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Yu J.,University of Pittsburgh | Yu J.,Hillman Cancer Center Research Pavilion
Translational Cancer Research | Year: 2013

Radiation and chemotherapy remain the most effective and widely used cancer treatments. These treatments cause DNA damage and selectively target rapidly proliferating cells such as cancer cells, as well as inevitably cause damage to normal tissues, particularly those undergoing rapid self renewal. The side effects associated with radiation and chemotherapy are most pronounced in the hematopoietic (HP) system and gastrointestinal (GI) tract. These tissues are fast renewing and have a well-defined stem cell compartment that plays an essential role in homeostasis, and in treatment-induced acute injury that is dose limiting. Using recently defined intestinal stem cell markers and mouse models, a great deal of insight has been gained in the biology of intestinal stem cells (ISCs), which will undoubtedly help further mechanistic understanding of their injury. This review will cover historic discoveries and recent advances in the identification and characterization of intestinal stem cells, their responses to genotoxic stress, and a new crypt and intestinal stem cell culture system. The discussion will include key pathways regulating intestinal crypt and stem cell injury and regeneration caused by cancer treatments, and strategies for their protection. The focus will be on the acute phase of cell killing in mouse radiation models, where our understanding of the mechanisms in relation to intestinal stem cells is most advanced and interventions appear most effective. © 2011-2016 Translational Cancer Research. Source


Ferris R.L.,Hillman Cancer Center Research Pavilion | Kraus D.H.,New Hill
Clinical and Experimental Metastasis | Year: 2012

Metastasis to the regional lymph node is the most important prognostic indicator for the outcomes of patients with sold cancer. In general, it is well recognized that cancer development is genetically determined with progression from the microenvironment of the primary tumor site, oftentimes via the SLN gateway, to the distant sites. In about 20 % of the time, the cancer cells may spread directly through the blood vascular system to the distant sites. Thus, in general, cancer progression is consistent with Hellman's spectrum theory in that development of nodal and systemic metastasis from a localized cancer growth is a progressive process. Cancer proliferation within the tumor microenvironment may give rise to increased tumor heterogeneity, which is further complicated by its continuous change through its evolution within the host in a Darwinian sense. It is crucial to understand the molecular process of lymphangiogenesis and hemangiogenesis in the tumor microenvironment with respect to the initial steps of cancer cells entering into the lymphatic and vascular systems so that rational therapy can be developed to curb the process of specific routes of metastasis. This chapter elucidates the role of lymphatics, nodal metastasis and antitumor immunity. We present novel immune targets in nodal metastases, the importance of the lymph node as a pre-metastatic niche, and immune-related proteins as biomarkers of metastasis. © Springer Science+Business Media B.V. 2012. Source


Donnenberg V.S.,University of Pittsburgh | Donnenberg A.D.,University of Pittsburgh | Donnenberg A.D.,Hillman Cancer Center Research Pavilion
Journal of Clinical Pharmacology | Year: 2015

The cancer stem cell paradigm, the epithelial-to-mesenchymal transition and its converse, the mesenchymal-to-epithelial transition, have reached convergence. Implicit in this understanding is the notion that cancer cells can change state, and with such change come bidirectional alterations in motility, proliferative activity, and drug resistance. As such, tumors present a moving target for antineoplastic therapy. This article will review the evolving adult stem cell paradigm and how changes in our understanding of the bidirectional nature of cancer cell differentiation may affect the selection and timing of antineoplastic therapy. The goal is to determine how to best administer therapies potentially targeted against the cancer stem cell state in the context of established treatment regimens, and to evaluate long-term effects beyond tumor regression. © 2015, The American College of Clinical Pharmacology. Source


Xiao D.,University of Pittsburgh | Singh S.V.,University of Pittsburgh | Singh S.V.,Hillman Cancer Center Research Pavilion
Pharmaceutical Research | Year: 2010

Purpose. The present study was undertaken to determine efficacy of phenethyl isothiocyanate (PEITC) for sensitization of androgen-independent human prostate cancer cells (AIPC) to Docetaxel-induced apoptosis using cellular and xenograft models. Methods. Cell viability was determined by trypan blue dye exclusion, assay. Microscopy and DNA fragmentation assay were performed, to quantify apoptotic cell death in cultured cells. Protein levels were determined by immunoblotting. PC-3 prostate cancer xenograft model was utilized to determine in vivo efficacy of the PEITC and/or Docetaxel treatments. Results. Pharmacologic concentrations of PEITC augmented Docetaxel-induced apoptosis in PC-3 and DU145 cells in association with suppression of Bcl-2 and XIAP protein levels and induction of Bax and Bak. The PEITC-Docetaxel combination was markedly more efficacious against PC-3 xenograft in vivo compared with PEITC or Docetaxel alone. Significantly higher counts of apoptotic bodies were also observed in tumor sections from mice treated with the PEITC-Docetaxel combination compared with PEITC or Docetaxel alone. The PEITC and/or Docetaxel-mediated changes in the levels of apoptosis regulating proteins in the tumor were generally consistent with the molecular alterations observed in cultured cells. Conclusion. These results offer obligatory impetus to test PEITC-Docetaxel combination for the treatment of AIPC in a clinical setting. © 2010 Springer Science+Husiness Media, LLC. Source


Stephenson R.M.,University of Pittsburgh | Lim C.M.,University of Pittsburgh | Matthews M.,VentiRx | Dietsch G.,VentiRx | And 3 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

Background: Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10-20 % of patients. An immunological mechanism of action such as natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells. Objective: To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells. Methods: Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8+ T cells were isolated and analyzed using 51Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR853-861 tetramer staining. Results: TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFα (p < 0.0001), IFNγ (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co-cultures significantly increased DC priming of EGFR-specific CD8+ T cells in the presence of cetuximab. Discussion: VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response. © 2013 Springer-Verlag Berlin Heidelberg. Source

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