Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 142Author(s): Leilei Zhang, Jie Zhang, Zhiwei Ye, Danyelle M. Townsend, Kenneth D. Tew Isoflavones isolated from members of the Fabaceae (primarily Leguminosae) family have been characterized for their phytoestrogenic properties, but certain derivatives have also shown potential as possible cancer therapeutic agents. ME-344, related to phenoxodiol (Fig. 1), is a second generation isoflavone with a recent history of both preclinical and early clinical testing. The drug has unusual cytotoxicity profiles, where cancer cell lines can be categorized as either intrinsically sensitive or resistant to the drug. Evolving studies show that the cytotoxic properties of the drug are enacted through targeting mitochondrial bioenergetics. While the drug has undergone early Phase I/II trials in solid tumors with confined dose limiting effects and some evidence of disease response, there is a continuing need to define specific cellular targets that determine sensitivity, with the long-term goal of applying such information to individualized therapy. This review article details some of the existing and ongoing studies that are assisting in the continued drug development processes that may lead to new drug application (NDA) status.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 142Author(s): John R. Šedý, Parham Ramezani-Rad Somatic mutations in cancer cells may influence tumor growth, survival, or immune interactions in their microenvironment. The tumor necrosis factor receptor family member HVEM (TNFRSF14) is frequently mutated in cancers and has been attributed a tumor suppressive role in some cancer contexts. HVEM functions both as a ligand for the lymphocyte checkpoint proteins BTLA and CD160, and as a receptor that activates NF-κB signaling pathways in response to BTLA and CD160 and the TNF ligands LIGHT and LTα. BTLA functions to inhibit lymphocyte activation, but has also been ascribed a role in stimulating cell survival. CD160 functions to co-stimulate lymphocyte function, but has also been shown to activate inhibitory signaling in CD4+ T cells. Thus, the role of HVEM within diverse cancers and in regulating the immune responses to these tumors is likely context specific. Additionally, development of therapeutics that target proteins within this network of interacting proteins will require a deeper understanding of how these proteins function in a cancer-specific manner. However, the prominent role of the HVEM network in anti-cancer immune responses indicates a promising area for drug development.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 142Author(s): Manny D. Bacolod, Francis Barany, Karsten Pilones, Paul B. Fisher, Romulo J. de Castro Recent clinical studies document the power of immunotherapy in treating subsets of patients with advanced cancers. In this context and with multiple cancer immunotherapeutics already evaluated in the clinic and a large number in various stages of clinical trials, it is imperative to comprehensively examine genomics data to better comprehend the role of immunity in different cancers in predicting response to therapy and in directing appropriate therapies. The approach we chose is to scrutinize the pathways and epigenetic factors predicted to drive immune infiltration in different cancer types using publicly available TCGA transcriptional and methylation datasets, along with accompanying clinico-pathological data. We observed that the relative activation of T cells and other immune signaling pathways differs across cancer types. For example, pathways related to activation and proliferation of helper and cytotoxic T cells appear to be more highly enriched in kidney, skin, head and neck, and esophageal cancers compared to those of lung, colorectal, and liver or bile duct cancers. The activation of these immune-related pathways positively associated with prognosis in certain cancer types, most notably melanoma, head and neck, and cervical cancers. Integrated methylation and expression data (along with publicly available, ENCODE-generated histone ChIP Seq and DNAse hypersensitivity data) predict that epigenetic regulation is a primary factor driving transcriptional activation of a number of genes crucial to immunity in cancer, including T cell receptor genes (e.g., CD3D, CD3E), CTLA4, and GZMA. However, the extent to which epigenetic factors (primarily methylation at promoter regions) affect transcription of immune-related genes may vary across cancer types. For example, there is a high negative correlation between promoter CpG methylation and CD3D expression in renal and thyroid cancers, but not in brain tumors. The types of analyses we have undertaken provide insights into the relationships between immune modulation and cancer etiology and progression, offering clues into ways of therapeutically manipulating the immune system to promote immune recognition and immunotherapy.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 142Author(s): Adam D. Scheid, Thomas C. Beadnell, Danny R. Welch The role of genetics in cancer has been recognized for centuries, but most studies elucidating genetic contributions to cancer have understandably focused on the nuclear genome. Mitochondrial contributions to cancer pathogenesis have been documented for decades, but how mitochondrial DNA (mtDNA) influences cancer progression and metastasis remains poorly understood. This lack of understanding stems from difficulty isolating the nuclear and mitochondrial genomes as experimental variables, which is critical for investigating direct mtDNA contributions to disease given extensive crosstalk exists between both genomes. Several in vitro and in vivo models have isolated mtDNA as an independent variable from the nuclear genome. This review compares and contrasts different models, their advantages and disadvantages for studying mtDNA contributions to cancer, focusing on the mitochondrial-nuclear exchange (MNX) mouse model and findings regarding tumor progression, metastasis, and other complex cancer-related phenotypes.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 142Author(s): Ryan M. Phillips, Christine Lam, Hailun Wang, Phuoc T. Tran Altered metabolism is one of the hallmarks of cancer. The best-known cancer metabolic anomaly is an increase in aerobic glycolysis, which generates ATP and other basic building blocks, such as nucleotides, lipids, and proteins to support tumor cell growth and survival. Epithelial plasticity (EP) programs such as the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are evolutionarily conserved processes that are essential for embryonic development. EP also plays an important role during tumor progression toward metastasis and treatment resistance, and new roles in the acceleration of tumorigenesis have been found. Recent evidence has linked EMT-related transcriptomic alterations with metabolic reprogramming in cancer cells, which include increased aerobic glycolysis. More recent studies have revealed a novel connection between EMT and altered glycosylation in tumor cells, in which EMT drives an increase in glucose uptake and flux into the hexosamine biosynthetic pathway (HBP). The HBP is a side-branch pathway from glycolysis which generates the end product uridine-5′-diphosphate-N-acetylglucosamine (UDP-GlcNAc). A key downstream utilization of UDP-GlcNAc is for the post-translational modification O-GlcNAcylation which involves the attachment of the GlcNAc moiety to Ser/Thr/Asn residues of proteins. Global changes in protein O-GlcNAcylation are emerging as a general characteristic of cancer cells. In our recent study, we demonstrated that the EMT-HBP-O-GlcNAcylation axis drives the O-GlcNAcylation of key proteins such as c-Myc, which previous studies have shown to suppress oncogene-induced senescence (OIS) and contribute to accelerated tumorigenesis. Here, we review the HBP and O-GlcNAcylation and their putative roles in driving EMT-related cancer processes with examples to illuminate potential new therapeutic targets for cancer.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 142Author(s): Jayashri Ghosh, Bryant Schultz, Christos Coutifaris, Carmen Sapienza The “CpG Island Methylator Phenotype” (CIMP) has been found to be a useful concept in stratifying several types of human cancer into molecularly and clinically distinguishable subgroups. We have identified an additional epigenetic stratification category, the “Outlier Methylation Phenotype” (OMP). Whereas CIMP is defined on the basis of hyper-methylation in tumor genomes, OMP is defined on the basis of highly variant (either or both hyper- and hypo-methylation) methylation at many sites in normal tissues. OMP was identified and defined, originally, as being more common among low birth weight individuals conceived in vitro but we have also identified OMP individuals among colon cancer patients profiled by us, as well as multiple types of cancer patients in the TCGA database. The cause(s) of OMP are unknown, as is whether these individuals identify a clinically useful subgroup of patients, but both the causes of, and potential consequences to, this epigenetically distinct group are of great interest.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 141Author(s): Aksinija A. Kogan, Rena G. Lapidus, Maria R. Baer, Feyruz V. Rassool Acute myeloid leukemia (AML) derives from the clonal expansion of immature myeloid cells in the bone marrow, and results in the disruption of normal hematopoiesis and subsequent bone marrow failure. The bone marrow microenvironment (BME) and its immune and other supporting cells are regarded to facilitate the survival, differentiation and proliferation of leukemia stem cells (LSCs), which enables AML cells to persist and expand despite treatment. Recent studies have identified epigenetic modifications among AML cells and BME constituents in AML, and have shown that epigenetic therapy can potentially reprogram these alterations. In this review, we summarize the interactions between the BME and LSCs, and discuss changes in how the BME and immune cells interact with AML cells. After describing the epigenetic modifications seen across chromatin, DNA, the BME, and the immune microenvironment, we explore how demethylating agents may reprogram these pathological interactions, and potentially re-sensitize AML cells to treatment.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 141Author(s): Lisha Xiang, Gregg L. Semenza Clinical studies have revealed that breast cancers contain regions of intratumoral hypoxia (reduced oxygen availability), which activates hypoxia-inducible factors (HIFs). The relationship between intratumoral hypoxia, distant metastasis and cancer mortality has been well established. A major mechanism by which intratumoral hypoxia contributes to disease progression is through induction of the breast cancer stem cell (BCSC) phenotype. BCSCs are a small subpopulation of cells with the capability for self-renewal. BCSCs have been implicated in resistance to chemotherapy, disease recurrence, and metastasis. In this review, we will discuss our current understanding of the molecular mechanisms underlying HIF-dependent induction of the BCSC phenotype in response to hypoxia or chemotherapy.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 141Author(s): Syed Mohammed Musheer Aalam, Philip Anthony Beer, Nagarajan Kannan The discovery of rare, heterogeneous self-renewing stem cells with shared developmental and molecular features within epithelial components of mammary gland and breast cancers has provided a conceptual framework to understand cellular composition of these tissues and mechanisms that control their number. These normal mammary epithelial stem cells (MaSCs) and breast cancer stem cells (BCSCs) were identified and analyzed using transplant assays (namely mammary repopulating unit (MRU) assay, mammary tumor-initiating cell (TIC) assay), which reveal their latent ability to regenerate respective normal and malignant epithelial tissues with self-renewing units displaying hierarchical cellular differentiation over multiple generations in recipient mice. “Next-generation” methods using “barcoded” normal and malignant mammary cells, with the help of next-generation sequencing (NGS) technology, have revealed hidden complexity and heterogeneous growth potential of MaSCs and BCSCs. Several single markers or combinations of markers have been reported to prospectively enrich MaSCs and BCSCs. Such markers and the extent to which they enrich for MaSCs and BCSCs activity require a critical appraisal. Also, knowledge of the functional assays and their limitations and harmonious reporting of results is a prerequisite to improve our understanding of MaSCs and BCSCs. This chapter describes evolution of the concept of MaSCs and BCSCs, and specific methodologies to investigate them.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 141Author(s): Alexander J. Silver, Siddhartha Jaiswal Clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. This phenomenon has been observed in populations across the globe and, while virtually non-existent in children is estimated to affect> 10% of the 70-and-older age group. The mutations are thought to occur in stem cells, which makes them pre-cancerous, and precursors to cancer stem cells. Many of the genes most commonly mutated in clonal hematopoiesis are also recurrently mutated in leukemia, genes such as DNMT3A, TET2, ASXL1, JAK2, and TP53. However, between 40% and 60% of cases arise from the accumulation of what appear to be random mutations outside of known driver genes. Clonal hematopoiesis is frequently present in otherwise healthy individuals and may persist for many years. Though largely asymptomatic, carrying these somatic mutations confers a small but significantly increased risk of leukemic transformation, affecting 0.5–1% carriers per year; although most genes confer an increased risk of transformation, mutations in TP53 and U2AF1 appear to carry a particularly high risk for transformation. Additionally, a patient's history of prior treatment with cytotoxic chemotherapy and/or radiation are correlated with the development of clonal hematopoiesis; in the setting of chemotherapy treatment of solid tumors, hematopoietic mutations in TP53 and PPM1D appear to contribute to outgrowth of clones that may lead to subsequent malignancy. The presence of a clone also imparts a significantly increased risk of cardiovascular disease, which in some cases appears to be due to increased inflammation and atherosclerosis. Clonal hematopoiesis is correlated with several other diseases as well, including diabetes, chronic pulmonary disease, and aplastic anemia, with other associations probably yet to be uncovered.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 141Author(s): Sarmistha Talukdar, Praveen Bhoopathi, Luni Emdad, Swadesh Das, Devanand Sarkar, Paul B. Fisher Dormancy occurs when cells remain viable but stop proliferating. When most of a cancer population undergoes this phenomenon, the result is called tumor dormancy, and when a single cancer cell undergoes this process, it is termed quiescence. Cancer stem cells (CSCs) share several overlapping characteristics and signaling pathways with dormant cancer cells, including therapy resistance, and an ability to metastasize and evade the immune system. Cancer cells can be broadly grouped into dormancy-competent CSCs (DCCs), cancer-repopulating cells (CRCs), dormancy-incompetent CSCs and disseminated tumor cells (DTCs). The settings in which cancer cells exploit the dormancy phase to survive and adapt are: (i) primary cancer dormancy; (ii) metastatic dormancy; (iii) therapy-induced dormancy; and (iv) immunologic dormancy. Dormancy, therapy resistance and plasticity of CSCs are fundamentally interconnected processes mediated through mechanisms involving reversible genetic alterations. Niches including metastatic, bone marrow, and perivascular are known to harbor dormant cancer cells. Mechanisms of dormancy induction are complex and multi-factorial and can involve angiogenic switching, addictive oncogene inhibition, immunoediting, anoikis, therapy, autophagy, senescence, epigenetic, and biophysical regulation. Therapy can have opposing effects on cancer cells with respect to dormancy; some therapies can induce dormancy, while others can reactivate dormant cells. There is a lack of consensus relative to the value of therapy-induced dormancy, i.e., some researchers view dormancy induction as a beneficial strategy as it can lead to metastasis inhibition, while others argue that reactivating dormant cancer cells and then eliminating them through therapy are a better approach. More focused investigations of intrinsic cell kinetics and environmental dynamics that promote and maintain cancer cells in a dormant state, and the long-term consequences of dormancy are critical for improving current therapeutic treatment outcomes.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 141Author(s): Tami J. Kingsbury, MinJung Kim, Curt I. Civin The PAX-SIX-EYA-DACH network (PSEDN) is a central developmental transcriptional regulatory network from Drosophila to humans. The PSEDN is comprised of four conserved protein families; including paired box (PAX), sine oculis (SIX), eyes absent (EYA), and dachshund (DACH). Aberrant expression of PSEDN members, particularly SIX1, has been observed in multiple human cancers, where SIX1 expression correlates with increased aggressiveness and poor prognosis. In conjunction with its transcriptional activator EYA, the SIX1 transcription factor increases cancer stem cell (CSC) numbers and induces epithelial-mesenchymal transition (EMT). SIX1 promotes multiple hallmarks and enabling characteristics of cancer via regulation of cell proliferation, senescence, apoptosis, genome stability, and energy metabolism. SIX1 also influences the tumor microenvironment, enhancing recruitment of tumor-associated macrophages and stimulating angiogenesis, to promote tumor development and progression. EYA proteins are multifunctional, possessing a transcriptional activation domain and tyrosine phosphatase activity, that each contributes to cancer stem cell properties. DACH proteins function as tumor suppressors in solid cancers, opposing the actions of SIX-EYA and reducing CSC prevalence. Multiple mechanisms can lead to increased SIX1 expression, including loss of SIX1-targeting tumor suppressor microRNAs (miRs), whose expression correlates inversely with SIX1 expression in cancer patient samples. In this review, we discuss the major mechanisms by which SIX1 confers CSC and EMT features and other important cancer cell characteristics. The roles of EYA and DACH in CSCs and cancer progression are briefly highlighted. Finally, we summarize the clinical significance of SIX1 in cancer to emphasize the potential therapeutic benefits of effective strategies to disrupt PSEDN protein interactions and functions.
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