1,721,071 research outputs found
Reverse-phase protein microarray highlights HER2 signaling activation in immunohistochemistry/FISH/HER2-negative breast cancers.
No full text"Evaluation of: Wulfkuhle JD, Berg D, Wolff C et al. Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping. Clin. Cancer Res. 18(23), 6426-6435 (2012). Exhaustive characterization and mapping of pivotal molecules and downstream effectors deregulated in breast cancer is of fundamental clinical value to define the most effective therapy. Wulfkuhle et al. applied reverse-phase protein microarray, a highly sensitive immunoassay able to perform quantitative and multiplexed analysis of total and\/or modified cellular proteins, to assess protein levels and activation\/phosphorylation status of the HER family (EGFR, HER2, HER3) and downstream signaling molecules in HER2(+) and HER2(-) breast cancers. The research was performed using laser capture microdissected tumor epithelial cells from frozen samples and formalin-fixed paraffin embedded specimens, which were also analyzed by immunohistochemistry (IHC) and FISH. This study identified a subgroup of IHC\/FISH\/HER2(-) patients with HER2 activation\/phosphorylation levels comparable with those obtained from IHC\/FISH\/HER2(+) tumors. HER2 signaling activation was independent from total HER2 expression and involved HER3 and EGFR activation. These findings indicate that molecular characterization by reverse-phase protein microarray of HER2 and its partners\/effectors in the signaling cascade enables the identification of a subgroup of IHC\/FISH\/HER2(-) patients showing HER2 signaling activation. These patients, currently excluded from targeted therapy administration, could potentially benefit from this and it could improve prognosis and survival.
Pro-angiogenic potential of adipose-derived mesenchymal stem cells (AD-MSCs) in hypoxic condition
No full textID4-dependent reprogramming of tumor associated macrophages in triple negative breast cancer
Full text linkBreast cancer is one of the most common cancer affecting especially women worldwide and it shows a particularly aggressive behavior in the triple negative (TNBC) and basal-like breast cancer (BLBC) subtypes that are characterized by poor prognosis and by the lack of targeted therapies. Moreover, it is well established that the presence of a massive leukocyte infiltrate, is involved in the promotion of tumor progression, contributing in particular to the angiogenic switch that occurs in the early phases of tumor progression. Among the variety of cells infiltrating breast tumors, macrophages have been extensively shown to tightly control the angiogenic onset and progression to malignancy. Here, we investigated whether ID4 protein, previously reported to enhance the angiogenic potential of breast cancer cells, exerts its function also modulating the activity of tumor-associated macrophages. We first assessed the significant association between the expression of ID4 and the macrophages marker CD68 in series of triple negative breast tumors. Of note, high ID4 mRNA expression in presence of a high macrophage infiltrate (determined as the expression of 8 macrophage markers) in BLBC is a strong predictor of poor survival. In vitro and in vivo migration assays evidenced that expression of ID4 in breast cancer cells is able to influence macrophages motility. At gene expression level we observed induction of ID4 itself, in macrophages co-cultured with breast cancer cells, induction that was impaired when breast cancer cells were depleted of ID4 expression. The same ID4-dependent behavior was observed for HIF-1A and for an angiogenesis-related signature in macrophages. Expression of angiogenesis-related genes was further controlled by miR-107, down-regulated in macrophages in ID4-dependent manner. Altogether our results highlight a key role for ID4 in dictating the angiogenic behavior of tumor-associated macrophages in breast cancer
Targeting costimulatory molecules to improve antitumor immunity.
No full text"""\\\\"The full activation of T cells necessitates the concomitant activation of two signals, the engagement of T-cell receptor by peptide\\\\\\\\\\\\\\\/major histocompatibility complex II and an additional signal delivered by costimulatory molecules. The best characterized costimulatory molecules belong to B7\\\\\\\\\\\\\\\/CD28 and TNF\\\\\\\\\\\\\\\/TNFR families and play crucial roles in the modulation of immune response and improvement of antitumor immunity. Unfortunately, tumors often generate an immunosuppressive microenvironment, where T-cell response is attenuated by the lack of costimulatory molecules on the surface of cancer cells. Thus, targeting costimulatory pathways represent an attractive therapeutic strategy to enhance the antitumor immunity in several human cancers. Here, latest therapeutic approaches targeting costimulatory molecules will be described.\\\\"""
In the Crosshairs: NF-κB Targets the JNK Signaling Cascade.
No full textNF-κB/Rel transcription factors are well-known for their roles in the regulation of inflammation and immunity. NF-κB also blocks programmed cell death (PCD) or apoptosis triggered by proinflammatory cytokine, tumor necrosis factor (TNF)α. Through transcriptional induction of distinct subsets of cyto-protective target genes, NF-κB inhibits the execution of apoptosis activated by this cytokine. This protective action is mediated, in part, by factors (such as A20, GADD45β, and XIAP) that downregulate the pro-apoptotic c-Jun-N-terminal (JNK) pathway. A suppression of reactive oxygen species (ROS), which are themselves major cell death-inducing elements activated by TNFα, is an additional protective function recently ascribed to NF-κB. This function of NF-κB involves an induction of mitochondrial anti-oxidant enzyme, manganese superoxide dismutase (Mn-SOD), and a control of cellular iron availability through upregulation of Ferritin heavy chain – one of two subunits of Ferritin, the major iron storage protein complex of the cell. An emerging view of NF-κB is that, while integrated, its actions in immunity and in promoting cell survival are executed through upregulation of distinct subsets of target genes. Thus, these inducible blockers of apoptosis may provide potential new targets to inhibit specific functions of NF-κB. In the future, this might allow for a better treatment of complex human diseases involving dysregulated NF-κB activity, including chronic inflammatory conditions and cancer
NF-kappaB meets ROS: an 'iron-ic' encounter
No full textSince becoming abundant in the atmosphere approximately 2.3 billion years ago, oxygen has been a defining element for life on our planet. One needs not be a biologist to know the importance of oxygen for sustaining life – termed in fact ‘aerobic’ life. Our body is built around the need to maximize exploitation of oxygen for the production of energy. The respiratory and cardiovascular systems are exemplary illus- trations of this need. Like all good things, however, oxygen can also be extremely harmful. Its original accumulation on Earth caused the extinction of most existing life forms, defenseless against oxidative damage. Even a layperson is aware of this potential toxicity of oxygen. Indeed, nowadays antioxidants are among the most heavily advertised dietary supplements on the market. Yet, it would surprise most to know that the potent reactivity of oxygen and its products – so- called reactive oxygen species (ROS) – is purposefully used by nature to transduce signals that actively trigger cell suicide or programmed cell death (PCD), as well as other biological responses.
One pathway that seems to fully exploit this reactivity of ROS for inflicting cell death is that initiated by TNFa engagement of TNF-R1, a pathway that plays a central role in immunity, inflammation, cell growth, cell death and differentiation.1–3 This pathway is also crucial for pathogen- esis of human diseases such as cancer and chronic inflammatory conditions, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).1,3,4 Not surprisingly, it has been the subject of intense investigation for over one century.1 TNFa-induced killing is antagonized by activation of NF-kB-family transcription factors3,4 – which act as master coordinators of immune and inflammatory responses.4 The prosurvival activity of NF-kB is also crucial for lymphocyte development, tumorigenesis and cancer chemoresistance.4,5 In recent years, remarkable progress has been made in our understanding of the mechanisms governing TNFa-induced death and NF-kB-mediated survival.3,4 As it turns out, ROS have now taken center stage in the intricate multitude of players that control cell fate downstream of TNF-R1, as they appear to be at an obligatory crossroads of the opposing pathways for life and death elicited by stimulation of this receptor. Indeed, now there is hope that this new under-
standing of TNF-R-induced pathways may lead to the development of new approaches for treatment of widespread human diseases
The NF-kappaB-mediated control of ROS and JNK signaling
No full textNF-kappaB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-kappaB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radio- and chemoresistance in cancer. With regard to TNFalpha, the NF-kappaB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45beta/Myd118. Notably, NF-kappaB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFalpha, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-kappaB. The antioxidant activity of NF-kappaB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC)--a component of Ferritin, the primary iron-storage protein complex found in cells--and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-kappaB controls proapoptotic JNK signaling triggered by TNFalpha. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-kappaB, including some cancers and chronic inflammatory conditions
Oxygen JNKies: phosphatases overdose on ROS
No full textProinflammatory cytokine TNFalpha triggers cell death by inducing reactive oxygen species (ROS). These then inflict cytotoxicity through downstream activation of the JNK MAPK cascade. Yet the mechanisms by which ROS trigger JNK signaling have remained elusive. In a recent issue of Cell, Kamata et al. now provide one such mechanism
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