• Cancer experience in the relatives of an unselected series of breast cancer patients.

      Teare, M Dawn; Wallace, S A; Harris, Martin; Howell, Anthony; Birch, Jillian M; Cancer Research Campaign Paediatric and Familial Cancer Research Group, Christie Hospital NHS Trust, Manchester, UK. (1994-07)
      First- and second-degree relatives of an unselected series of 402 breast cancer patients have been studied for their cancer experience. In the first-degree relatives an excess of all cancers is seen [overall relative risk (RR) = 1.28, P = 0.002; males RR = 1.26, P = 0.047; females RR = 1.30, P = 0.022). There is a marked excess of sarcoma (RR = 4.26, P = 0.0064); females are at high risk of breast cancer (RR = 2.68, P < 0.0001) and males have an excess of carcinoma of the lip, oral cavity and pharynx (RR = 4.22, P = 0.0032). Second-degree relatives have a non-significant excess of all cancers (RR = 1.14, P = 0.14); females have a borderline excess of breast cancer (RR = 1.53, P = 0.08) and an excess of carcinoma of the kidney (RR = 7.46, P = 0.0012) and males have an excess of carcinoma of the trachea and lung (RR = 1.50, P = 0.032). No excess of prostate or ovarian carcinoma was seen. Relatives are at slightly higher risk if the index patient is diagnosed between the ages of 40 and 49 (first-degree RR = 1.64, P = 0.007; second-degree RR = 1.43, P = 0.02). The excess of cancers, including breast cancers, is not limited to a few high-risk families, but appears to be spread across many. These observations may be accounted for by shared environmental factors within families or a common predisposing gene with low penetrance.
    • Cancer metabolism: a therapeutic perspective.

      Martinez-Outschoorn, U; Peiris-Pagès, Maria; Pestell, R; Sotgia, Federica; Lisanti, Michael P; The Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA (2016-05-04)
      Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.
    • "Cancer moonshot connecting international liquid biopsy efforts through academic partnership".

      Dive, Caroline; Shishido, S; Kuhn, P (2017-02-09)
      The Kuhn laboratory at the University of Southern California and the Dive laboratory at the Cancer Research UK's Manchester Institute are teaming up to apply new cancer cell detection technology to identify patients that will progress after initial treatment. Researchers will take a simple blood sample to identify early those patients whose cancer has returned, while analyzing CTCs in great detail, providing new clues on the most effective therapy for the patient's cancer. This article is protected by copyright. All rights reserved.
    • Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

      Birch, Jillian M; Blair, Val; Kelsey, Anna M; Evans, D Gareth R; Harris, Martin; Tricker, K J; Varley, Jennifer; CRC Paediatric and Familial Cancer Research Group and Department of Histopathology, Royal Manchester Children's Hospital, UK. (1998-09-03)
      The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.
    • Cancer stem cell metabolism.

      Peiris-Pagès, Maria; Martinez-Outschoorn, U; Pestell, R; Sotgia, F; Lisanti, Michael P; The Breast Cancer Now Research Unit, Institute of Cancer Sciences, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester (2016)
      Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets.
    • Cancer stem cell mobilization and therapeutic targeting of the 5T4 oncofetal antigen.

      Harrop, R; O'Neill, E; Stern, Peter L; Oxford BioMedica plc, Windrush Court, Transport Way, Oxford, OX4 6LT, UK (2019)
      Cancer stem cells (CSCs) can act as the cellular drivers of tumors harnessing stem cell properties that contribute to tumorigenesis either as founder elements or by the gain of stem cell traits by the malignant cells. Thus, CSCs can self-renew and generate the cellular heterogeneity of tumors including a hierarchical organization similar to the normal tissue. While the principle tumor growth contribution is often from the non-CSC components, it is the ability of small numbers of CSCs to avoid the effects of therapeutic strategies that can contribute to recurrence after treatment. However, identifying and characterizing CSCs for therapeutic targeting is made more challenging by their cellular potency being influenced by a particular tissue niche or by the capacity of more committed cells to regain stem cell functions. This review discusses the properties of CSCs including the limitations of the available cell surface markers, the assays that document tumor initiation and clonogenicity, the roles of epithelial mesenchymal transition and molecular pathways such as Notch, Wnt, Hippo and Hedgehog. The ability to target and eliminate CSCs is thought to be critical in the search for curative cancer treatments. The oncofetal tumor-associated antigen 5T4 (TBGP) has been linked with CSC properties in several different malignancies. 5T4 has functional attributes that are relevant to the spread of tumors including through EMT, CXCR4/CXCL12, Wnt, and Hippo pathways which may all contribute through the mobilization of CSCs. There are several different immunotherapies targeting 5T4 in development including antibody-drug conjugates, antibody-targeted bacterial super-antigens, a Modified Vaccinia Ankara-basedvaccine and 5T4-directed chimeric antigen receptor T-cells. These immune therapies would have the advantage of targeting both the bulk tumor as well as mobilized CSC populations.
    • Cancer stem cells (CSCs): metabolic strategies for their identification and eradication.

      De Francesco, Ernestina M; Sotgia, F; Lisanti, M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy (2018-05-09)
      Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full repertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. As such, targeting CSCs may be a useful strategy to improve the effectiveness of classical anticancer therapies. Recently, metabolism has been considered as a relevant player in CSC biology, and indeed, oncogenic alterations trigger the metabolite-driven dissemination of CSCs. More interestingly, the action of metabolic pathways in CSC maintenance might not be merely a consequence of genomic alterations. Indeed, certain metabotypic phenotypes may play a causative role in maintaining the stem traits, acting as an orchestrator of stemness. Here, we review the current studies on the metabolic features of CSCs, focusing on the biochemical energy pathways involved in CSC maintenance and propagation. We provide a detailed overview of the plastic metabolic behavior of CSCs in response to microenvironment changes, genetic aberrations, and pharmacological stressors. In addition, we describe the potential of comprehensive metabolic approaches to identify and selectively eradicate CSCs, together with the possibility to 'force' CSCs within certain metabolic dependences, in order to effectively target such metabolic biochemical inflexibilities. Finally, we focus on targeting mitochondria to halt CSC dissemination and effectively eradicate cancer.
    • Cancer vaccines and immunotherapy.

      Dermime, Said; Armstrong, Anne C; Hawkins, Robert E; Stern, Peter L; CRC Department of Medical Oncology, University of Manchester and Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (2002)
      It is now clear that many human tumour antigens can be recognised by the immune system. These tumour antigens can be classified into several groups including cancer-testis, differentiation, tissue specific, over-expressed, and viral-associated antigens. In many cases, there is a known molecular basis of carcinogenesis which provides the explanation for the differentiated expression of these antigens in tumours compared with normal cells. Improved understanding of the biology of the immune response, particularly of immune recognition and activation of T-cells, allow better design of vaccines. Pre-clinical comparative studies allow evaluation of optimal vaccine strategies which can then be delivered to the clinic. Currently, a range of cancer vaccines are being tested including those using tumour cells, proteins, peptides, viral vectors, DNA or dendritic cells. Ultimately, this research should give rise to an entirely new modality of cancer treatments.
    • Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase.

      Brognard, John; Zhang, Y-W; Puto, L A; Hunter, T; Signalling Networks in Cancer Group, Cancer Research UK, Paterson Institute for Cancer Research, The University of Manchester, Manchester, United Kingdom. (2011-04-15)
      Cancer kinome sequencing studies have identified several protein kinases predicted to possess driver (i.e., causal) mutations. Using bioinformatic applications, we have pinpointed DAPK3 (ZIPK) as a novel cancer-associated kinase with functional mutations. Evaluation of nonsynonymous point mutations, discovered in DAPK3 in various tumors (T112M, D161N, and P216S), reveals that all three mutations decrease or abolish kinase activity. Furthermore, phenotypic assays indicate that the three mutations observed in cancer abrogate the function of the kinase to regulate both the cell cycle and cell survival. Coexpression of wild-type (WT) and cancer mutant kinases shows that the cancer mutants dominantly inhibit the function of the WT kinase. Reconstitution of a non-small cell lung cancer cell line that harbors an endogenous mutation in DAPK3 (P216S) with WT DAPK3 resulted in decreased cellular aggregation and increased sensitivity to chemotherapy. Our results suggest that DAPK3 is a tumor suppressor in which loss-of-function mutations promote increased cell survival, proliferation, cellular aggregation, and increased resistance to chemotherapy.
    • A cancer-associated, genome protective programme engaging PKC?

      Parker, P. J.; Lockwood, N.; Davis, K.; Kelly, Joanna R; Soliman, T. N.; Pardo, A. L.; Marshall, J. J. T.; Redmond, J. M.; Vitale, M.; Silvia, M.; et al. (2020)
      Associated with their roles as targets for tumour promoters, there has been a long-standing interest in how members of the protein kinase C (PKC) family act to modulate cell growth and division. This has generated a great deal of observational data, but has for the most part not afforded clear mechanistic insights into the control mechanisms at play. Here, we review the roles of PKC? in protecting transformed cells from non-disjunction. In this particular cell cycle context, there is a growing understanding of the pathways involved, affording biomarker and interventional insights and opportunities.
    • Cancers in Australia attributable to exposure to solar ultraviolet radiation and prevented by regular sunscreen use.

      Olsen, C; Wilson, L; Green, Adèle C; Bain, C; Fritschi, L; Neale, R; Whiteman, D; QIMR Berghofer Medical Research Institute, Queensland (2015-10)
      To estimate the proportion and numbers of cancers occurring in Australia attributable to solar ultraviolet radiation (UVR) and the proportion and numbers prevented by regular sun protection factor (SPF) 15+ sunscreen use.
    • Cancers in Australia in 2010 attributable to and prevented by the use of combined oral contraceptives.

      Jordan, S; Wilson, L; Nagle, C; Green, Adèle C; Olsen, C; Bain, C; Pandeya, N; Whiteman, D; Webb, P; QIMR Berghofer Medical Research Institute, Queensland (2015-10)
      To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to combined oral contraceptive pill (OCP) use.
    • Cancers in Australia in 2010 attributable to and prevented by the use of menopausal hormone therapy.

      Jordan, S; Wilson, L; Nagle, C; Green, Adèle C; Olsen, C; Bain, C; Pandeya, N; Whiteman, D; Webb, P; QIMR Berghofer Medical Research Institute, Queensland (2015-10)
      To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to menopausal hormone therapy (MHT) use.
    • Cancers in Australia in 2010 attributable to modifiable factors: introduction and overview.

      Whiteman, D; Webb, P; Green, Adèle C; Neale, R; Fritschi, L; Bain, C; Parkin, D; Wilson, L; Olsen, C; Nagle, C; et al. (2015-10)
      To describe the approach underpinning a national project to estimate the numbers and proportions of cancers occurring in Australia in 2010 that are attributable to modifiable causal factors.
    • Cancers in Australia in 2010 attributable to modifiable factors: summary and conclusions.

      Whiteman, D; Webb, P; Green, Adèle C; Neale, R; Fritschi, L; Bain, C; Parkin, D; Wilson, L; Olsen, C; Nagle, C; et al. (2015-10)
      To estimate the numbers and proportions of cancers occurring in Australia in 2010 attributable to modifiable causal factors.
    • Cancers in Australia in 2010 attributable to total breastfeeding durations of 12 months or less by parous women.

      Jordan, S; Wilson, L; Nagle, C; Green, Adèle C; Olsen, C; Bain, C; Pandeya, N; Whiteman, D; Webb, P; QIMR Berghofer Medical Research Institute, Queensland (2015-10)
      To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to parous women having breastfed for total durations of ≤12 months.
    • Cancers prevented in Australia in 2010 through the consumption of aspirin.

      Wilson, L; Green, Adèle C; Kendall, B; Jordan, S; Nagle, C; Bain, C; Neale, R; Whiteman, D; QIMR Berghofer Medical Research Institute, Queensland (2015-10)
      To estimate the proportion and number of cancers in Australia in 2010 that may have been prevented from occurring due to daily use of aspirin in the population.
    • Candidaemia and cancer: patients are not all the same.

      Pasqualotto, Alessandro C; Rosa, Daniela D; Medeiros, Lidia Rosi; Severo, Luiz Carlos; Medical School, The University of Manchester, UK. alessandro.pasqualotto@manchester.ac.uk (2006)
      BACKGROUND: Most of the studies about invasive Candida infections in cancer patients have focused on haematological patients. The aim of this study was to provide information about risk factors for candidaemia in patients with solid tumours. METHODS: Retrospective cohort study. During a 9-year period (1995-2003) we reviewed all cases of candidaemia that affected cancer patients in Santa Casa Complexo Hospitalar, Brazil. RESULTS: During the period of study, 210 patients had the diagnosis of candidaemia in our medical centre, and 83 of these patients had cancer (39.5%). The majority of patients with cancer had solid tumours (77.1%), mostly in the alimentary tract. Most of solid cancers were non-metastatic (71.9%). Major diagnoses in patients with haematological neoplasia were acute leukaemia (n = 13), high grade non-Hodgkin lymphoma (n = 5) and Hodgkin's disease (n = 1). Non-Candida albicans species caused 57.8% of the episodes of candidaemia in patients with cancer, mainly in patients with haematological malignancies (p = 0.034). Neutropenia and treatment with corticosteroids were more frequent in the haematological group, in comparison with patients with solid tumours. Only 22.2% of patients with solid tumours were neutropenic before candidaemia. Nonetheless, the presence of ileus and the use of anaerobicides were independent risk factors for candidaemia in patients with solid cancers. The overall mortality in cancer patients with candidaemia was 49.4%. We then compared 2 groups of adult patients with candidaemia. The first was composed of non-neutropenic patients with solid tumours, and the second group included patients without cancer. We found that central venous catheters and gastrointestinal surgery were independently associated with candidaemia in patients with solid tumour. CONCLUSION: Cancer patients with candidaemia seem to have very different predisposing factors to acquire the infection when stratified according to baseline diseases. This study provides some useful clinical information regarding risk for candidaemia in patients with solid tumours.
    • Candidate plasma biomarkers for predicting ascending aortic aneurysm in bicuspid aortic valve disease.

      Harrison, O; Cagampang, F; Ohri, S; Torrens, C; Salhiyyah, K; Modi, A; Moorjani, N; Whetton, Anthony D; Townsend, Paul A; Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. (2018-06-22)
      Bicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality affecting 1-2% of the population and is associated with a significantly increased risk of ascending aortic aneurysm. However, predicting which patients will develop aneurysms remains a challenge. This pilot study aimed to identify candidate plasma biomarkers for monitoring ascending aortic diameter and predicting risk of future aneurysm in BAV patients.
    • The capacity of peripheral blood stem cells mobilised with chemotherapy plus G-CSF to repopulate irradiated marrow stroma in vitro is similar to that of bone marrow.

      Demuynck, Hilde; Pettengell, Ruth; De Campos, Edson; Dexter, T Michael; Testa, Nydia G; CRC Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, U.K. (1992)
      After treatment of patients with intermediate or high grade non-Hodgkin lymphoma with chemotherapy plus G-CSF the numbers of haemopoietic progenitor cells in the circulation increased to a mean of 226-fold for mixed CFC (Mix-CFC), 278-fold for GM-CFC and 29-fold for erythroid burst forming unit (BFU-E). The mean increase was modest (7-12-fold) for patients treated with chemotherapy alone. Peripheral blood mononuclear cells harvested at the time of the peak in the numbers of progenitors, or 2-4 days before the peak, seeded onto irradiated marrow stroma in vitro, repopulated the stroma and generated active haemopoiesis at least as effectively as bone marrow cells on a cell per cell basis. This is in contrast to the poor repopulating capacity of pretreatment blood. The results indicate that not only the progenitor cells, but also the repopulating stem cells migrated into the blood after chemotherapy plus G-CSF in sufficient numbers to allow harvesting and successful grafting without the possible complication of late haemopoietic failure.