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Malignant Growth (malignant + growth)
Selected AbstractsHow apoptosis got the immune system in shapeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue S1 2007Christine Feig Abstract The discovery that apoptosis is an integral component of normal development has facilitated the widespread recognition that cell death is not at all inimical to life. For much of our lifetime the body maintains a cellular homeostasis persisting until, ultimately, it is broken during the aging process. However, unlike the body as a whole, fluctuations at any age in this cellular balance are frequent in the immune system, which responds to infections via massive clonal expansions and elimination of reactive T and B cells. Moreover, cell death also plays a key, and essential, role in the education of immune cells in the thymus and the bone marrow, where autoreactive cells are eliminated, thereby establishing tolerance to self tissues. Furthermore, the mechanism by which cytotoxic T and NK cells kill virus infected or transformed target cells is by inducing apoptotic cell death. Thus, cell death, and in particular apoptosis, is an integral facet of almost all aspects of immune function. Failure to execute apoptosis appropriately has dire consequences leading to the development of autoimmune disease and malignant growth. This narration provides a historical overview of the impact that the discovery of apoptosis had on the understanding of the function of the immune system. [source] Upregulation of plakophilin-2 and its acquisition to adherens junctions identifies a novel molecular ensemble of cell,cell-attachment characteristic for transformed mesenchymal cellsINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Steffen Rickelt Abstract In contrast to the desmosome-containing epithelial and carcinoma cells, normal and malignantly transformed cells derived from mesenchymal tissues and tumors are connected only by adherens junctions (AJs) containing N-cadherins and/or cadherin-11, anchored in a cytoplasmic plaque assembled by ,- and ,-catenin, plakoglobin, proteins p120 and p0071. Here, we report that the AJs of many malignantly transformed cell lines are characterized by the additional presence of plakophilin-2 (Pkp2), a protein hitherto known only as a major component of desmosomal plaques, i.e., AJs of epithelia and carcinomatous cells. This massive acquisition of Pkp2 and its integration into AJ plaques of a large number of transformed cell lines is demonstrated with biochemical and immunolocalization techniques. Upregulation of Pkp2 and its integration into AJs has also been noted in some soft tissue tumors insitu and some highly proliferative colonies of cultured mesenchymal stem cells. As Pkp2 has recently been identified as a functionally important major regulatory organizer in AJs and related junctions in epithelial cells and cardiomyocytes, we hypothesize that the integration of Pkp2 into AJs of "soft tissue tumor" cells also can serve functions in the upregulation of proliferation, the promotion of malignant growth in general as well as the close-packing of diverse kinds of cells and the metastatic behavior of such tumors. We propose to examine its presence in transformed mesenchymal cells and related tumors and to use it as an additional diagnostic criterion. © 2009 UICC [source] Noggin blocks invasive growth of murine B16-F1 melanoma cells in the optic cup of the chick embryo,,INTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Christian Busch Abstract Melanoma cells originate from the neural crest and are characterized by high migratory potential and invasive growth. After transplantation into the neural tube of the chick embryo, melanoma cells spontaneously emigrate along the neural crest pathways without tumor formation or malignant growth. This emigration depends on the constitutive over-expression of bone morphogenetic protein-2 (BMP-2) and can be ablated by the BMP-antagonist noggin. When transplanted into the embryonic optic cup, melanoma cells invade the host tissue and form malignant tumors. Here, we asked if the invasive growth of melanoma cells in the optic cup could be influenced by BMP-2 or noggin. Mouse B16-F1 cells were grown as aggregates, treated with BMP-2 or noggin during aggregation and transplanted into the optic cup of 3-day chick embryos. After 3 days of subsequent incubation, embryos were evaluated for melanoma cell invasiveness. Immunohistochemical examination revealed that untreated and BMP-2-treated melanoma cells had grown malignantly into the host tissue. However, noggin pretreatment of the aggregates had blocked melanoma cell invasiveness and tumor formation. We conclude that invasive growth of melanoma cells in vivo is BMP-dependent and can be ablated by noggin, thus rendering noggin a promising agent for the treatment of BMP-over-expressing melanoma. © 2007 Wiley-Liss, Inc. [source] Human T-cell leukemia virus type-I Tax induces expression of interleukin-6 receptor (IL-6R): Shedding of soluble IL-6R and activation of STAT3 signalingINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Sankichi Horiuchi Abstract Human T-cell leukemia virus type-I (HTLV-I) encodes for the viral protein Tax, which is known to significantly disrupt transcriptional control of cytokines, cytokine receptors and other immuno-modulatory proteins in T cells. Specific dysregulation of these factors can alter the course and pathogenesis of infection. Soluble interleukin-6 receptor (sIL-6R) was shown to circulate at elevated levels in HTLV-I-infected patients, and high expressions of IL-6R and sIL-6R by HTLV-I-infected T cells were clinically and experimentally associated with Tax activity. To examine roles of Tax in expression of the IL-6R gene, the JPX-9 cell line was used, which is derived from Jurkat cell line expressing Tax cDNA. Over-expression of Tax enhanced IL-6R expression but not in Tax mutant JPX-9/M cell line. The clinical relevance of these observations was further demonstrated by ELISA using sera obtained from HTLV-I-infected patients. Our results revealed that sIL-6R levels were apparently elevated in HAM/TSP patients who were expressing Tax in their cells, while ATL patients' cells barely expressed Tax. HTLV-I-infected T-cell lines stimulated by IL-6/sIL-6R showed gp130-mediated STAT3 activity. IL-6/sIL-6R enhanced proliferation of HTLV-I-infected T cells in association with activation of STAT3. Consequently, Tax-mediated regulations of IL-6R and sIL-6R observed in HTLV-I-associated disorders may contribute to proliferation of HTLV-I-infected T cells through activation of inducible STAT3, and ultimately affect malignant growth and transformation of T cells by HTLV-I. © 2006 Wiley-Liss, Inc. [source] Bone Regeneration Is Regulated by Wnt Signaling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2007Jae-Beom Kim Abstract Tissue regeneration is increasingly viewed as reactivation of a developmental process that, when misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration. Introduction: Some adult tissues have the ability to regenerate, and among these, bone is one of the most remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can have profound consequences, as exemplified by conditions such as osteoporosis and delayed skeletal repair. Here, our goal was to determine the role of Wnts in adult bone regeneration. Materials and Methods: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition, achieved through adenoviral expression of Dkk1 in the adult skeleton, prevented the differentiation of osteoprogenitor cells. Results: As a result, injury-induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co-receptor results in high bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration. In these transgenic mice, osteoprogenitor cells in the injury site were maintained in a proliferative state and differentiation into osteoblasts was delayed. Conclusions: When considered together, these data provide a framework for understanding the roles of Wnt signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where enhanced bone formation is desired. [source] Transforming growth factor-, signaling at the tumor,bone interface promotes mammary tumor growth and osteoclast activationCANCER SCIENCE, Issue 1 2009Mitsuru Futakuchi Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor,bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-, receptor 1 (TGF-,RI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-,RI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-, activity by neutralizing antibody to TGF-, or TGF-,RI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-,RI expression and its activation. In addition, we demonstrate a potential role of TGF-, as an important modifier of receptor activator of NF-,B ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-,RI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis. (Cancer Sci 2009; 100: 71,81) [source] | ||||||||||