquired drug resistance. Extensive research in the past identified several taxane resistance-related mechanisms being activated by pathologically altered single gene function. To date, however, a clinically relevant predictive biomarker for taxanes has not been derived yet from this knowledge, most likely due to the manifold of resistance mechanisms that may combine in one tumor, thereby fostering escape from taxane cytotoxicity.Here, we aimed to comprehensively review the current literature on taxane resistance mechanisms in breast cancer. Interestingly, besides altered microtubule physiology we identified the HER2 signaling cascade as a major dominator influencing several routes of cytotoxicity escape, such as cell survival, apoptosis, drug efflux, and drug metabolism. Furthermore, the transcription factor YBX-1, activated by HER2, facilitates a sustaining HER2 signaling feedback loop contributing to the establishment of cellular survival detours.In conclusion, taxane resistance in breast cancer follows a multiplex establishment of drug cytotoxicity escape routes, which may be most efficiently therapeutically targeted by interference with their mutually governing signaling nodes.
Keywords: Abbreviations; 4EBP1; factor 4E binding protein 1; ABCB1; ATP-binding cassette, sub-family B (MDR/TAP), member 1; ABCC3; ATP-binding cassette, sub-family C, member 3; aCGH; array comparative genomic hybridization; ASK1; apoptosis regulating signal kinase 1; BCL2; B-cell lymphoma 2; BCL2L1; B-cell lymphoma 2-like 1; CYP3A4; cytochrome P450 3A4; EGFR; epidermal growth factor receptor; ER; estrogen receptor; ERK1/2; extracellular signal-regulated kinase 1/2; GSTP1; glutathione S-transferase P1; GST; glutathione S-transferase; HER2; human epidermal growth factor receptor 2; ITGA6; integrin alpha 6; JNK; c-Jun N-terminal kinase; MAPK; mitogen-activated protein kinase; MAPT; microtubule associated protein τ; MBC; metastatic breast cancer; MRP3; multi resistance-associated protein 3; OR; odds ratio; OS; overall survival; pCR; pathologic complete response; P-gp; P-glycoprotein; pHER2; phosphorylated human epidermal growth factor receptor 2; PI3K/Akt; phosphoinositide-3-kinase/protein kinase B; RAF1; RAF proto-oncogene serine/threonine-protein kinase; src; sarcoma tyrosine kinase; STAT3; signal transducer and activator of transcription 3; YBX1; Y-box binding protein 1Breast cancer; Docetaxel; Drug resistance; HER2 signaling; Paclitaxel; Taxanes
Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells by Shanchun Guo; Mingli Liu; Guangdi Wang; Marta Torroella-Kouri; Ruben R. Gonzalez-Perez (pp. 207-222).
Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e., canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts.
Keywords: Leptin; Breast cancer; Tumor angiogenesis; Breast cancer stem cells; Leptin antagonist; Leptin signaling
Cooperation, amplification, and feed-back in epithelial–mesenchymal transition by Antonio García de Herreros; Josep Baulida (pp. 223-228).
The epithelial to mesenchymal transition (EMT) consists of a rapid change of cell phenotype, characterized by the loss of epithelial traits and the acquisition of a more motile phenotype reminiscent of a fibroblast. The study of this process has received considerable attention because of its potential role in the acquisition of several cancer traits, particularly in cell invasion. In this article we describe the current knowledge of the molecular mechanisms governing this transition. In particular we discuss how initiation of EMT is dependent on the mutually exclusive levels of the transmembrane cell to cell adhesion molecule E-cadherin and its transcriptional repressor Snail1 and how Snail1 and other E-cadherin transcriptional repressors drive the EMT process. We focus on several new aspects of Snail1 regulation and propose a model for understanding the initiation and progression of this transition, based on the existence of feed-back mechanisms that limit or amplify the response to extracellular cues.
Keywords: EMT; Snail1; E-cadherin
The p53 circuit board by Kelly D. Sullivan; Corrie L. Gallant-Behm; Ryan E. Henry; Jean-Luc Fraikin; Joaquín M. Espinosa (pp. 229-244).
The p53 tumor suppressor is embedded in a large gene network controlling diverse cellular and organismal phenotypes. Multiple signaling pathways converge onto p53 activation, mostly by relieving the inhibitory effects of its repressors, MDM2 and MDM4. In turn, signals originating from increased p53 activity diverge into distinct effector pathways to deliver a specific cellular response to the activating stimuli. Much attention has been devoted to dissecting how the various input pathways trigger p53 activation and how the activity of the p53 protein itself can be modulated by a plethora of co-factors and post-translational modifications. In this review we will focus instead on the multiple configurations of the effector pathways. We will discuss how p53-generated signals are transmitted, amplified, resisted and eventually integrated by downstream gene circuits operating at the transcriptional, post-transcriptional and post-translational levels. We will also discuss how context-dependent variations in these gene circuits define the cellular response to p53 activation and how they may impact the clinical efficacy of p53-based targeted therapies.
Keywords: Gene network; PUMA; p21; Apoptosis; Cell cycle arrest; Personalized medicine