• CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

      Zhuang, X.; Maione, F.; Robinson, J.; Bentley, M.; Kaul, B.; Whitworth, K.; Jumbu, N.; Jinks, E.; Bystrom, J.; Gabriele, P.; et al. (2020)
      Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-?, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer.
    • CAR T-cell therapy: toxicity and the relevance of preclinical models.

      Kalaitsidou, Milena; Kueberuwa, Gray; Schütt, Antje; Gilham, David E; "Clinical & Experimental Immunotherapy Group, Institute of Cancer Sciences, Academic Healthcare Science Centre, University of Manchester, Manchester Paterson Building, Wilmslow Road, Withington, Manchester, M20 4BX, UK. (2015-06)
      Chimeric antigen receptor (CAR) T cells form part of a broad wave of immunotherapies that are showing promise in early phase cancer clinical trials. This clinical delivery has been based upon preclinical efficacy testing that confirmed the proof of principle of the therapy. However, CAR T-cell therapy does not exist alone as T cells are generally given in combination with patient preconditioning, most commonly in the form of chemotherapy, and may also include systemic cytokine support, both of which are associated with toxicity. Consequently, complete CAR T-cell therapy includes elements where the toxicity profile is well known, but also includes the CAR T cell itself, for which toxicity profiles are largely unknown. With recent reports of adverse events associated with CAR T-cell therapy, there is now concern that current preclinical models may not be fit for purpose with respect to CAR T-cell toxicity profiling. Here, we explore the preclinical models used to validate CAR T-cell function and examine their potential to predict CAR T-cell driven toxicities for the future.
    • CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe.

      Gilham, David E; Debets, R; Pule, M; Hawkins, Robert E; Abken, Hinrich; Clinical and Experimental Immunotherapy Group, School of Cancer and Enabling Sciences, The University of Manchester, Withington, Manchester M20 4BX, UK. dgilham@picr.man.ac.uk (2012-07)
      Recent reports on the impressive efficacy of adoptively transferred T cells to challenge cancer in early phase clinical trials have significantly raised the profile of T cell therapy. Concomitantly, general expectations are also raised by these reports, with the natural aspiration to deliver this therapy over a wide range of tumor indications. Chimeric antigen receptors (CARs) endow T cell populations with defined antigen specificities that function independently of the natural T cell receptor and permit targeting of T cells towards virtually any tumor. Here, we review the current clinical application of CAR-T cells and relate clinical efficacy and safety of CAR-T cell trials to parameters considered critical for CAR engineering, classified as the three T's of CAR-T cell manipulation.
    • Carbohydrate-binding properties of lectins: a possible approach to lectin nomenclature and classification. Review.

      Gallagher, John T; University Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Wilmslow Road, Withington, Manchester M20 9BX, UK (1984-08)
    • Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix.

      Loncaster, Juliette A; Harris, Adrian L; Davidson, Susan E; Logue, John P; Hunter, Robin D; Wycoff, C C; Pastorek, J; Ratcliffe, P J; Stratford, Ian J; West, Catharine M L; et al. (2001-09-01)
      There is increasing evidence that hypoxia-regulated gene expression influences tumor aggressiveness, contributing to the poorer outcome of patients with hypoxic tumors. The role of the transcriptional complex hypoxia-inducible factor-1 as an important mediator of hypoxia-regulated gene expression is one of the best documented pathways. Recently, it has emerged that certain tumor-associated carbonic anhydrases (CAs) can be added to the list of known hypoxia-inducible factor-responsive genes. Here we show that the immunohistochemical expression of the tumor-associated CA IX is correlated with the level of hypoxia in human cervical tumors. We performed a prospective study in 68 patients where needle electrodes were used to make direct measurements of tumor oxygenation levels. CA IX expression was evaluated immunohistochemically in pretreatment tumor biopsies. There was a significant positive correlation between the level of tumor hypoxia (HP5) and the extent of CA IX expression. A retrospective study of 130 squamous cell cervical carcinomas demonstrated that a semiquantitative immunohistochemical analysis of CA IX expression in tumor biopsies is a significant and independent prognostic indicator of overall survival and metastasis-free survival after radiation therapy. These studies provide clinical evidence that CA IX expression is up-regulated in hypoxic human cervical tumors and is associated with a poor prognosis. CA IX may act as an intrinsic marker of tumor hypoxia and poor outcome after radiation therapy. The level of CA IX expression may be used to aid in the selection of patients who would benefit most from hypoxia-modification therapies or bio-reductive drugs.
    • Carcinogenicity of single doses of N-nitroso-N-methylurea and N-nitroso-N-ethylurea in Syrian golden hamsters and the persistence of alkylated purines in the DNA of various tissues.

      Likhachev, A J; Ivanov, M N; Brésil, H; Planche-Martel, G; Montesano, R; Margison, Geoffrey P; IARC, 69372 Lyon Cedex 08, France (1983-02)
      The carcinogenicity of N-nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU) has been determined in adult male Syrian golden hamsters following a single i.p. injection or two-thirds of the acute 50% lethal dose, or 30 and 60 mg/kg, respectively. The principal site of action of these agents was the forestomach, squamous cell papillomas of this organ developing in 53 and 61% of the animals receiving the higher doses of NMU and N-nitroso-N-ethylurea, respectively. NMU also induced a low incidence of liver tumors (17%). Very few tumors were seen at other sites. The formation and removal of alkylated purines in DNA was measured in various tissues up to 50 hr after administration of [14C]NMU. Methylation products were detected in all tissues examined, the level in liver being somewhat higher than in other tissues. The removal of 7-methylguanine and 3-methyladenine from DNA occurred at approximately similar rates in all tissues examined, indicating no substantial differences in N-glycosylase activities. Removal of the promutagenic DNA lesion O6-methylguanine varied considerably from tissue to tissue; very little occurred in brain or kidney, while up to 36 and 32% were lost from DNA of intestine and testes, respectively. In the liver, there were relatively small changes in O6-methylguanine levels up to 24 hr; but by 50 hr, 38% had been removed. The persistence of O6-methylguanine relative to 7-methylguanine was highest in the DNA of the brain and intestine and lowest in that of the liver. These results indicate that in this experimental system, the formation and persistence of O6-methylguanine in DNA is insufficient alone to account for the organotropic effect of NMU.
    • Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression.

      Shimoda, Masayuki; Mellody, Kieran T; Orimo, Akira; Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (2010-02)
      Tumours are highly complex tissues composed of carcinoma cells and surrounding stroma, which is constructed by various different types of mesenchymal cells and an extracellular matrix (ECM). Carcinoma-associated fibroblasts (CAFs), which consist of both fibroblasts and myofibroblasts, are frequently observed in the stroma of human carcinomas, and their presence in large numbers is often associated with the development of high-grade malignancies and poor prognoses. Moreover, in human tumour xenograft models, CAFs extracted from the tumour are more capable of promoting tumour growth through their interactions with carcinoma cells when compared to those isolated from non-cancerous stroma. Taken together, these observations strongly suggest that CAFs actively contribute to tumour progression. In this review we highlight the emerging roles of these cells in promoting tumourigenesis, and we discuss the molecular mechanisms underlying their tumour-promoting capabilities and their cellular origin.
    • Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells.

      Polanska, Urszula M; Orimo, Akira; CR-UK Stromal-Tumour Interaction Group, Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2013-03-04)
      Cancerous stroma coevolves alongside tumour progression, thereby promoting the malignant conversion of epithelial carcinoma cells. To date, an abundance of data have supported crucial roles of the tumour microenvironment (TME) in providing cancer cells with proliferative, migratory, survival and invasive propensities favouring the processes of tumourigenesis. The cancerous reactive stroma is frequently populated by a large number of myofibroblasts (MFs), which are activated, non-transformed fibroblasts expressing α-smooth muscle actin (α-SMA). MFs together with non-MF cells present in the tumour-associated stroma are collectively referred to as carcinoma-associated fibroblasts (CAFs), one of the major stromal cell types recognised in various human carcinomas. Recruitment of fibroblasts and/or their progenitors to a tumour mass and their subsequent transdifferentiation into MFs, as well as ongoing maintenance of their activated state, are believed to be essential processes facilitating tumour progression. However, the complex networks of signalling pathways mediating the phenotypic conversion into CAFs, as well as those underlying their tumour-promoting interactions with other tumour-constituting cells, have yet to be fully explored. Histopathological confirmation of the presence of large numbers of CAF MFs within TME and their altered gene expression profiles are known to be associated with disease progression and to serve as independent negative prognostic factors for a wide range of tumour types. In this review, we examine the current evidence shedding light on the emerging roles of tumour-promoting CAFs, cells that are pivotal for epithelial cancer development and progression, and discuss the therapeutic potential of targeting these cells. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    • Carcinomatous meningitis in patients with breast cancer. An aggressive disease variant.

      Jayson, Gordon C; Howell, Anthony; Harris, Martin; Morgenstern, Godfrey R; Chang, James; Ryder, W David J; Department of Medical Oncology, Christie Hospital National Health Service Trust, Withington, Manchester, United Kingdom. (1994-12-15)
      BACKGROUND: Carcinomatous meningitis is a rare and often devastating complication in patients with breast cancer, and the treatment is controversial. METHODS: A retrospective analysis of 35 patients with carcinomatous meningitis from breast cancer was performed to define the biology of the disease and to guide treatment. RESULTS: An aggressive variant of breast cancer was revealed: meningeal metastasis complicates less than 3.5% of cases of metastatic breast carcinoma. Sixty-seven percent of these patients had tumors that were lobular or combined lobular/ductal histology; the median intervals from primary treatment to disease recurrence and from recurrence to death were 10.9 and 15 months, respectively. The median survival after diagnosis of carcinomatous meningitis was 77 days. The most significant prognostic factor was the Karnofsky performance status (KP) at presentation of meningeal disease. Patients with a KP greater or equal to 70 survived a median of 313 days, whereas those with a KP of 60 or less survived for a median of 36 days (P = 0.0002). In addition, there was a trend suggesting that the response 2 weeks after treatment was initiated, correlated with survival. CONCLUSIONS: Carcinomatous meningitis from breast carcinoma is an aggressive metastatic complication with a poor prognosis. The authors suggest that patients with a poor KP (< 70) should be treated symptomatically and those with a good KP (> or = 70) should receive more aggressive treatment. The patients' survival in this study compared well with other reports, and yet, only one patient was treated with intraventricular chemotherapy. Therefore, these data question the superiority of intraventricular treatment versus other modalities.
    • Carcinosarcoma of the ovary treated over a 10-year period at the Christie Hospital.

      Prendiville, Joseph A; Murphy, D; Renninson, J; Buckley, H; Crowther, Derek; CRC Department of Medical Oncology, Christie Hospital & Holt Radium Institute, Wilmslow Road,Department of Reproductive Pathology, St Mary's Hospital, Oxford Road, Manchester, UK. (1994-05)
      Carcinosarcomas (previously termed malignant mixed Müllerian tumors) are highly malignant but rare tumors of the ovary. Most patients have been treated according to a wide variety of protocols for soft tissue sarcoma or for epithelial ovarian carcinoma and as a result the optimal treatment for this neoplasm is unknown. We describe here 20 patients with this ovarian tumor (15 with heterologous sarcomatous elements and five with homologous sarcomatous elements) referred to our institute. Five patients were treated with surgery alone, two patients with chemotherapy alone and 13 patients with a combination of surgery and chemotherapy. A variety of chemotherapeutic regimens were used reflecting the 10-year time span it took to accrue these patients. Forty-five per cent of all patients died within 1 year of initial surgery and there was a median survival of 14 months. Two patients achieved a complete remission following treatment with 10 cycles of intravenous cyclophosphamide and are still alive at 103 and 106 months follow-up. We suggest that a chemotherapy regimen combining cyclophosphamide and a platinum analog may be useful for the management of patients with carcinosarcoma of the ovary requiring further therapy following surgery.
    • Cardiac disease in childhood cancer survivors treated with radiotherapy: final results from the PENTEC group

      Bates, JE; Keshavarz, H; Rancati, T; Gagliardi, G; Aznar, Marianne Camille; Moiseenko, V; Yorke, ED; Armenian, S; Kremer, L; Chen, MH; et al. (2019)
    • Carotene-oxygen radical interactions.

      Conn, P F; Lambert, C; Land, Edward J; Schalch, W; Truscott, T G; Department of Chemistry, Keele University, Staffs, UK. (1992)
      All-trans beta-carotene radical anion efficiently transfers an electron to oxygen but the reverse reaction is not observed and, instead we suggest the formation of a beta-carotene-superoxide radical addition complex. On the other hand, all-trans lycopene undergoes a reversible electron transfer with the superoxide radical. This distinctive behaviour may be related to the anti-cancer properties of these molecules.
    • Carotenoid Radical - Melanin Interactions

      Edge, Ruth; Land, Edward J; Rozanowska, Malgorzata; Sarna, Tadeusz; Truscott, T G; School of Chemistry and Physics, Keel University, Staffordshire, ST5 5BG, UK (2000)
    • Carotenoid triplet state lifetimes

      Burke, Marc; Land, Edward J; McGarvey, David J; Truscott, T G; School of Chemistry and Physics, Lennard-Jones Laboratories, Keel University, Keele, Staffs, ST5 5BG, UK (2000)
    • Carotenoids Enhance Vitamin E Antioxidant Efficiency.

      Böhm, F; Edge, R; Land, Edward J; McGarvey, D J; Truscott, T G; Department of Dermatology (Charité) Humboldt University, 10117 Berlin, Germany Department of Chemistry Keele University, ST5 5BG, UK (1997)
    • Case of extra pulmonary, pleuro-pulmonary blastoma in a child: pathological and cytogenetic findings.

      Kelsey, Anna M; McNally, K; Birch, Jillian M; Mitchell, Erika L D; Department of Pathology, Manchester Children's Hospitals, Pendlebury, United Kingdom. (1997-07)
      We report the cytogenetic findings in a case of Pleuro-Pulmonary Blastoma of Childhood Type II. This is a rare intrathoracic tumour that can occur in the lungs with up to 25% of cases being extra pulmonary.
    • A casein kinase 1 and PAR proteins regulate asymmetry of a PIP(2) synthesis enzyme for asymmetric spindle positioning.

      Panbianco, Costanza; Weinkove, David; Zanin, Esther; Jones, David R; Divecha, Nullin; Gotta, Monica; Ahringer, Julie; The Gurdon Institute and Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB21QN, UK. (2008-08)
      Spindle positioning is an essential feature of asymmetric cell division. The conserved PAR proteins together with heterotrimeric G proteins control spindle positioning in animal cells, but how these are linked is not known. In C. elegans, PAR protein activity leads to asymmetric spindle placement through cortical asymmetry of Galpha regulators GPR-1/2. Here, we establish that the casein kinase 1 gamma CSNK-1 and a PIP(2) synthesis enzyme (PPK-1) transduce PAR polarity to asymmetric Galpha regulation. PPK-1 is posteriorly enriched in the one-celled embryo through PAR and CSNK-1 activities. Loss of CSNK-1 causes uniformly high PPK-1 levels, high symmetric cortical levels of GPR-1/2 and LIN-5, and increased spindle pulling forces. In contrast, knockdown of ppk-1 leads to low GPR-1/2 levels and decreased spindle forces. Furthermore, loss of CSNK-1 leads to increased levels of PIP(2). We propose that asymmetric generation of PIP(2) by PPK-1 directs the posterior enrichment of GPR-1/2 and LIN-5, leading to posterior spindle displacement.
    • Caspase activation during spontaneous and radiation-induced apoptosis in the murine intestine.

      Marshman, Emma; Ottewell, Penny; Potten, Christopher S; Watson, Alastair; Department of Medicine, University of Liverpool, UCD Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. (2001-10)
      The aim of this study was to characterize the activation of caspase-3 along the crypt/villus axis in the normal and irradiated intestine and to compare active caspase-3 expression with existing apoptosis detection techniques. Small and large intestine were removed from mice at various time points after exposure to 8 Gy gamma-radiation. Positive apoptotic cells stained with an antibody against active caspase-3, haematoxylin and eosin (H&E) or TUNEL were scored in histological sections of small and large intestinal crypts and villi. In the control intestine, active caspase-3 expression was rarely observed; however, expression was markedly increased following exposure to radiation and was predominantly confined to apoptotic bodies. Measurement of apoptosis in intestinal crypts using active caspase-3 expression gave similar results to apoptosis detected from H&E-stained sections. In the normal villus, active caspase-3 expression was observed infrequently and did not significantly increase following radiation, consistent with a lack of apoptotic body formation from H&E sections. This study indicates that caspase-3 is activated in intestinal crypts but not in villi following gamma-radiation. Active caspase-3 detection compared favourably with existing immunological techniques, suggesting that it is a suitable alternative method for apoptosis quantification.
    • A caspase-3 'death-switch' in colorectal cancer cells for induced and synchronous tumor apoptosis in vitro and in vivo facilitates the development of minimally invasive cell death biomarkers.

      Simpson, Kathryn L; Cawthorne, C; Zhou, Cong; Hodgkinson, Cassandra L; Walker, Michael J; Trapani, F; Kadirvel, M; Brown, G; Dawson, M J; Macfarlane, M; et al. (2013)
      Novel anticancer drugs targeting key apoptosis regulators have been developed and are undergoing clinical trials. Pharmacodynamic biomarkers to define the optimum dose of drug that provokes tumor apoptosis are in demand; acquisition of longitudinal tumor biopsies is a significant challenge and minimally invasive biomarkers are required. Considering this, we have developed and validated a preclinical 'death-switch' model for the discovery of secreted biomarkers of tumour apoptosis using in vitro proteomics and in vivo evaluation of the novel imaging probe [(18)F]ML-10 for non-invasive detection of apoptosis using positron emission tomography (PET). The 'death-switch' is a constitutively active mutant caspase-3 that is robustly induced by doxycycline to drive synchronous apoptosis in human colorectal cancer cells in vitro or grown as tumor xenografts. Death-switch induction caused caspase-dependent apoptosis between 3 and 24 hours in vitro and regression of 'death-switched' xenografts occurred within 24 h correlating with the percentage of apoptotic cells in tumor and levels of an established cell death biomarker (cleaved cytokeratin-18) in the blood. We sought to define secreted biomarkers of tumor apoptosis from cultured cells using Discovery Isobaric Tag proteomics, which may provide candidates to validate in blood. Early after caspase-3 activation, levels of normally secreted proteins were decreased (e.g. Gelsolin and Midkine) and proteins including CD44 and High Mobility Group protein B1 (HMGB1) that were released into cell culture media in vitro were also identified in the bloodstream of mice bearing death-switched tumors. We also exemplify the utility of the death-switch model for the validation of apoptotic imaging probes using [(18)F]ML-10, a PET tracer currently in clinical trials. Results showed increased tracer uptake of [(18)F]ML-10 in tumours undergoing apoptosis, compared with matched tumour controls imaged in the same animal. Overall, the death-switch model represents a robust and versatile tool for the discovery and validation of apoptosis biomarkers.
    • Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.

      Cuzick, J; Stewart, H; Rutqvist, L; Houghton, J; Edwards, R; Redmond, C; Peto, R; Baum, Michael; Fisher, B; Host, H; et al. (1994-03)
      PURPOSE: To examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial. PATIENTS AND METHODS: We studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified. RESULTS: The increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P < .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials. CONCLUSION: The reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control. Use of techniques that minimize cardiac dose is important in reducing the risks of adjuvant radiotherapy, especially in good-prognosis patients.