• 1p13 is the most frequently involved band in structural chromosomal rearrangements in human breast cancer.

      Mitchell, Erika L D; Santibanez-Koref, Mauro F; Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1990-11)
      Cytogenetic data on 14 breast carcinomas were examined to determine which chromosome arms and bands are preferentially involved in structural chromosome changes. Chromosome arms 17p, 16q, and 1p and band 1p13 were found to be significantly involved. A review of the world literature confirmed 1p as being the most frequently involved arm in structural chromosome changes in breast cancer and 1p13 as being the band most frequently involved in such changes. The two sets of results were pooled, and the analysis of 113 tumours revealed 229 of 304 bands to be involved, with 1p13 affected in 20% of the tumours.
    • 2'-Deacetoxyaustrospicatine from the stem bark of Taxus baccata.

      Breeden, S W; Jordan, Allan M; Lawrence, N J; McGown, Alan T; Department of Chemistry, UMIST, P.O. Box 88, Manchester, UK. (1996-02)
    • A [2+2] photo-adduct of 8-methoxypsoralen and thymine - x-ray crystal-structure - a model for the reaction of psoralens with dna in the phototherapy of psoriasis

      Land, Edward J; Rushton, Francis A P; Beddoes, R L; Bruce, J M; Cernik, R J; Dawson, S C; Mills, O S; Paterson Laboratories, Christie Hospital & Holt Radium Institute, Manchester, M20 9BX, U.K. (1982)
    • 20 alpha-hydroxysteroid dehydrogenase expression in hemopoietic cell cultures and its relationship to interleukin 3.

      Garland, John M; Dexter, T Michael; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Withington, Manchester, M20 9BX, UK (1982-12)
      Expression of 20 alpha-hydroxysteroid dehydrogenase (20 alpha-SDH) has been investigated in long-term bone marrow cultures derived from normal and nude mice in the presence of horse serum and hydrocortisone. 20 alpha-SDH expression rises markedly in the adherent cells derived from normal bone marrow. Early (1-5 days) lipid profiles are similar to those seen in T cells, but at later times (6-14 days) stromal-type lipid patterns dominate. Similar culture of fetal liver and nu/nu bone marrow cells shows rises in 20 alpha-SDH expression, in situations where T cells are notably absent. The expression of 20 alpha-SDH is not associated with detectable endogenous production of "interleukin 3" activity, and although addition of "IL 3" to bone marrow cultures increases the levels of 20 alpha-SDH, this is associated with granulopoiesis rather than lymphoid development.
    • 21st L H Gray Conference: the radiobiology/radiation protection interface.

      West, Catharine M L; Martin, C J; Sutton, D G; Wright, Eric G; Academic Department of Radiation Oncology, University of Manchester, Christie Hospital, UK. catharine.west@manchester.ac.uk (2009-05)
      The 21st L H Gray Conference, organised by the L H Gray Trust with the Society for Radiological Protection, brought together international experts in radiobiology, epidemiology and risk assessment, and scientists involved in diagnostic and therapeutic radiation exposure. The meeting - held in Edinburgh, Scotland, on 4-6 June 2008 - aimed to raise awareness, educate and share knowledge of important issues in radiation protection. A distinguished group of speakers discussed topics that included (i) non-targeted effects of radiation, (ii) exposure to high natural background radiation, (iii) non-cancer effects in Japanese bomb survivors, (iv) lessons learnt from Chernobyl, (v) radiation in the workplace, (vi) biokinetic modelling, (vii) uncertainties in risk estimation, (viii) issues in diagnostic medical exposures, (ix) lessons leant from the polonium-210 incidence and (x) how the radiobiology/radiation oncology community is needed to help society prepare for potential future acts of radiation terrorism. The conference highlighted the importance, relevance and topicality of radiobiology today.
    • 265 NM Laser flash photolysis of some ortho-substituted anilides and related N-formylkynurenine derivatives.

      Pileni, M P; Santus, R; Land, Edward J; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1978)
    • 3'-UTR poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers.

      Kishore, S; Piscuoglio, S; Kovac, M; Gylling, A; Wenzel, F; Trapani, Francesca; Altermatt, H J; Mele, V; Marra, G; Peltomäki, P; et al. (2014-01-01)
      The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers.
    • 3-substituted-5-aziridinyl-1-methylindole-4,7-diones as NQO1-directed antitumour agents: mechanism of activation and cytotoxicity in vitro.

      Jaffar, Mohammed; Phillips, Roger M; Williams, Kaye J; Mrema, Ibrahim; Cole, Christian; Wind, Natasha S; Ward, Timothy H; Stratford, Ian J; Patterson, Adam V; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK. (2003-10-01)
      Indolequinone agents are a unique class of bioreductive cytotoxins that can function as dual substrates for both one- and two-electron reductases. This endows them with the potential to be either hypoxia-selective cytotoxins or NAD(P)H:quinone oxidoreductase 1 (NQO1)-directed prodrugs, respectively. We have studied the structure-activity relationships of four novel indolequinone analogues with regard to one- and/or two-electron activation. Single-electron metabolism was achieved by exposing the human carcinoma cell line T47D to each agent under hypoxic conditions, whilst concerted two-electron metabolism was assessed by stably expressing the cDNA for human NQO1 in a cloned cell line of T47D. The C-3 and C-5 positions of the indolequinone nucleus were modified to manipulate reactivity of the reduction products and the four prodrugs were identified as NQO1 substrates of varying specificity. Two of the four prodrugs, in which both C-3 and C-5 groups remained functional, proved to be NQO1-directed cytotoxins with selectivity ratios of 60- to 80-fold in the T47D (WT) versus the NQO1 overexpressing T47D cells. They also retained selectivity as hypoxic cytotoxins with oxic/hypoxic ratios of 20- to 22-fold. Replacement of the C-3 hydroxymethyl leaving group with an aldehyde group ablated all selectivity in air and hypoxia in both cell lines. Addition of a 2-methyl group on the C-5 aziridinyl group to introduce steric hinderance reduced but did not abolish NQO1-dependent metabolism. However, it enhanced single-electron metabolism-dependent DNA cross-linking in a manner that was independent of cytotoxicity. These data demonstrate that subtle structure-activity relationship exists for different cellular reductases and under certain circumstances distinct forms of DNA damage can arise, the cytotoxic consequences of which can vary. This study identifies a candidate indolequinone analogue for further development as a dual hypoxia and NQO1-directed prodrug.
    • 32P-post-labelling analysis of DNA adducts formed in the upper gastrointestinal tissue of mice fed bracken extract or bracken spores.

      Povey, Andrew C; Potter, D; O'Connor, Peter J; Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. (1996-11)
      Bracken toxicity to both domestic and laboratory animals is well established and tumours are formed when rodents are treated with either bracken extracts or bracken spores. In this study we have administered bracken spores and extract to mice in order to investigate whether such exposure leads to the formation of DNA adducts. DNA, isolated from the upper gastrointestinal tract and liver, was digested to 3'-nucleotides. Adducts were extracted with butanol, 32P-post-labelled, separated by thin layer chromatography (TLC) and visualised and quantified using storage-phosphor technology. A cluster of adducts was clearly seen in the DNA of the upper gastrointestinal tract, but not liver, 5 and 24 h after treatment with bracken extract or bracken spores. These adducts were not observed in DNA extracted from vehicle-treated animals. Whereas, after 5 h adduct levels in extract and spore-treated animals were similar, after 24 h adduct levels in the extract-treated animals had diminished by > 75%, but levels in spore-treated animals remained similar to those found after 5 h. This suggests that the DNA-reactive compounds were being released slowly from the spores, even though the spores had been sonicated before administration. Adducts were also quantified after the addition of an internal standard (deoxyinosine 3'-monophosphate) by comparing the amount of label incorporated into the adducts with that found in a known amount of the internal standard. Adduct levels using this internal standard approach were similar to those found by direct measurement of radioactivity incorporated into the adduct, indicating that the labelling of adducts was quantitative. We have tried, unsuccessfully, to synthesise ptaquiloside, the principal carcinogenic component present within bracken. However, similar patterns of adducts were observed when two other compounds, (1-(4-chlorophenyl sulphonyl)-l-cyclopropane carbonitrile and 3-cyclopropylindeno [1,2-c] pyrazol-4-(O-methyl)oxime), which both contain a cyclopropyl ring, were administered to mice. The adducts detected in bracken-treated animals may, thus, have arisen from ptaquiloside but, whether these adducts arise directly from the compounds and bracken spores/extract themselves or via an indirect mechanism, remains to be determined. As bracken-induced DNA adducts are detectable in rodent tissues by a 32P-post-labelling procedure commonly employed to investigate DNA damage in human populations, it may prove possible to apply such approaches to determine human exposure.
    • 32P-postlabelling of alkylated thymidines using Epstein-Barr virus encoded thymidine kinase.

      Povey, Andrew C; Cooper, Donald P; Littler, Edward; Cancer Research Campaign Department of Carcinogenesis, Patterson Institute for Cancer Research, Manchester, UK. (1991-04)
      Alkylated nucleotides have been detected by 32P-postlabelling using the enzyme T4 polynucleotide kinase which phosphorylates the 3'-mononucleotides to give the 3',[5'-32P]bisphosphates. These may then be separated by two-dimensional TLC as the bisphosphates or the [5'-32P]monophosphates. We describe here an alternative approach using the Epstein-Barr virus (EBV) encoded thymidine kinase (TK) to directly phosphorylate adducted nucleosides to give the [5'-32P]monophosphates. Using a series of methyl, ethyl and butyl thymidines EBV-encoded TK was shown to phosphorylate a wide range of adducted thymidines with varying degrees of labelling efficiency; N3-methyl thymidine was labelled with the highest efficiency and O4-ethyl thymidine the lowest. Whereas O4-methyl thymidine was labelled at a higher efficiency than O2-methyl thymidine, O4-ethyl and O4-butyl thymidines were labelled at a much lower efficiency than the corresponding O2-alkyl thymidines. Labelling efficiency increased with pH in the range pH 7 to pH 9, but the relative labelling efficiency was ATP independent. This direct phosphorylation of adducted nucleosides offers an alternative approach to the detection of alkylated residues in DNA which may complement current postlabelling procedures.
    • 3D modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model.

      Maguire, S; Peck, B; Wai, Patty T; Campbell, J; Barker, H; Gulati, A; Daley, F; Vyse, S; Huang, P; Lord, C; et al. (2016-08-11)
      The initiation and progression of breast cancer from the transformation of the normal epithelium to ductal carcinoma in situ (DCIS) and invasive disease is a complex process involving the acquisition of genetic alterations, changes in gene expression, alongside microenvironmental and recognised histological alterations. Here we sought to comprehensively characterise the genomic and transcriptomic features of the MCF10 isogenic model of breast cancer progression and to functionally validate potential driver alterations in 3-dimensional (3D) spheroids that may give insight into breast cancer progression and identify targetable alterations in conditions more similar to those encountered in vivo. We performed whole genome, exome and RNA sequencing of the MCF10 progression series to catalogue the copy number, mutational and transcriptomic landscapes associated with progression. We identified a number of predicted driver mutations (including PIK3CA and TP53) that were acquired from non-malignant MCF10A cells to their malignant counterparts that are also present in primary breast cancers re-analysed from The Cancer Genome Atlas (TCGA). Acquisition of genomic alterations identified MYC amplification and previously un-described RAB3GAP1-HRAS and UBA2-PDCD2L expressed in-frame fusion genes in malignant cells. Comparison of pathway aberrations associated with progression identified that when cells are grown as 3D spheroids, they show perturbations of cancer-relevant pathways. Functional interrogation of the dependency on predicted driver events, identified alterations in HRAS, PIK3CA, and TP53 that selectively decreased cell growth and were associated with progression from pre-invasive to invasive disease, only when cells were grown as spheroids. Our results have identified changes in the genomic repertoire in cell lines representative of the stages of breast cancer progression and demonstrate that genetic dependencies can be uncovered when cells are grown in conditions more like in vivo. The MCF10 progression series, therefore, represents a good model to dissect potential biomarkers and evaluation of therapeutic targets involved in the progression of breast cancer.
    • 3H-thymidine labelling index (TLI) as a marker of tumour growth heterogeneity: evaluation in human solid carcinomas.

      Becciolini, A; Balzi, M; Barbarisi, M; Faraoni, P; Biggeri, A; Potten, Christopher S; Department of Clinical Physiopathology, University of Florence, Italy. (1997)
      Many studies deal with the analysis of cell kinetic, cytogenetic, biochemical and molecular cell biology parameters to identify prognostic factors relating to tumour growth but all methods use only a small part of the total tumour mass. This study is devoted to the analysis of the heterogeneity of the growth of human solid tumours assaying proliferative activity by means of 3H-thymidine labelling index (TLI) in a fixed number of samples collected in different areas of the lesion (larynx and colon cancers), or in different lesions of the same subject (breast and bladder cancers). Each sample (at the macroscopic level) was divided into small fragments (at the microscopic level) and proliferative activity was determined. The analysis of variance for hierarchical designs demonstrated that in all cases a high component of the variance is attributable to the subjects and to the fragments whereas the variance attributable to the different areas is very low. The heterogeneity of proliferative activity displays a higher focal variability among the fragments (microscopic level) compared with that among areas (macroscopic level) within subjects, provided an adequate number of fragments and cells are counted. In multiple synchronous carcinoma of the bladder the wide variability of proliferation among the single lesions demonstrated that it is necessary to analyse all the tumours in a subject because each one is characterized by a different cell growth potential.
    • 5T4 as a target for immunotherapy in renal cell carcinoma.

      Elkord, Eyad; Shablak, Alaaeldin; Stern, Peter L; Hawkins, Robert E (2009-12)
    • 5T4 glycoprotein regulates the sensory input-dependent development of a specific subtype of newborn interneurons in the mouse olfactory bulb.

      Yoshihara, S; Takahashi, H; Nishimura, N; Naritsuka, H; Shirao, T; Hirai, H; Yoshihara, Y; Mori, K; Stern, Peter L; Tsuboi, A; et al. (2012-02-08)
      Sensory input has been shown to regulate development in a variety of species and in various structures, including the retina, cortex, and olfactory bulb (OB). Within the mammalian OB specifically, the development of dendrites in mitral/tufted cells is well known to be odor-evoked activity dependent. However, little is known about the developmental role of sensory input in the other major OB population of the GABAgenic interneurons, such as granule cells and periglomerular cells. Here, we identified, with DNA microarray and in situ hybridization screenings, a trophoblast glycoprotein gene, 5T4, whose expression in a specific subtype of OB interneurons is dependent on sensory input. 5T4 is a type I membrane protein, whose extracellular domain contains seven leucine-rich repeats (LRR) flanked by characteristic LRR-N-flanking and C-flanking regions, and a cytoplasmic domain. 5T4 overexpression in the newborn OB interneurons facilitated their dendritic arborization even under the sensory input-deprived condition. By contrast, both 5T4 knockdown with RNAi and 5T4 knockout with mice resulted in a significant reduction in the dendritic arborization of 5T4(+) granule cells. Further, we identified the amino acid sequence in the 5T4 cytoplasmic domain that is necessary and sufficient for the sensory input-dependent dendritic shaping of specific neuronal subtypes in the OB. Thus, these results demonstrate that 5T4 glycoprotein contributes in the regulation of activity-dependent dendritic development of interneurons and the formation of functional neural circuitry in the OB.
    • 5T4 interacts with TIP-2/GIPC, a PDZ protein, with implications for metastasis.

      Awan, Abida; Lucic, Melinda R; Shaw, David M; Sheppard, Freda C; Westwater, Caroline; Lyons, Steve; Stern, Peter L; CRC Immunology Group, CRC Molecular Biology Group, The Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom. (2002-01-25)
      Overexpression of the 5T4 transmembrane glycoprotein can have marked effects on both the actin cytoskeleton and cell migration. Using a yeast two-hybrid approach, we describe a novel interaction between 5T4 and TIP-2/GIPC, a cytoplasmic interacting protein containing a PDZ domain. The cytoplasmic tail of 5T4 contains a class I PDZ-binding motif (Ser-Asp-Val) and we demonstrate that this region, in particular the terminal valine, is required for 5T4 interaction with TIP-2/GIPC. HeLa cells expressing hemagglutinin-tagged TIP-2/GIPC (HA-TIP-2/GIPC) have an altered distribution of endogenous 5T4, which colocalizes with HA-TIP-2/GIPC, thus supporting an interaction. Furthermore, TIP-2/GIPC can be coimmunoprecipitated with 5T4 from HeLa cell lysates. Identification of the 5T4 and TIP-2/GIPC interaction provides the first link between 5T4 and the actin cytoskeleton. Since other proteins, like 5T4, associate with TIP-2/GIPC and are linked with cancer, we explore the possibility that TIP-2/GIPC may be a common factor involved in the cancer process.
    • 5T4 oncofetal antigen expression in ovarian carcinoma.

      Wrigley, E; McGown, Alan T; Rennison, J; Swindell, Ric; Crowther, Derek; Starzynska, T; Stern, Peter L; CRC Department of Medical Oncology, Christie Hospital, CRC Department of Experimental Chemotherapy, Paterson Institute, CRC Department of Medical Statistics, Christie Hospital, CRC Department of Immunology, Paterson Institute, Manchester, UK. (1995-07)
      5T4 oncofetal antigen is defined by a monoclonal antibody raised against human placental trophoblast, and recognizes a 72 kD glycoprotein expressed in many different carcinomas but detected only at low levels in some normal epithelia. Analysis of the patterns of expression of 5T4 oncofetal antigen in colorectal carcinomas has indicated a significant association between the presence of the antigen in tumor cells and metastatic spread. The 5T4 antigen expression of 72 epithelial ovarian carcinomas has been investigated by immunohistochemistry; 71% of the carcinomas demonstrated positive 5T4 immunoreactivity in adenocarcinoma cells and/or associated stromal tissue. In order to assess any relationship to prognosis, the 5T4 phenotypes were analyzed with respect to various clinicopathologic features of the tumors and the clinical outcome of the patients assessed by survival and disease-free interval. There was a significant correlation between 5T4 expression and more advanced stage of disease (FIGO stages III and IV) (P < 0.001) and with poorly differentiated tumors (P = 0.036) compared to well or moderately differentiated tumors. Patients with tumors expressing 5T4 were less likely to respond well to adjuvant therapy (P = 0.030) and had a significantly worse outlook in terms of survival (P = 0.033) and disease-free interval (P = 0.033). This significance was not demonstrated as acting independently of FIGO stage and tumor differentiation.
    • 5T4 oncofetal antigen in gastric carcinoma and its clinical significance.

      Starzynska, T; Wiechowska-Kozlowska, A; Marlicz, K; Bromley, Michael; Roberts, Stephen A; Lawniczak, M; Kolodziej, B; Zyluk, A; Stern, Peter L; Department of Gastroenterology, Medical Pomeranian Academy, Szczecin, Poland. (1998-06)
      OBJECTIVE: To evaluate the role of 5T4 antigen in gastric cancer progression and prognosis. DESIGN: A prospective study of 5T4 antigen expression in primary, secondary and recurrent gastric carcinoma, the relationship to selected prognostic parameters and the course of disease. PATIENTS: Eighty six patients operated on for gastric cancer. TISSUE: One hundred and twenty two gastric tumours were studied, including 86 primary carcinomas, 32 coexisting lymph node metastases and four recurrent carcinomas. METHODS: Immunohistochemistry using 5T4 monoclonal antibody on frozen sections. RESULTS: The 5T4 antigen was detected in 41% of primary gastric tumours including early gastric cancer. A strong relationship was found between 5T4 positivity and tumour histology. Thus, 52% of gastric carcinomas of intestinal type expressed 5T4 antigen compared with 28% of the diffuse type (P = 0.028). Among 16 sets of primary gastric carcinomas and regional lymph node metastases, coordinate 5T4 expression was seen in 14 cases; the other two showed acquisition of positivity on metastatic tumour cells (carcinomas of diffuse type). 5T4 antigen was detected more frequently in carcinomas with p53 accumulation compared with those with undetectable p53 levels (P = 0.015). The presence of 5T4 in cancer cells was correlated with poor short-term prognosis (24% vs 49% of 2 year survival for 5T4 positive and negative tumours respectively, P = 0.024). The effect on survival was evident in the p53 negative group, with patients 5T4 positive showing worse survival (28% vs 60% in 2 years). CONCLUSIONS: Our results suggest that the assessment of 5T4 expression in gastric carcinoma can be helpful in identifying patients with poor short-term prognosis.
    • 5T4 oncofetal antigen is expressed in high risk of relapse childhood pre-B acute lymphoblastic leukemia and is associated with a more invasive and chemotactic phenotype.

      Castro, Fernanda V; McGinn, Owen J; Krishnan, S; Marinov, Georgi; Li, J; Rutkowski, A J; Elkord, Eyad; Burt, Deborah J; Holland, M; Vaghjiani, R; et al. (2012-01-23)
      Although the overall prognosis in childhood acute lymphoblastic leukemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterized by the occurrence of disease at extramedullary sites, such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival advantage and give rise to disease recurrence. Gene expression profiling of 85 diagnostic pre-B-ALL bone marrow samples revealed higher 5T4 oncofetal antigen transcript levels in cytogenetic high-risk subgroups of patients (P<0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P=0.005). The high-risk Sup-B15 pre-B-ALL line showed heterogeneity in 5T4 expression, and the derived, 5T4(+) (Sup5T4) and 5T4(-) (Sup) subline cells, displayed differential spread to the omentum and ovaries following intraperitoneal inoculation of immunocompromised mice. Consistent with this, Sup5T4 compared with Sup cells show increased invasion in vitro concordant with increased LFA-1 and VLA-4 integrin expression, adhesion to extracellular matrix and secretion of matrix metalloproteases (MMP-2/-9). We also show that 5T4-positive Sup-B15 cells are susceptible to 5T4-specific superantigen antibody-dependent cellular toxicity providing support for targeted immunotherapy in high-risk pre-B-ALL.Leukemia advance online publication, 17 February 2012; doi:10.1038/leu.2012.18.
    • The 5T4 oncofoetal antigen is an early differentiation marker of mouse ES cells and its absence is a useful means to assess pluripotency.

      Ward, Christopher M; Barrow, Katie M; Woods, Andrew M; Stern, Peter L; Immunology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. cward@picr.man.ac.uk (2003-11-15)
      5T4 oncotrophoblast antigen is a transmembrane glycoprotein expressed by trophoblast and many carcinomas but not most normal adult tissues. Results from overexpression of human and mouse 5T4 cDNA in cell lines are consistent with it having an influence on adhesion, shape and motility. We show that murine embryonic stem cell lines are 5T4 negative but that there is rapid up regulation of protein and transcripts upon differentiation, including derivatives of each primary germ layer, as evidenced by cell surface FACS, western and RT-PCR analyses. The kinetics of differentiation and 5T4 expression are closely correlated, with early events linking 5T4 expression to changes in motility and morphology. Comparison of 5T4 expression with other ES cell transcript (Oct 3/4; Rex-1) and antigen markers (Forsmann, SSEA-1) establishes 5T4 as a useful marker for the non-destructive detection of early differentiation of ES cells. For example, 'undifferentiated' ES phenotype defined as SSEA-1 positive and 5T4 negative is seven times more efficient at chimera formation than SSEA-1-positive/5T4-positive cells. Thus, 5T4 glycoprotein expression is associated with early differentiative events of ES cells involving altered motility, and it has useful practical consequences for assessing ES potency and studying similar processes in development and metastasis.
    • 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer.

      Stern, Peter L; Harrop, R; Institute of Cancer Studies, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX (2016-10-18)
      The natural history of a patient's cancer is often characterised by genetic diversity and sequential sweeps of clonal dominance. It is therefore not surprising that identifying the most appropriate tumour-associated antigen for targeted intervention is challenging. The 5T4 oncofoetal antigen was identified by searching for surface molecules shared between 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. The 5T4 protein is expressed by many different cancers but rarely in normal adult tissues. 5T4 molecules are 72 kD, heavily N-glycosylated proteins with several leucine-rich repeats which are often associated with protein-protein interactions. 5T4 expression is associated with the directional movement of cells through epithelial mesenchymal transition, potentiation of CXCL12/CXCR4 chemotaxis and inhibition of canonical Wnt/beta-catenin while favouring non-canonical pathway signalling; all processes which help drive the spread of cancer cells. The selective pattern of 5T4 tumour expression, association with a tumour-initiating phenotype plus a mechanistic involvement with cancer spread have underwritten the clinical development of different immunotherapeutic strategies including a vaccine, a tumour-targeted superantigen and an antibody drug conjugate. In addition, a chimeric antigen receptor T cell approach targeting 5T4 expressing tumour cells is in pre-clinical development. A key challenge will include how best to combine each 5T4 targeted immunotherapy with the most appropriate standard of care treatment (or adjunct therapy) to maximise the recovery of immune control and ultimately eliminate the tumour.