2d Gauge Theories and Generalized Geometry

We show that in the context of two-dimensional sigma models minimal coupling of an ordinary rigid symmetry Lie algebra $\mathfrak{g}$ leads naturally to the appearance of the "generalized tangent bundle" $\mathbb{T}M \equiv TM \oplus T^*M$ by means of composite fields. Gauge transformations of the composite fields follow the Courant bracket, closing upon the choice of a Dirac structure $D \subset \mathbb{T}M$ (or, more generally, the choide of a "small Dirac-Rinehart sheaf" $\cal{D}$), in which the fields as well as the symmetry parameters are to take values. In these new variables, the gauge theory takes the form of a (non-topological) Dirac sigma model, which is applicable in a more general context and proves to be universal in two space-time dimensions: A gauging of $\mathfrak{g}$ of a standard sigma model with Wess-Zumino term exists, \emph{iff} there is a prolongation of the rigid symmetry to a Lie algebroid morphism from the action Lie algebroid $M \times \mathfrak{g}\to M$ into $D\to M$ (or the algebraic analogue of the morphism in the case of $\cal{D}$). The gauged sigma model results from a pullback by this morphism from the Dirac sigma model, which proves to be universal in two-spacetime dimensions in this sense.Comment: 22 pages, 2 figures; To appear in Journal of High Energy Physic

Inhibition of integrin alpha(V)beta(6) changes fibril thickness of stromal collagen in experimental carcinomas

Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF beta 1 and -beta 3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. Methods: The potential role of a(v)beta(6) integrin-mediated activation of latent TGF-beta was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal a(v)beta(6) integrin-speafic monoclonal antibody 3G9 was used to inhibit the a(v)beta(6) integrin activity. Results: Both KAT-4 and Capan-2 cells expressed the a(v)beta(6) integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-beta in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-beta 1 and -beta 3 reduced collagen fibril thickness in both tumor models. Conclusion: Our data demonstrate that the a(v)beta(6)-directed activation of latent TGF-beta plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to a(v)beta(6) inhibition depends on the simultaneous presence of alternative paths for latent TGF-beta activation and the extent of desmoplasia.De fyra första författarna delar förstaförfattarskapet.</p

Hypoxia Induces EMT in Low and Highly Aggressive Pancreatic Tumor Cells but Only Cells with Cancer Stem Cell Characteristics Acquire Pronounced Migratory Potential

<div><p>Tumor hypoxia induces epithelial-mesenchymal transition (EMT), which induces invasion and metastasis, and is linked to cancer stem cells (CSCs). Whether EMT generates CSCs <em>de novo</em>, enhances migration of existing CSCs or both is unclear. We examined patient tissue of pancreatic ductal adenocarcinoma (PDA) along with carcinomas of breast, lung, kidney, prostate and ovary. For <em>in vitro</em> studies, five established PDA cell lines classified as less (CSC^low) and highly aggressive CSC-like cells (CSC^high) were examined by single and double immunofluorescence microscopy, wound-, transwell-, and time-lapse microscopy. HIF-1α and Slug, as well as HIF-2α and CD133 were co-expressed pointing to a putative co-existence of hypoxia, EMT and CSCs <em>in vivo</em>. CSC^high cells exhibited high basal expression of the mesenchymal Vimentin protein but low or absent expression of the epithelial marker E-cadherin, with the opposite result in CSC^low cells. Hypoxia triggered altering of cell morphology from an epithelial to a mesenchymal phenotype, which was more pronounced in CSC^high cells. Concomitantly, E-cadherin expression was reduced and expression of Vimentin, Slug, Twist2 and Zeb1 enhanced. While hypoxia caused migration in all cell lines, velocity along with the percentage of migrating, polarized and pseudopodia-forming cells was significantly higher in CSC^high cells. These data indicate that hypoxia-induced EMT occurs in PDA and several other tumor entities. However although hypoxia-induced EMT signaling occurs in all tumor cell populations, only the stem-like cells acquire high migratory potential and thus may be responsible for invasion and metastasis.</p> </div

Hypoxia-induced expression of EMT-related proteins in vitro.

<p>BxPc-3 and Capan-2 CSC^low and MIA-PaCa2, AsPC-1 and Capan-1 CSC^high cells were exposed to normoxia or hypoxia for 48 h. Expression of EMT-related proteins was detected by double immunofluorescent staining followed by photographing the cells under 400<i>x</i> magnification. The size of pictures taken was further increased threefold in Photoshop. E-cadherin (red), Twist 2 (green), Slug (red), Vimentin (green), ZEB1 (red). Nuclei are stained with Dapi (blue). Changes in the levels of EMT-related proteins are shown below the photographs. No expression detectable (−), weak expression (+), median expression (++), strong expression (+++).</p

Co-expression of hypoxia, EMT and CSC markers in pancreatic cancer tissues.

<p>(<b>A</b>) Double immunofluorescence stainings of tumor samples from patients with pancreatic cancer. Nuclear expression of HIF-1α (green, arrow) and membrane expression of E-cadherin (red, arrow) or Slug (red, arrow) is shown. Yellow color on merged images indicates co-expression of E-cadherin or Slug in HIF-1α-positive cells. (<b>B</b>) Membrane expression of E-cadherin (red), cytoplasmic expression of Vimentin (green) along with Dapi-staining of nuclei (blue). White squares indicate Vimentin-positive cells within the tumor mass that are negative for E-cadherin or <i>vice versa</i>. Bar: 100 μm. Twofold magnifications of the areas surrounded by white squares are shown on the left. (<b>C</b>) Nuclear expression of HIF-2α and membrane expression of CD133 is shown as single staining and as merged staining in which the yellow color indicates double-positivity.</p