CD44-negative prostate cancer cells give rise to CD44 high cells that display phenotypical and functional stem-like traits

Hormonal therapy is effective for advanced prostate cancer (PCa) but the disease often recurs and becomes hormone-refractory. Neuroendocrine (NE) cells, expressing selectively the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. Our group demonstrated that the Toll-Like receptor (TLR) 3 agonist poly (I:C) induces apoptosis in the androgen-dependent prostate tumor cell line LNCaP, negative for NE and CD44 markers, while the androgen-independent PC3 and DU-145 cell lines are partially resistant and are positive for NE and CD44 markers. In order to investigate if the apoptosis resistance to poly (I:C) can be correlated to CD44 expression, the modulation of membrane-CD44 protein in PC3 cells after poly (I:C) treatment was assessed by flow cytometry. We found very small CD44-negative cells, resistant to poly (I:C), that gave rise to a CD44-positive population in PC3 cells after sorting. The same rate of conversion was observed in the 2-4% of sorted CD44-negative very small in size cells contained in parental PC3 and DU-145 cells. Moreover, clonogenic assay indicated that CD44-negative-sorted PC3 cells converted in CD44high cells, expanded in vitro culture, displayed an higher clonogenic potential than sorted CD44high -derived population producing mainly holoclones described to be enriched in stem-like cells, whereas CD44high population generated mainly meroclones, a mixture of cells of different proliferative potential. In addition, all the clones produced by CD44-negative cells became positive for CD44. Each individual clone was subjected to secondary clonogenic assay that showed a greater clonogenic potential in CD44-negative-derived clones compared to those generated by CD44high -sorted population. The cells generated by CD44-negative-sorted population were indistinguishable from the CD44high -derived cells in terms of CD44 expression, but CD44-negative population re-expressed specifically CD44 v8-v10 splice variant isoform in both the androgen-independent cell lines PC3 and DU-145. Because CD44v isoforms are more specifically expressed in CSCs than CD44s, the presence of a specific CD44v isoform might be better CSC marker than CD44s isoform. These results show that CD44high cells, described to be stem-like and more tumorigenic in prostate cancer, may arise from a CD44-negative population. Moreover CD44high -derived population contain a smaller proportion of self-renewing cells than CD44-negative-derived population

CD44-negative prostate cancer cells give rise to CD44 high cells that display phenotypical and functional stem-like traits

Hormonal therapy is effective for advanced prostate cancer (PCa) but the disease often recurs and becomes hormone-refractory. Neuroendocrine (NE) cells, expressing selectively the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. Our group demonstrated that the Toll-Like receptor (TLR) 3 agonist poly (I:C) induces apoptosis in the androgen-dependent prostate tumor cell line LNCaP, negative for NE and CD44 markers, while the androgen-independent PC3 and DU-145 cell lines are partially resistant and are positive for NE and CD44 markers. In order to investigate if the apoptosis resistance to poly (I:C) can be correlated to CD44 expression, the modulation of membrane-CD44 protein in PC3 cells after poly (I:C) treatment was assessed by flow cytometry. We found very small CD44-negative cells, resistant to poly (I:C), that gave rise to a CD44-positive population in PC3 cells after sorting. The same rate of conversion was observed in the 2-4% of sorted CD44-negative very small in size cells contained in parental PC3 and DU-145 cells. Moreover, clonogenic assay indicated that CD44-negative-sorted PC3 cells converted in CD44high cells, expanded in vitro culture, displayed an higher clonogenic potential than sorted CD44high -derived population producing mainly holoclones described to be enriched in stem-like cells, whereas CD44high population generated mainly meroclones, a mixture of cells of different proliferative potential. In addition, all the clones produced by CD44-negative cells became positive for CD44. Each individual clone was subjected to secondary clonogenic assay that showed a greater clonogenic potential in CD44-negative-derived clones compared to those generated by CD44high -sorted population. The cells generated by CD44-negative-sorted population were indistinguishable from the CD44high -derived cells in terms of CD44 expression, but CD44-negative population re-expressed specifically CD44 v8-v10 splice variant isoform in both the androgen-independent cell lines PC3 and DU-145. Because CD44v isoforms are more specifically expressed in CSCs than CD44s, the presence of a specific CD44v isoform might be better CSC marker than CD44s isoform. These results show that CD44high cells, described to be stem-like and more tumorigenic in prostate cancer, may arise from a CD44-negative population. Moreover CD44high -derived population contain a smaller proportion of self-renewing cells than CD44-negative-derived population

N=4 Extended MSSM

We investigate a perturbative N=4 sector coupled to the MSSM and show that it allows for a stable vacuum correctly breaking the electroweak symmetry. The particle spectrum of the MSSM is enrichened by several new particles stemming out from the new N=4 sector of the theory, and a new lepton doublet required to cancel global and gauge anomalies of the theory. Even if the conformal invariance of the N=4 sector is explicitly broken, a nontrivial UV behavior of the coupling constants is possible: by studying the renormalization group equations at two loops we find that the Yukawa couplings of the heavy fermionic states flow to a common fixed point at a scale of a few TeVs. The parameter space of the new theory is reduced imposing naturalness of the couplings and soft supersymmetry breaking masses, perturbativity of the model at the EW scale as well as phenomenological constraints. Our preliminary results on the spectrum of the theory suggest that the LHC can rule out a significant portion of the parameter space of this model.Comment: 22 pages, 2 figure

The Limits of Custodial Symmetry

We introduce a toy model implementing the proposal of using a custodial symmetry to protect the Zbb coupling from large corrections. This "doublet-extended standard model" adds a weak doublet of fermions (including a heavy partner of the top quark) to the particle content of the standard model in order to implement an O(4) x U(1)_X = SU(2)_L x SU(2)_R x P_{LR} x U(1)_X symmetry that protects the Zbb coupling. This symmetry is softly broken to the gauged SU(2)_L x U(1)_Y electroweak symmetry by a Dirac mass M for the new doublet; adjusting the value of M allows us to explore the range of possibilities between the O(4)-symmetric (M to 0) and standard-model-like (M to infinity) limits. In this simple model, we find that the experimental limits on the Zbb coupling favor smaller M while the presence of a potentially sizable negative contribution to T strongly favors large M. A fit to all precision electroweak data shows that the heavy partner of the top quark must be heavier than about 3.4 TeV, making it difficult to search for at LHC. This result demonstrates that electroweak data strongly limits the amount by which the custodial symmetry of the top-quark mass generating sector can be enhanced relative to the standard model. Using an effective field theory calculation, we illustrate how the leading contributions to alpha T, alpha S and the Zbb coupling in this model arise from an effective operator coupling right-handed top-quarks to the Z-boson, and how the effects on these observables are correlated. We contrast this toy model with extra-dimensional models in which the extended custodial symmetry is invoked to control the size of additional contributions to alpha T and the Zbb coupling, while leaving the standard model contributions essentially unchanged.Comment: 19 pages, 11 eps figures. Typos correcte

Vector resonances at LHC Run II in composite 2HDM

We consider a model where the electroweak symmetry breaking is driven by strong dynamics, resulting in an electroweak doublet scalar condensate, and transmitted to the standard model matter fields via another electroweak doublet scalar. At low energies the effective theory therefore shares features with a type-I two Higgs doublet model. However, important differences arise due to the rich composite spectrum expected to contain new vector resonances accessible at the LHC. We carry out a systematic analysis of the vector resonance signals at LHC and find that the model remains viable, but will be tightly constrained by direct searches as the projected integrated luminosity, around 200 fb(-1), of the current run becomes available.Peer reviewe

Stabilizing the Higgs potential with a Z '

Current data point toward metastability of the electroweak vacuum within the Standard Model. We study the possibility of stabilizing the Higgs potential in U(1) extensions thereof. A generic Z' boson improves stability of the scalar potential in two ways: it increases the Higgs self-coupling, due to a positive contribution to the beta-function of the latter, and it decreases the top quark Yukawa coupling, which again has a stabilizing effect. We determine the range of U(1) charges which leads to a stable electroweak vacuum. In certain classes of models, such stabilization is possible even if the Z' does not couple to the Higgs and is due entirely to the reduction of the top Yukawa coupling. We also study the effect of the kinetic mixing between the extra U(1) and hypercharge gauge fields. (C) 2015 The Authors. Published by Elsevier B.V.Peer reviewe