Combining individual and aggregated data to investigate the role of socioeconomic disparities on cancer burden in Italy.

Quantifying socioeconomic disparities and understanding the roots of inequalities are growing topics in cancer research. However, socioeconomic differences are challenging to investigate mainly due to the lack of accurate data at individual-level, while aggregate indicators are only partially informative. We implemented a multiple imputation algorithm within a statistical matching framework that combines diverse sources of data to estimate individual-level associations between income and risk of breast and lung cancer, adjusting for potential confounding factors in Italy. The framework is computationally flexible and can be adapted to similar contexts.

Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Morphogenetic fields of embryonic development in locoregional cancer spread.

The ontogenetic theory of locoregional cancer spread regards cancer as a clinical manifestation of the pathological reactivation and maintenance of the sequential developmental programmes that previously controlled the stepwise embryological morphogenesis of the tissue from which the cancer originated. In the state of morphostasis that characterises adult organisms, these programmes are silenced. During malignant progression, these programmes run in retrograde sequence, which leads to cancer infiltration of ever larger tissue areas. However, because the reactivated morphogenetic programmes need topologically defined tissue domains--morphogenetic fields--to provide positional information for their interpretation, local tumour propagation is confined to permissive compartments (topographically defined tissue domains where malignant cells can survive, migrate, and proliferate), which are determined by the state of malignant progression. The tissue at risk of local tumour spread, the cancer field, is the mature tissue derived from the corresponding morphogenetic field in the embryo, which is labelled with the respective positional information. The theory can be tested morphologically and clinically for all tumours. Verification of this theory would offer substantial potential to improve prognostic assessment and surgical treatment. Identification of the complementary positional information for tumour cells in different ontogenetic stages, and their associated cancer fields, could be a molecular research strategy to further test the theory.

Role of indoleamine 2,3-dioxygenase in health and disease.

IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

A PANorama of PAX genes in cancer and development.

Populations of self-renewing cells that arise during normal embryonic development harbour the potential for rapid proliferation, migration or transdifferentiation and, therefore, tumour generation. So, control mechanisms are essential to prevent rapidly expanding populations from malignant growth. Transcription factors have crucial roles in ensuring establishment of such regulation, with the Pax gene family prominent amongst these. This review examines the role of Pax family members during embryogenesis, and their contribution to tumorigenesis when subverted.

Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line.

Dmrt1 (doublesex and mab-3 related transcription factor (1) is a regulator of testis development in vertebrates that has been implicated in testicular germ cell tumors of mouse and human. In the fetal mouse testis Dmrt1 regulates germ cell pluripotency in a strain-dependent manner. Loss of Dmrt1 in 129Sv strain mice results in a >90% incidence of testicular teratomas, tumors consisting cells of multiple germ layers; by contrast, these tumors have never been observed in Dmrt1 mutants of C57BL/6J (B6) or mixed genetic backgrounds. To further investigate the interaction between Dmrt1 and genetic background we compared mRNA expression in wild type and Dmrt1 mutant fetal testes of 129Sv and B6 mice at embryonic day 15.5 (E15.5), prior to overt tumorigenesis. Loss of Dmrt1 caused misexpression of overlapping but distinct sets of mRNAs in the two strains. The mRNAs that were selectively affected included some that changed expression only in one strain or the other and some that changed in both strains but to a greater degree in one versus the other. In particular, loss of Dmrt1 in 129Sv testes caused a more severe failure to silence regulators of pluripotency than in B6 testes. A number of genes misregulated in 129Sv mutant testes also are misregulated in human testicular germ cell tumors (TGCTs), suggesting similar etiology between germ cell tumors in mouse and man. Expression profiling showed that DMRT1 also regulates pluripotency genes in the fetal ovary, although Dmrt1 mutant females do not develop teratomas. Pathway analysis indicated disruption of several signaling pathways in Dmrt1 mutant fetal testes, including Nodal, Notch, and GDNF. We used a Nanos3-cre knock-in allele to perform conditional gene targeting, testing the GDNF coreceptors Gfra1 and Ret for effects on teratoma susceptibility. Conditional deletion of Gfra1 but not Ret in fetal germ cells of animals outcrossed to 129Sv caused a modest but significant elevation in tumor incidence. Despite some variability in genetic background in these crosses, this result is consistent with previous genetic mapping of teratoma susceptibility loci to the region containing Gfra1. Using Nanos3-cre we also uncovered a strong genetic interaction between Dmrt1 and Nanos3, suggesting parallel functions for these two genes in fetal germ cells. Finally, we used chromatin immunoprecipitation (ChIP-seq) analysis to identify a number of potentially direct DMRT1 targets. This analysis suggested that DMRT1 controls pluripotency via transcriptional repression of Esrrb, Nr5a2/Lrh1, and Sox2. Given the strong evidence for involvement of DMRT1 in human TGCT, the downstream genes and pathways identified in this study provide potentially useful candidates for roles in the human disease.

The Capicua repressor--a general sensor of RTK signaling in development and disease.

Receptor tyrosine kinase (RTK) signaling pathways control multiple cellular decisions in metazoans, often by regulating the expression of downstream genes. In Drosophila melanogaster and other systems, E-twenty-six (ETS) transcription factors are considered to be the predominant nuclear effectors of RTK pathways. Here, we highlight recent progress in identifying the HMG-box protein Capicua (CIC) as a key sensor of RTK signaling in both Drosophila and mammals. Several studies have shown that CIC functions as a repressor of RTK-responsive genes, keeping them silent in the absence of signaling. Following the activation of RTK signaling, CIC repression is relieved, and this allows the expression of the targeted gene in response to local or ubiquitous activators. This regulatory switch is essential for several RTK responses in Drosophila, from the determination of cell fate to cell proliferation. Furthermore, increasing evidence supports the notion that this mechanism is conserved in mammals, where CIC has been implicated in cancer and neurodegeneration. In addition to summarizing our current knowledge on CIC, we also discuss the implications of these findings for our understanding of RTK signaling specificity in different biological processes.

Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective.

Cell lineage commitment and differentiation are governed by a complex gene regulatory network. Disruption of these processes by inappropriate regulatory signals and by mutational rewiring of the network can lead to tumorigenesis. Cancer cells often exhibit immature or embryonic traits and dysregulated developmental genes can act as oncogenes. However, the prevailing paradigm of somatic evolution and multi-step tumorigenesis, while useful in many instances, offers no logically coherent reason for why oncogenesis recapitulates ontogenesis. The formal concept of "cancer attractors", derived from an integrative, complex systems approach to gene regulatory network may provide a natural explanation. Here we present the theory of attractors in gene network dynamics and review the concept of cell types as attractors. We argue that cancer cells are trapped in abnormal attractors and discuss this concept in the light of recent ideas in cancer biology, including cancer genomics and cancer stem cells, as well as the implications for differentiation therapy.

Mechanisms of cancer metastasis: involvement of cancer stem cells?

The leading cause of death from cancer is tumor expansion, which usually leads to dissemination and metastasis of malignant cells. Accumulating evidence suggests growing tumors contain some very rare primitive cells that are mobile and thus endowed with metastatic potential. If these cells survive radio/chemotherapy, they are responsible for tumor re-growth after treatment. In this review, we discuss the origin of these cells, which: 1) are true cancer stem cells (CSCs) that initiate tumor growth and are subsequently responsible for metastatic dissemination; or 2) are derived from transformed tumor cells by the epithelial mesenchymal transition phenomenon. We also address major molecular mechanisms involved in trafficking of these cells during metastasis, paying special attention to the underappreciated side effects of radio/chemotherapy that may induce pro-metastatic environments in various organs. Overall, we envision that the process of pathological metastasis of cancer cells reflects a physiological property of normal SCs for their ability to migrate, as seen during embryogenesis. Finally, we discovered highly migratory, very small embryonic-like SCs that are deposited during development in adult tissues. As we hypothesize, these cells could: 1) give rise to some primitive types of tumors; and 2) may have a direct role in cancer expansion by being involved in tumor angiogenesis and formation of tumor stroma.

[Cancer microenvironment affects biological properties of tumor cells--tumor as an embryologic problem?]. / Nádorové mikroprostredí ovlivnuje biologické vlastnosti nádorové bunky--nádor jako embryologický problém?

Mutual epithelial-mesenchymal interaction represents a fundamental control mechanism during the development of organs and tissues. This review article demonstrates the importance of such interaction for tumor formation where it influences the biological properties of cancer stem cell and tumor itself. The teratoma and melanoma are employed as examples to demonstrate the influence of embryonic microenvironment on the biological properties of tumor, mainly on its potential to metastasize. The manipulation of cancer microenvironment represents the perspective therapeutic tool for cancer treatment in future.

Involvement of the IGF system in fetal growth and childhood cancer: an overview of potential mechanisms.

Fetal growth is determined by a complex interplay of genetic, nutritional, environmental, and hormonal factors. Greater than expected fetal growth has been positively associated with the risk of the development of some cancers in childhood, particularly acute lymphoblastic leukemia, and the biological mechanisms underlying such associations are thought to involve insulin-like growth factors (IGFs). Circulating IGF levels are highly correlated with fetal growth, and IGFs are believed to play an important role in carcinogenesis; however, these two bodies of evidence have not been well integrated and, as a result, the potential underlying biological mechanisms linking the IGF system with the development of specific childhood cancers have not been elucidated. This review aims to draw together and summarize the literature linking the IGF system, rapidity of fetal growth, and risk of some specific childhood cancers; suggest explanations for some of the inconsistencies observed in previous studies of these associations; and propose an integrated framework for the putative involvement of the IGF system in the development of at least some childhood cancers. If the challenges involved in studying the complex IGF system can be overcome, this field presents an exciting opportunity to elucidate etiological pathways to childhood malignancies.

Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale?

There is substantial evidence which shows that constraints in the early life environment are an important determinant of risk of metabolic disease and CVD. There is emerging evidence that higher birth weight, which reflects a more abundant prenatal environment, is associated with increased risk of cancer, in particular breast cancer and childhood leukaemia. Using specific examples from epidemiology and experimental studies, this review discusses the hypothesis that increased susceptibility to CVD, metabolic disease and cancer have a common origin in developmental changes induced in the developing fetus by aspects of the intra-uterine environment including nutrition which involve stable changes to the epigenetic regulation of specific genes. However, the induction of specific disease risk is dependent upon the nature of the environmental challenge and interactions between the susceptibility set by the altered epigenome and the environment throughout the life course.

Tumours of the fetal body: a review.

Tumours of the fetal body are rare, but lesions have been reported in all spaces, especially in the mediastinum, the pericardial space, the adrenals, the kidney, and the liver. Lymphangioma and teratoma are the commonest histological types encountered, followed by cardiac rhabdomyoma. Adrenal neuroblastoma is the commonest malignant tumour. Imaging plays an essential role in the detection and work-up of these tumours. In addition to assisting clinicians it also helps in counselling parents. Most tumours are detected by antenatal US, but fetal MRI is increasingly used as it brings significant additional information in terms of tumour extent, composition and complications.

Developmental origins and emerging therapeutic opportunities for childhood cancer.

Cancer is the leading disease-related cause of death in children in developed countries. Arising in the context of actively growing tissues, childhood cancers are fundamentally diseases of dysregulated development. Childhood cancers exhibit a lower overall mutational burden than adult cancers, and recent sequencing studies have revealed that the genomic events central to childhood oncogenesis include mutations resulting in broad epigenetic changes or translocations that result in fusion oncoproteins. Here, we will review the developmental origins of childhood cancers, epigenetic dysregulation in tissue stem/precursor cells in numerous examples of childhood cancer oncogenesis and emerging therapeutic opportunities aimed at both cell-intrinsic and microenvironmental targets together with new insights into the mechanisms underlying long-term sequelae of childhood cancer therapy.

Risk factors for a five-year death in the interASIA-south cohort.

OBJECTIVE: To determine the mortality rate and risk factors for death in a selected population in Songkhla province in southern Thailand. MATERIAL AND METHOD: The southern subjects were part of the Thai cohort which together with the cohort from China comprised the InterASIA survey which was conducted in the year 2000. Collected variables were the conventional ones and included the 2 ethnic groups which are specific for southern Thailand, i.e. Malay Muslims and Thai-Chinese Buddhists. Causes of death were determined by reviewing hospital records, verbal autopsies and a consensus by 2-3 physicians. Kaplan Meier's model was used to evaluate the independent factors related to death. RESULTS: The follow-up was 5 years. Out of the original 1,006 subjects, the status could be examined in 86% and of these, 50 had died giving the Kaplan Meier 5-year survival rate of 94.3%. Sixteen died from cardiovascular diseases (CVD), 6 from strokes and 10 from coronary heart disease, and 15 died from cancer. Half of the deaths occurred in subjects older than 70 years. Independent risks for death were age, hypertension and diabetes mellitus. Risk for the major causes of death did not include ethnicity. Similar to the only existing prospective report of risk factors for death in Thailand (the Electricity Generating Authority of Thailand study), neither high total cholesterol, high triglyceride nor obesity were independent risks for death from CVD, but the present study differed in that the high density lipoprotein cholesterol was not found to be a protective factor for CVD death. CONCLUSION: Risk factors for death in a five-year follow-up in Southern Thailand did not include lipids, ethnicity or urbanization but hypertension and diabetes mellitus did.

An embryonic 100µg/L lead exposure results in sex-specific expression changes in genes associated with the neurological system in female or cancer in male adult zebrafish brains.

Developmental lead (Pb) exposure is linked to neurological health issues. Results from non-human primate and rodent studies suggest detrimental effects of an early life Pb exposure, showing transcriptional disturbances and pathological evidence of Alzheimer's disease in the adult animal brain. To elucidate the impacts of an embryonic Pb exposure on the adult brain, transcriptomic analysis was completed on the brain of zebrafish aged 12months exposed to a control treatment or to an embryonic 100µg/L Pb exposure by sex. In the adult female zebrafish brain, significant changes in expression profiles occurred in a number of genes involved in neurological disease and nervous system development and function. On the other hand, in adult males, a number of genes with significant expression alterations were found to be associated with cancer and tumors. p38 mitogen-activated protein kinase (p38 MAPK) was also indicated as an upstream regulator of observed gene expression changes. Western blot analysis confirmed activation of p38 MAPK in the form of phosphorylated p38 MAPK in the male zebrafish brain. In addition, we compared transcriptomic changes observed in this study to a previous study with an embryonic exposure of 10µg/L Pb by sex, showing unique sets of genes dependent on Pb concentration. Overall, these results show sex-specific and concentration-dependent disturbances of global gene expression patterns in the brain of adult zebrafish exposed to Pb during embryogenesis.

DNA repair helicases as targets for anti-cancer therapy.

The genetic complexity of cancer has posed a formidable challenge to devising successful therapeutic treatments. Tumor resistance to cytotoxic chemotherapy drugs and radiation which induce DNA damage has limited their effectiveness. Targeting the DNA damage response is a strategy for combating cancer. The prospect for success of chemotherapy treatment may be improved by the selective inactivation of a DNA repair pathway. A key class of proteins involved in various DNA repair pathways is comprised of energy-driven nucleic acid unwinding enzymes known as helicases. DNA helicases have been either implicated or have proposed roles in nucleotide excision repair, mismatch repair, base excision repair, double strand break repair, and most recently cross-link repair. In addition to DNA repair, helicases have been implicated in the cellular processes of replication, recombination, transcription, and RNA stability/processing. The emerging evidence indicates that helicases have vital roles in pathways necessary for the maintenance of genomic stability. In support of this, a growing number of human genetic disorders are attributed to mutations in helicase genes. Because of their essential roles in nucleic acid metabolism, and more specifically the DNA damage response, helicases may be a suitable target of chemotherapy. In this review, we have explored this hypothesis and provided a conceptual framework for combinatorial treatments that might be used for combating cancer by inhibiting helicase function in tumor cells that already have compromised DNA repair and/or DNA damage signaling. This review is focused on helicase pathways, with a special emphasis on DNA cross-link repair and double strand break repair, that impact cancer biology and how cancer cells may be chemosensitized through the impairment of helicase function.

Newer vascular targets: endosialin (review).

The identification of cell surface markers expressed selectively by tumor vasculature is challenging. To get as close to the human disease as possible, investigators have isolated endothelial cells from fresh human tumor specimens and subjected them to RNA-based gene expression analysis. The data indicate that there are few proteins that distinguish tumor vasculature from normal vasculature and re-enforce the notion that the endothelium is a tissue specialized cell-type. Endosialin was identified as a cell surface tumor endothelial marker. The selective expression of endosialin by tumor vasculature and stroma has been confirmed. Although the function of endosialin remains to be elucidated, the expression pattern for this protein may be favorable for cancer therapy.

Epigenetic processes and cancer risk assessment.

The U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment encourages the use of mechanistic data in the assessment of human cancer risk at low (environmental) exposure levels. The key events that define a particular mode of action for tumor formation have been concentrated to date more on mutational responses that are broadly the result of induced DNA damage and enhanced cell proliferation. While it is clear that these processes are important in terms of tumor induction, other modes that fall under the umbrella of epigenetic responses are increasingly being considered to play an important role in susceptibility to tumor induction by environmental chemicals and as significant modifiers of tumor responses. Alterations in gene expression, DNA repair, cell cycle control, genome stability and genome reprogramming could be the result of modification of DNA methylation and chromatin remodeling patterns as a consequence of exposure to environmental chemicals. These concepts are described and discussed.