Emerging views of integrin signaling: implications for prostate cancer

Integrins are heterodimeric transmembrane cellular receptors that link the cell to its underlying substratum. Alterations in integrin expression and signaling have been implicated in many aspects of tumorigenesis and metastasis including cell survival, migration, and invasion. In prostate cancer, the progression from normal to metastatic cells is accompanied by changes in the repertoire of integrins expressed and up-regulation of key adhesion-dependent signaling pathways. Recent work from several laboratories indicates the emergence of new mechanisms for the regulation of growth and migratory pathways by integrin engagement. These pathways are likely to provide novel sites of therapeutic intervention for the treatment of prostate cancer.     

Integration of growth factor and nutrient signaling: implications for cancer biology

Signaling networks that promote cell growth are frequently dysregulated in cancer. One regulatory network, which converges on effectors such as 4EBP1 and S6K1, leads to growth by promoting protein synthesis. Here, we discuss how this network is regulated by both extracellular signals, such as growth factors, and intracellular signals, such as nutrients. We discuss how mutations amplifying either type of signal can lead to tumor formation. In particular, we focus on the recent discovery that a tumor suppressor complex whose function is lost in tuberous sclerosis patients regulates the nutrient signal carried by the critical signaling protein TOR to the effectors 4EBP1 and S6K1. Finally, we describe how the small molecule rapamycin, which inhibits TOR and thereby the activation of these effectors, could be useful to treat tumors that have become dependent upon this pathway for growth.     

The Myc connection: ES cells and cancer

Gene profiling experiments have revealed similarities between cancer and embryonic stem (ES) cells. Kim et al. (2010) dissect the gene expression signature of ES cells into three functional modules and find that the Myc module, including genes targeted by Myc-interacting proteins, accounts for most of the similarity between ES and cancer cells.     

Kips off to Myc: Implications for TGFβ signaling

Loss of sensitivity to the negative growth regulator transforming growth factor β (TGFβ) is a feature of many different tumor types and is likely involved in tumor progression. In some cases this loss of sensitivity to TGFβ has been shown to be manifest in the absence of membrane-associated TGFβ receptor complexes, thus preventing initiation of antiproliferative signals from the cell surface. In others, loss of sensitivity to TGFβ-induced inhibitory signals has been attributed to loss of function of intracellular effectors of TGFβ-induced inhibitory signals due to mutation or allelic loss of effector genes and their products. The intracellular effectors of TGFβ inhibitory signals have been shown to be involved in the normal regulation of progression through the cell cycle, specifically during G₁ phase. In this manner, elucidation of the mechanisms by which TGFβ inhibits cell growth not only helps us identify steps involved in tumor progression, but also allows us to better understand how cells regulate progression through the cell cycle. J. Cell. Biochem. 66:427–432, 1997. © 1997 Wiley-Liss, Inc.     

Non-canonical androgen signaling pathways and implications in prostate cancer

Androgen signaling is a critical determinant of timely and proper development of all male organs including the prostate. Maturation of prostate and its neoplastic transformation is intricately associated with accurate androgen signaling. Ablation of androgen has therefore been the primary treatment mechanism of Prostate cancer (PCa) patients for several decades. Upon removal, the tumor recedes for a while, yet it reappears soon, in an androgen independent state, untreatable by current therapeutic regimens. Studies reveal that apart from the classical androgen signaling pathway known and targeted for almost a century, there exist several non-canonical pathways, with marked impact on classical androgen signaling and PCa growth. These include non-genomic signaling by androgens via alternate membrane GPCRs, signaling by non-androgens that ultimately impact the androgen signaling pathway, or an integration of non-genomic and genomic response as seen in case of protein kinase A activation. Accurate understanding of these various non-canonical androgen signaling pathways and their influence on the typical androgen signaling pathway can help design important interventions for PCa patients. This review analyses in detail the various non-classical androgen signaling pathways and their impact, if any, on classical mode of androgen action and PCa.     

Signal transduction: implications for Ras-dependent ERK signaling

Ras interacts with numerous downstream effectors to transmit a diverse array of cellular signals. A new study shows that a protein known as Impedes Mitogenic signal Propagation, IMP, is an E3 ubiquitin ligase that binds Ras and modulates MAP kinase signaling by regulating the scaffolding activity of KSR.     

JNK signaling pathway is required for bFGF-mediated surface cadherin downregulation on HUVEC

Angiogenesis, the process of new blood vessel formation, is important in wound healing, inflammation, tumorigenesis and metastases. During this process, it is a critical step of the loosening of cellular interactions between endothelial cells, which are dependent on the architecture of adherens junction constructed by homophilic interactions of cell surface cadherins. Several studies suggested that the dynamic changes of cadherins are necessary during angiogenesis. However, the mechanism of cadherins regulation on endothelial cells requires further delineation. Here, we showed that basic fibroblast growth factor (bFGF), a pivotal pro-angiogenic factor, can downregulate typical cadherins (E-, N-, P- and VE-cadherin) expression on the surface of human umbilical vein endothelial cells (HUVECs) via FGF receptor 1 (FGFR1) signaling. The bFGF-mediated surface cadherin downregulation was significantly reversed only when the HUVECs were treated with JNK inhibitor (SP600125), but not ERK (PD98059) or p38 inhibitor (SB203580). Infecting HUVECs with a dominant negative H-Ras mutant (Ras(S17N)) interferes bFGF-mediated cadherin downregulation, and the result suggests that bFGF attenuates surface cadherin expression on HUVECs via FGFR1 and intracellular Ras-JNK signaling. However, after growth factors withdrawal, FGFR1 blockade or JNK inhibition for 16 h, cadherins were re-expressed on cell surface of HUVECs. But the mRNA or total protein of cadherins had no significant change, suggesting that the effect of bFGF on cadherin expression may work through a post-translational control. Our data first suggest that JNK participates in bFGF-mediated surface cadherin downregulation. Loss of surface cadherins may affect the cell-cell interaction between endothelial cells and facilitate angiogenesis.     

Animal personalities and their implications for complex signaling

Animal personalities have been a major focus of behavioral ecology over the past decade. Consistent individual dif ferences in behavior have been found across taxa, and have been shown to influence a range of ecological processes. The role of personalities in sexual selection has been considered, and examples exist that show selection for personality traits with both assortative and disassortative mating patterns between personality types. One overlooked aspect of the personality and sexual se lection literature is the potential for personalitysignaling interactions, specifically with complex signaling. Complex signaling is a diverse topic in itself, and in short, consists of multiple signals within one or more modalities that interact to elicit a receiver response. Research into complex signaling has been thorough, although at times studies discover complex signaling systems that fail to fit into one of the existing hypotheses in the literature. Here, we argue that personalities may interact with complex signal ing, which should be considered by researchers of both personality and sexual selection and communication. We describe several ways in which personalitycomplex signaling interactions could affect both the signaler and receiver, and the way in which they may drive personalityspecific signals as well as receiver preferences. Finally, we discuss how considering personality in com plex signaling studies may inform theory as well as improve the ability of researchers to accurately describe its function.     

Molecular characterization of the surface of apoptotic neutrophils: implications for functional downregulation and recognition by phagocytes

We have used a panel of monoclonal antibodies and lectins to examine the profile of surface molecule expression on human neutrophils that have undergone spontaneous apoptosis during in vitro culture. Neutrophil apoptosis was found to be accompanied by down-regulation of the immunoglobulin superfamily members PECAM-1 (CD31), ICAM-3 (CD50), CD66acde, and CD66b and the integrin-associated proteins CD63 and urokinase plasminogen activator receptor (CD87) that may alter the potential for adhesive interactions. Cellular interactions may be further influenced by the reduction of the expression of surface carbohydrate moieties, including sialic acid. Reduced expression of FcgammaRII (CD32), complement receptor type 1 (CD35) and receptors for pro-inflammatory mediators C5a (CD88) and TNFalpha (CD120b) associated with apoptosis might limit neutrophil responsiveness to stimuli that trigger degranulation responses. Although many of the receptors we have examined are expressed at reduced levels on apoptotic neutrophils, we found that there was differential loss of certain receptors (e.g. CD16, CD15 and CD120b) and increased expression of aminopeptidase-N (CD13). Together with our previous data showing that expression of certain molecules e.g. LFA-3 (CD58) is not altered during neutrophil apoptosis, these data are suggestive of specific changes in receptor mobilisation and shedding associated with apoptosis. Although reduced expression of CD63 (azurophilic granules) and CR1 (specific granules) indicates that granule mobilisation does not accompany apoptosis, a monoclonal antibody (BOB78), that recognises a 90 kDa antigen localised in intracellular granules, defines a subpopulation of apoptotic neutrophils that exhibit nuclear degradation yet retain intact plasma membranes. BOB78 positive neutrophils were found to bind biotinylated thrombospondin, suggesting that this mAb defines surface molecular changes associated with exposure of thrombospondin binding moieties.     

Protease signaling to G protein-coupled receptors: implications for inflammation and pain

Proteases, like thrombin, trypsin, cathepsins, or tryptase, can signal to cells by cleaving in a specific manner, a family of G protein-coupled receptors, the protease-activated receptors (PARs). Proteases cleave the extracellular N-terminal domain of PARs to reveal tethered ligand domains that bind to and activate the receptors. Recent evidence has supported the involvement of PARs in inflammation and pain. Activation of PAR(1), PAR(2), and PAR(4) either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Recent studies suggest a crucial role for the different PARs in innate immune response. The role of PARs in the activation of pain pathways appears to be dual. Subinflammatory doses of PAR(2) agonists induce hyperalgesia and allodynia, and PAR(2) activation has been implicated in the generation of inflammatory hyperalgesia. In contrast, subinflammatory doses of PAR(1) or PAR(4) increase nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as analgesic mediators. PARs have to be considered as an additional subclass of G protein-coupled receptors that are active participants to inflammation and pain responses and that could constitute potential novel therapeutic targets.     

Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges

Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.