• Ubiquitin-like proteins: meet the family.

      Wilkinson, Caroline R M; Paterson Institute for Cancer research, Christie Hospital, Manchester, UK. cwilkinson@picr.man.ac.uk (2004-04)
    • The Ubiquitin/UBL drug target repertoire

      Osborne, Hugh C; Irving, E.; Schmidt, Christine K; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Manchester M20 4GJ, (2020)
    • UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer.

      Daskalos, A; Oleksiewicz, U; Filia, A; Nikolaidis, G; Xinarianos, G; Gosney, J; Malliri, Angeliki; Field, J; Liloglou, T; Roy Castle Lung Cancer Research Programme, University of Liverpool, Department of Clinical and Molecular Cancer Medicine, Liverpool, United Kingdom. (2011-03-01)
      The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear.
    • UKEMS collaborative genotoxicity trial. Cytogenetic tests of 4CMB, BC and 4HMB: summary and appraisal.

      Scott, David; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX (Great Britain) (1982)
    • Ultrastructural and morphometric alterations in bone marrow stromal tissue after 7 Gy irradiation.

      Yamazaki, K; Allen, Terence D; Department of Pathology, School of Medicine, Keio University, Tokyo, Japan. (1991)
      To evaluate the response of marrow stroma to 7 Gy irradiation, femoral bone marrow was fixed by vascular perfusion (so as to avoid the artificial destruction of sinus endothelia), and was examined using light and electron microscopy with morphometric methods. The radiation caused a marked decrease in hematopoietic cell number (NHC) within 3 days post-irradiation, followed by total recovery of hematopoiesis, which occurred gradually over 28 days. An increased number of fat cells was seen by 7 days. During the whole course of hypoplasia and recovery, the continuity of sinus wall, three-dimensional reticular mesh work in hematopoietic parenchyma, gap junctions (GJ) between stromal cells, the adventitial cell cover of sinus wall (ACC), and the stromal cell numbers of reticular cells (RC), sinus endothelia (SE), and macrophages (MP) were maintained. The cellularity of stromal components of RC, SE, and MP seemed passively increased in contrast to a reduction in numbers of NHC. A similar tendency was observed (1) between NHC and ACC and (2) between GJ and the cellularity of fat cells, which had a statistical significant correlation (p less than 0.05; t-test). The mechanism of radio resistance in bone marrow stroma and the possible functional adaptation and cellular coordination after irradiation are discussed.
    • Ultrastructural aspects of erythropoietic differentiation in long-term bone marrow culture.

      Allen, Terence D; Dexter, T Michael; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Withington, Manchester, M20 9BX, UK (1982)
      Long-term liquid cultures of mouse bone marrow produce stem cell (CFU-S) and differentiated granulocytes for many months. Addition of AMS (anaemic mouse serum) to the cultures almost entirely eliminates the granulopoietic activity and stimulates erythropoiesis, with full erythroid maturation and the production of adult haemoglobin. Ultrastructural analysis of in situ fixed material reveals the cell shape and surface morphology of the erythroid maturation series, and the generation of erythroblastic islands in vitro. Each erythroblastic island consists of one or more synchronously maturing cohorts of erythroid cells undergoing four or five divisions between proerythroblast and normoblast. Each island is centered on a macrophage, which interacts with the developing erythroid population in several ways. Expelled nuclei are phagocytosed by te macrophage, which also has large areas of closely apposed membrane with the erythroid cells, gap junctions, and possible reciprocal vesicular activity. Changes in the adherent layer (stromal cells) also occur with the transition from granulopoiesis to erythropoiesis. There is a reduction in the endothelial cell cover, and mobilisation of lipid from the granulopoietic associated apidocytes.
    • Ultrastructural changes in Osmunda regalis Prothalli induced by X-irradiation.

      Allen, Terence D; Haigh, M V; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-01)
    • Ultrastructural morphology of three-dimensional colonies of cells derived from a hepatocellular carcinoma.

      Allen, Terence D; Iype, P; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1979)
      Cultured hepatocellular carcinoma cells were studied during anchorage-independent growth in semi solid medium (Methocel). The regular occurrence of mitotic figures both at the surface and within the colonies precludes the possibility of such colonies being formed by re-aggregation. The estimated population doubling time in the three-dimensional (3-D) colonies is consistent with those two-dimensional of (2-D) colonies. Structures resembling bile canaliculi were observed between the closely opposed membranes from the well packed adjacent cells. Cell surface and ultrastructural features of the colonies and individual cells are presented and comparisons made with 2-D growth of normal and malignant liver cells in vitro. The formation of 3-D colonies may not only be an assay for transformed cells but also for predicting the type of tumors produced by re-innoculation of the in vitro transformed cells.
    • Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the "neuro-reticular complex".

      Yamazaki, K; Allen, Terence D; Department of Pathology, School of Medicine, Keio University, Tokyo, Japan. (1990-03)
      In order to extend our understanding of the role of nerve fibers in the structure and function of bone marrow stroma, we have examined nerve terminals, arterioles, and capillaries in femoral bone marrow tissues of 50 C57BL strain mice, using electron microscopy and morphometric methods. Within the adventitia of arterioles, a particular type of cell, termed periarterial adventitial (PAA) cell, is characterized by a thin veil-like cytoplasm which concentrically surrounds both nerves and arterioles. Nerve fibers containing both unmyelinated and myelinated axons are distributed mainly between the layers of PAA cells, but are found rarely on the sinus walls or within the hematopoietic parenchyma. Quantitatively, the efferent nerve terminals with many synaptic vesicles are distributed mainly beside arterial smooth muscle cells (Type I: 58.8%) or between the layers of PAA cells (Type III: 33.2%), and rarely in hematopoietic parenchyma (Type II: 5.3%) or on sinus walls (Type IV: 2.7%). In the case of Type II-IV nerve terminals, efferent (autonomic) nerves and bone marrow stromal cells which are connected by gap junctions (sinus adventitial reticular cells, intersinusoidal reticular cells, and PAA cells) appear to constitute a potential functional unit for signal conduction. We would like to propose a new term for this anatomical unit in marrow, the "neuro-reticular complex."
    • Ultrastructural site variations in mouse epidermal organization.

      Allen, Terence D; Potten, Christopher S; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1976-07)
      Mouse dorsal, ear, tail and foot epidermis are compared according to their tissue architecture and cell kinetics. Cell proliferation is expected in terms of the daily volume of keratin replaced. The stratum corneum may be organized into vertical columns of squames, which may have minimal overlap as in dorsum and ear, or maximal overlap as in tail. Individual areas are adapted to their function both in squame fine structure and rate of cell replacement. The surface keratin loss/replacement rate is at its highest in foot and tail, and lowest in ear and dorsum. Observations on hairless mouse dorsum are also included.
    • Ultrastructure of cell loss in intestinal mucosa.

      Potten, Christopher S; Allen, Terence D; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1977-08)
    • Ultrastructure of giant plastids in a radiation induced mutant of Osmunda regalis.

      Allen, Terence D; Haigh, M V; Howard, Alma; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-03)
    • Ultraviolet light and melanoma.

      Craig, Sarah; Earnshaw, C; Virós, Amaya; Skin Cancer and Ageing Laboratory, CRUK Manchester Institute, The University of Manchester, UK (2018-01-30)
      Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion

      Budden, Timothy; Gaudy, C.; Nagore, E; Viros, Amaya; Cancer Research UK Manchester Institute, Nether Alderley, Macclesfield, (2021)
      Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma. The ageing, sunexposed dermis accumulates UVR damage, and older patients develop more melanomas at UVR-exposed sites. As fibroblasts play key roles in the stromal response to UVR and in cancer progression, we investigated how long term UVR modifies dermal fibroblast function and how this affects melanoma invasion. Chronic UVR exposure on dermal fibroblasts showed that extracellular matrix pathways, particularly those involved in collagen catabolism, were upregulated in the absence of acute UVR. Importantly, the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) was persistently upregulated. This resulted in persistent degradation of collagen 1, and an overall degraded and disorganised matrix. Collagen degradation by MMP1 decreased melanoma invasion in vitro. Conversely, both inhibiting extracellular matrix degradation and MMP1, or higher collagen 1 expression, restored the invasion of melanoma through collagen. Primary cutaneous melanomas of aged humans confirmed these in vitro findings, revealing significantly fewer cancer cells invade as single cells at the invasive front of melanomas arising in chronic sun damaged skin. We show high collagen deposition and melanoma cell invasion in the dermis are robust predictors of poor melanoma-specific survival in 3, international cohorts of primary melanoma. Thus, melanomas arising over UVR-damaged, collagen-poor skin are less invasive, and this reduced invasion improves survival. However, we discovered a subset of melanomas arising over collagen-poor, UVR-damaged dermis have a poor outcome, and found that increased new collagen synthesis by melanoma-associated fibroblasts at the invasive front in these cases restores melanoma single cell invasion and drives poor outcome. Finally, we demonstrate high COL1A1 gene expression is an early stage biomarker of poor outcome across a broad range of primary cancers.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion

      Budden, Timothy; Gaudy-Marqueste, C.; Porter, Andrew P; Kay, E.; Gurung, Shilpa; Earnshaw, Charles H; Roeck, K.; Craig, S.; Traves, V.; Krutmann, J.; et al. (2021)
      Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.
    • Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.

      Trucco, Lucas D; Mundra, Piyushkumar A; Hogan, Kate; Garcia-Martinez, Pablo; Viros, Amaya; Mandal, Amit Kumar; Macagno, N; Gaudy-Marqueste, C; Allan, D; Baenke, Franziska; et al. (2018)
      Erratum in Publisher Correction: Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma. [Nat Med. 2018] Abstract The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.
    • Understanding and exploiting 5T4 oncofoetal glycoprotein expression.

      Stern, Peter L; Brazzatti, J; Sawan, S; McGinn, Owen J; Institute of Cancer Sciences, University of Manchester, UK (2014-12)
      Oncofoetal antigens are present during foetal development with generally limited expression in the adult but are upregulated in cancer. These molecules can sometimes be used to diagnose or follow treatment of tumours or as a target for different immunotherapies. The 5T4 oncofoetal glycoprotein was identified by searching for shared surface molecules of human trophoblast and cancer cells with the rationale that they may function to allow survival of the foetus as a semi-allograft in the mother or a tumour in its host, potentially influencing growth, invasion or altered immune surveillance of the host. 5T4 tumour selective expression has stimulated the development of 5T4 vaccine, 5T4 antibody targeted-superantigen and 5T4 antibody-drug therapies through preclinical and into clinical studies. It is now apparent that 5T4 expression is a marker of the use (or not) of several cellular pathways relevant to tumour growth and spread. Thus 5T4 expression is mechanistically associated with the directional movement of cells through epithelial mesenchymal transition, facilitation of CXCL12/CXCR4 chemotaxis, blocking of canonical Wnt/beta-catenin while favouring non-canonical pathway signalling. These processes are highly regulated in development and in normal adult tissues but can contribute to the spread of cancer cells. Understanding the differential impact of these pathways marked by 5T4 can potentially improve existing, or aid development of novel cancer treatment strategies.
    • Understanding cancer: from the gene to the organism. Conference on genes and cancer.

      Hagan, Iain M; Sharrocks, Andrew D; School of Biological Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. (2002-05)
    • Understanding FOXO, new views on old transcription factors.

      Zanella, Fabian; Link, Wolfgang; Carnero, Amancio; Experimental Therapeutics programme, Spanish National Cancer Research Centre, Madrid, Spain. (2010-03-01)
      FOXO proteins are evolutionarily conserved transcription factors implicated in several fundamental cellular processes, functioning as end-point for transcriptional programs involved in apoptosis, stress response and longevity. Abrogation of FOXO function is very frequent in human cancer, therefore the mechanisms of regulation of the FOXO proteins are receiving increasing attention in cancer research. The FOXO proteins integrate regulatory inputs from a variety of upstream signaling pathways, most importantly in response to growth factor and stress signalling. Recently, FOXO factors have been established as tumor suppressors, promoting the transcription of pro-apoptotic molecules like FasL and Bim when the PI3K/Akt pathway is downregulated due to nutrient or serum starvation and cellular stress. Therefore, understanding the modulation of FOXO transcription factors will allow the design of new compounds with antitumor potential.
    • Understanding the "lethal" drivers of tumor-stroma co-evolution: Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment.

      Lisanti, Michael P; Martinez-Outschoorn, U E; Chiavarina, B; Pavlides, S; Whitaker-Menezes, D; Tsirigos, A; Witkiewicz, A; Lin, Z; Balliet, R; Howell, Anthony; et al. (2010-09-19)
      We have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other stromal cells. Oxidative stress in the tumor stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer cells, thereby promoting the anabolic growth of cancer cells (via an energy imbalance). We also show that ketones and lactate help "fuel" tumor growth and cancer cell metastasis and can act as chemo-attractants for cancer cells. We have termed this new paradigm for accelerating tumor-stroma co-evolution, "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism". Heterotypic signaling in cancer-associated fibroblasts activates the transcription factors HIF1alpha and NFκB, potentiating the onset of hypoxic and inflammatory response(s), which further upregulates the autophagic program in the stromal compartment. Via stromal autophagy, this hypoxic/inflammatory response may provide a new escape mechanism for cancer cells during anti-angiogenic therapy, further exacerbating tumor recurrence and metastasis.