Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells

Epidermal growth factor receptor (EGFR) is an important regulator of epithelial cell growth and survival in normal and cancerous tissues and is a principal therapeutic target for cancer treatment. EGFR is associated in epithelial cells with the heavily glycosylated transmembrane mucin protein MUC1, a natural ligand of galectin-3 that is overexpressed in cancer. This study reveals that the expression of cell surface MUC1 is a critical enhancer of EGF-induced EGFR activation in human breast and colon cancer cells. Both the MUC1 extracellular and intracellular domains are involved in EGFR activation but the predominant influence comes from its extracellular domain. Binding of galectin-3 to the MUC1 extracellular domain induces MUC1 cell surface polarization and increases MUC1–EGFR association. This leads to a rapid increase of EGFR homo-/hetero-dimerization and subsequently increased, and also prolonged, EGFR activation and signalling. This effect requires both the galectin-3 C-terminal carbohydrate recognition domain and its N-terminal ligand multi-merization domain. Thus, interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in epithelial cancer cells. As MUC1 and galectin-3 are both commonly overexpressed in most types of epithelial cancers, their interaction and impact on EGFR activation likely makes important contribution to EGFR-associated tumorigenesis and cancer progression and may also influence the effectiveness of EGFR-targeted cancer therapy

Tumor necrosis is associated with increased alphavbeta3 integrin expression and poor prognosis in nodular cutaneous melanomas

<p>Abstract</p> <p>Background</p> <p>Tumor necrosis and apoptotic activity are considered important in cancer progression, but these features have not been much studied in melanomas. Our hypothesis was that rapid growth in cutaneous melanomas of the vertical growth phase might lead to tissue hypoxia, alterations in apoptotic activity and tumor necrosis. We proposed that these tumor characteristics might be associated with changes in expression of cell adhesion proteins leading to increased invasive capacity and reduced patient survival.</p> <p>Methods</p> <p>A well characterized series of nodular melanoma (originally 202 cases) and other benign and malignant melanocytic tumors (109 cases) were examined for the presence of necrosis, apoptotic activity (TUNEL assay), immunohistochemical expression of hypoxia markers (HIF-1 α, CAIX, TNF-α, Apaf-1) and cell adhesion proteins (α_vβ₃integrin, CD44/HCAM and osteopontin). We hypothesized that tumor hypoxia and necrosis might be associated with increased invasiveness in melanoma through alterations of tumor cell adhesion proteins.</p> <p>Results</p> <p>Necrosis was present in 29% of nodular melanomas and was associated with increased tumor thickness, tumor ulceration, vascular invasion, higher tumor proliferation and apoptotic index, increased expression of α_vβ₃integrin and poor patient outcome by multivariate analysis. Tumor cell apoptosis did also correlate with reduced patient survival. Expression of TNF-α and Apaf-1 was significantly associated with tumor thickness, and osteopontin expression correlated with increased tumor cell proliferation (Ki-67).</p> <p>Conclusion</p> <p>Tumor necrosis and apoptotic activity are important features of melanoma progression and prognosis, at least partly through alterations in cell adhesion molecules such as increased α_vβ₃integrin expression, revealing potentially important targets for new therapeutic approaches to be further explored.</p

The Relationship of Sleep with Temperature and Metabolic Rate in a Hibernating Primate

STUDY OBJECTIVES: It has long been suspected that sleep is important for regulating body temperature and metabolic-rate. Hibernation, a state of acute hypothermia and reduced metabolic-rate, offers a promising system for investigating those relationships. Prior studies in hibernating ground squirrels report that, although sleep occurs during hibernation, it manifests only as non-REM sleep, and only at relatively high temperatures. In our study, we report data on sleep during hibernation in a lemuriform primate, Cheirogaleus medius. As the only primate known to experience prolonged periods of hibernation and as an inhabitant of more temperate climates than ground squirrels, this animal serves as an alternative model for exploring sleep temperature/metabolism relationships that may be uniquely relevant to understanding human physiology. MEASUREMENTS AND RESULTS: We find that during hibernation, non-REM sleep is absent in Cheirogaleus. Rather, periods of REM sleep occur during periods of relatively high ambient temperature, a pattern opposite of that observed in ground squirrels. Like ground squirrels, however, EEG is marked by ultra-low voltage activity at relatively low metabolic-rates. CONCLUSIONS: These findings confirm a sleep-temperature/metabolism link, though they also suggest that the relationship of sleep stage with temperature/metabolism is flexible and may differ across species or mammalian orders. The absence of non-REM sleep suggests that during hibernation in Cheirogaleus, like in the ground squirrel, the otherwise universal non-REM sleep homeostatic response is greatly curtailed or absent. Lastly, ultra-low voltage EEG appears to be a cross-species marker for extremely low metabolic-rate, and, as such, may be an attractive target for research on hibernation induction

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs. There are, however, two different aspects of the problem caused by tumor hypoxia when cancer therapy is concerned: One is due to the chemical reactions that molecular oxygen enters intoin therapeutically targeted cells. This results in a direct chemical protection against therapy by the hypoxic microenvironment which has little to do with cellular biological regulatory processes. This part of the protective effect of hypoxia has been known for more than half a century and has been studied extensively. However, in recent years more focus has been put into the other aspect of hypoxia, namely the effect of this microenvironmental condition on selecting cells with certain genetical pre-requisites that are negative with respect to patient prognosis. There are adaptive mechanisms, where hypoxia induces regulatory cascades in cells resulting in a changed metabolism or changes in extra cellular signalling. These processes may lead to changes in cellular intrinsic sensitivity to treatment irrespective of oxygenation and furthermore, may also have consequences for tissue organization. Thus, the adaptive mechanisms induced by hypoxia itself may have a selective effect on cells with a fine-tuned protection against damage and stress of many kinds. It therefore could be that the adaptive mechanisms may be taken advantage of for new tumor labelling/imaging and treatment strategies. One of the Achilles’ heels of hypoxia research has always been exact measurements of tissue oxygenation as well as control of oxygenation in biological tumor models. Thus, development of technology that can ease this control is vital in order to study mechanisms and perform drug development under relevant conditions. An integrated EU Framework project 2004-2009, termed Euroxy, demonstrates several pathways involved in transcription and translation control of the hypoxic cell phenotype and evidence of cross talk with responses to pH and redox changes. The carbon anhydrase isoenzyme CA IX was selected for further studies due to its expression on the surface of many types of hypoxic tumors. The effort has lead to marketable culture flaks with sensors and incubation equipment and the synthesis of new drug candidates against new molecular targets. New labelling/imaging methods for cancer diagnosing and imaging of hypoxic cancer tissue now are being tested in xeno-graft models and also are in early clinical testing while new potential anticancer drugs are undergoing tests using xenografted tumor cancers. The present paper describes the above results in individual consortium partner presentations