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Howard B.A.,The Institute of Cancer Research | Lu P.,University of Manchester
Seminars in Cell and Developmental Biology | Year: 2014

The stroma, which is composed of supporting cells and connective tissue, comprises a large component of the local microenvironment of many epithelial cell types, and influences several fundamental aspects of cell behaviour through both tissue interactions and niche regulation. The significance of the stroma in development and disease has been increasingly recognised. Whereas normal stroma is essential for various developmental processes during vertebrate organogenesis, it can be deregulated and become abnormal, which in turn can initiate or promote a disease process, including cancer. The mouse mammary gland has emerged in recent years as an excellent model system for understanding stromal function in both developmental and cancer biology. Here, we take a systematic approach and focus on the dynamic interactions that the stroma engages with the epithelium during mammary specification, cell differentiation, and branching morphogenesis of both the embryonic and postnatal development of the mammary gland. Similar stromal-epithelial interactions underlie the aetiology of breast cancer, making targeting the cancer stroma an increasingly important and promising therapeutic strategy to pursue for breast cancer treatment. © 2014 Elsevier Ltd.

Ashworth A.,The Institute of Cancer Research
Cold Spring Harbor perspectives in biology | Year: 2010

Genetic screens were for long the prerogative of those that studied model organisms. The discovery in 2001 that gene silencing through RNA interference (RNAi) can also be brought about in mammalian cells paved the way for large scale loss-of-function genetic screens in higher organisms. In this article, we describe how functional genetic studies can help us understand the biology of breast cancer, how it can be used to identify novel targets for breast cancer therapy, and how it can help in the identification of those patients that are most likely to respond to a given therapy.

Dearden C.,The Institute of Cancer Research
British Journal of Haematology | Year: 2011

The WHO classification recognises three distinct disorders of large granular lymphocytes: T-cell large granular lymphocytic leukaemia (T-LGL), chronic lymphoproliferative disorders of NK-cells (CLPD-NK) and agressive NK-cell leukaemia. Despite the different cell of origin, there is considerable overlap between T-LGL and CLPD-NK in terms of clinical presentation and therapy. Many patients are asymptomatic and do not require treatment. Therapy, with immunosuppressant agents such as low dose methotrexate or ciclosporin, is usually indicated to correct cytopenias. In contrast, aggressive NK-cell leukaemia and the rare CD56 + aggressive T-LGL leukaemia follow a fulminant clinical course, affect younger individuals and require more intensive combination chemotherapy followed by allogeneic stem cell transplant in eligible patients. The relative rarity of these disorders means that there have been few clinical trials to inform management. However, there is now considerable interest in the pathogenesis of the chronic LGL leukaemias and this has stimulated early trials to evaluate novel agents which target the dysregulated apoptotic pathways characteristic of this disease. © 2010 Blackwell Publishing Ltd.

Howard B.A.,The Institute of Cancer Research
Seminars in Cell and Developmental Biology | Year: 2012

The mammary primordium is comprised of an aggregate of immature, undifferentiated mammary epithelial cells and its associated mammary mesenchyme, a specialised tissue which harbours mammary-inductive capacity. The mammary primordium forms during embryogenesis as a result of inductive interactions between its two component tissues, the mammary mesenchyme and epithelium. These two tissues constitute a signalling centre that directs the formation of the mammary gland through a series of reciprocal mesenchymal-epithelial interactions. A rudimentary mammary ductal tree and stroma is formed prior to birth as a result of these interactions. The subsequent mammary outgrowths that arise upon hormonal stimulation during puberty originate from this rudimentary tissue. The initial appearance of the embryonic mammary primordium during embryogenesis represents the earliest morphological evidence of commitment to the mammary lineage. Classic tissue recombination studies of mouse mammary primordial cells have demonstrated that the epithelial cells are already functionally determined as mammary at the embryonic mammary bud stage. Recent studies have determined the molecular identity of the embryonic mammary cells by transcriptomic profiling and these have provided new insights into signalling components that mediate early embryonic mammary inductive signalling and lineage commitment. This review highlights what is currently known about the morphogenesis, function, and behaviour of embryonic mammary cells and examine current knowledge of the genetics underlying mammary cell fate and establishment of the mammary lineage during embryogenesis. © 2012.

Davies F.,The Institute of Cancer Research | Baz R.,H. Lee Moffitt Cancer Center and Research Institute
Blood Reviews | Year: 2010

New effective strategies are required that specifically address the challenges of multiple myeloma (MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities. Recent preclinical and clinical findings suggest that the IMiDs® immunomodulatory compound lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and immunomodulation, which may result in rapid and sustained control of MM, respectively. The tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption of stromal support, induction of tumor suppressor genes, and activation of caspases. The immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation, and increased expression of death effector molecules, lead to enhanced immune cell function and may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences - lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of dexamethasone may influence lenalidomide's direct and immunomodulatory effects. Lenalidomide in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis; however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide. A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative effects, without affecting immunomodulatory activity. As preclinical and clinical research continue, additional insights into the dual mechanism of action of lenalidomide will help to further optimize the use of lenalidomide in MM. © 2010 Elsevier Ltd.

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