PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-12 (12)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
1.  Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Progression 
Advances in cancer research  2013;119:107-125.
Breast cancer is a highly complex tissue composed of neoplastic and stromal cells. Carcinoma-associated fibroblasts (CAFs) are commonly found in the cancer stroma, where they promote tumor growth and enhance vascularity in the microenvironment. Upon exposure to oxidative stress, fibroblasts undergo activation to become myofibroblasts. These cells are highly mobile and contractile and often express numerous mesenchymal markers. CAF activation is irreversible, making them incapable of being removed by nemosis. In breast cancer, almost 80% of stromal fibroblasts acquire an activated phenotype that manifests by secretion of elevated levels of growth factors, cytokines, and metalloproteinases. They also produce hydrogen peroxide, which induces the generation of subsequent sets of activated fibroblasts and tumorigenic alterations in epithelial cells. While under oxidative stress, the tumor stroma releases high energy nutrients that fuel cancer cells and facilitate their growth and survival. This review describes how breast cancer progression is dependent upon oxidative stress activated stroma and proposes potential new therapeutic avenues.
doi:10.1016/B978-0-12-407190-2.00003-4
PMCID: PMC3950899  PMID: 23870510
Oxidative stress; Reactive oxygen species; Breast cancer; Microenvironment; Stroma-associated fibroblasts; Myofibroblasts; Cancer-associated fibroblasts
2.  Acquired Resistance to Drugs Targeting Receptor Tyrosine Kinases 
Biochemical Pharmacology  2011;83(8):1041-1048.
Development of resistance to chemotherapeutic drugs represents a significant hindrance to the effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over half a century and have revealed the lack of a single cause. Rather, a multitude of mechanisms have been delineated ranging from induction and expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system and altered metabolism to name a few. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. This has also been true for molecularly targeted drugs. Considerable experience has been gained from the study of agents targeting the Bcr-Abl tyrosine kinase including imatinib, dasatinib and sunitinib. It is clear that mutations alone are not responsible for the many resistance mechanisms in play. Rather, additional mechanisms are involved, ranging from epigenetic changes, alternative splicing and the induction of alternative/compensatory signaling pathways. In this review, resistance to receptor tyrosine kinase inhibitors (RTKIs), RTK-directed antibodies and antibodies that inactivate ligands for RTKs are discussed. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. The recent observation that many RTKs, including the IGF-1R, are dependence receptors that induce apoptosis in a ligand-independent manner will be discussed and the implications this signaling paradigm has on therapeutic strategies will be considered.
doi:10.1016/j.bcp.2011.12.025
PMCID: PMC3299940  PMID: 22227013
Receptor tyrosine kinases; Bcr-Abl; epidermal growth factor receptor; dependence receptors
3.  Loss of Expression and Function of SOCS3 Is an Early Event in HNSCC: Altered Subcellular Localization as a Possible Mechanism Involved in Proliferation, Migration and Invasion 
PLoS ONE  2012;7(9):e45197.
Background
Suppressor of cytokine signaling 3 (SOCS3) is an inducible endogenous negative regulator of signal transduction and activator of transcription 3 (STAT3). Epigenetic silencing of SOCS3 has been shown in head and neck squamous cell carcinoma (HNSCC), which is associated with increased activation of STAT3. There is scarce information on the functional role of the reduction of SOCS3 expression and no information on altered subcellular localization of SOCS3 in HNSCC.
Methodology/Principal Findings
We assessed endogenous SOCS3 expression in different HNSCC cell lines by RT-qPCR and western blot. Immunofluorescence and western blot were used to study the subcellular localization of endogenous SOCS3 induced by IL-6. Overexpression of SOCS3 by CMV-driven plasmids and siRNA-mediated inhibition of endogenous SOCS3 were used to verify the role of SOCS3 on tumor cell proliferation, viability, invasion and migration in vitro. In vivo relevance of SOCS3 expression in HNSCC was studied by quantitative immunohistochemistry of commercially-available tissue microarrays. Endogenous expression of SOCS3 was heterogeneous in four HNSCC cell lines and surprisingly preserved in most of these cell lines. Subcellular localization of endogenous SOCS3 in the HNSCC cell lines was predominantly nuclear as opposed to cytoplasmic in non-neoplasic epithelial cells. Overexpression of SOCS3 produced a relative increase of the protein in the cytoplasmic compartment and significantly inhibited proliferation, migration and invasion, whereas inhibition of endogenous nuclear SOCS3 did not affect these events. Analysis of tissue microarrays indicated that loss of SOCS3 is an early event in HNSCC and was correlated with tumor size and histological grade of dysplasia, but a considerable proportion of cases presented detectable expression of SOCS3.
Conclusion
Our data support a role for SOCS3 as a tumor suppressor gene in HNSCC with relevance on proliferation and invasion processes and suggests that abnormal subcellular localization impairs SOCS3 function in HNSCC cells.
doi:10.1371/journal.pone.0045197
PMCID: PMC3445460  PMID: 23028842
4.  What’s new in the IGF-binding proteins? 
Since their initial discovery over 25 years ago as IGF carrier proteins, the insulin-like growth factor binding protein (IGFBP) family has grown to six members, ranging in size from 216 to 289 amino acids. The assumption over the years has been that this family of proteins, having higher affinities for IGF-I and IGF-II than does the IGF-IR, serves to block access of these ligands to the receptor. Although the need for such regulatory proteins is consistent with the constitutive secretion of IGFs from many cell types, it is not surprising that additional functions have begun to be uncovered for these proteins. This review will examine new and old actions of the IGFBPs from a biochemical and cell biological perspective.
doi:10.1016/j.ghir.2004.02.003
PMCID: PMC3347923  PMID: 15336228
Insulin-like growth factor (IGF); IGF binding protein (IGFBP); IGF-I receptor (IGF-IR); Binding site; Structure–function
5.  Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2 
Summary
Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4+ and CD8+ T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which, in turn, leads to suppression of T-cell functions.
doi:10.1097/CJI.0b013e3181b91c9c
PMCID: PMC3333835  PMID: 20145550
endothelial cell; T cells; tumor immunity; lung; cytokines
6.  Defining the pathway to insulin-like growth factor system targeting in cancer 
Biochemical pharmacology  2010;80(8):1115-1124.
The insulin-like growth factors (IGFs; IGF-1 and IGF-2) play central roles in cell growth, differentiation, survival, transformation and metastasis. The biologic effects of the IGFs are mediated by the IGF-1 receptor (IGF-1R), a receptor tyrosine kinase with homology to the insulin receptor (IR). Dysregulation of the IGF system is well recognized as a key contributor to the progression of multiple cancers, with IGF-1R activation increasing the tumorigenic potential of breast, prostate, lung, colon and head and neck squamous cell carcinoma (HNSCC). Despite this relationship, targeting the IGF-1R has only recently undergone development as a molecular cancer therapeutic. As it has taken hold, we are witnessing a robust increase and interest in targeting the inhibition of IGF-1R signaling. This is accentuated by the list of over 30 drugs, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) that are under evaluation as single agents or in combination therapies [1]. The IGF binding proteins (IGFBPs) represent the third component of the IGF system consisting of a class of six soluble secretory proteins. They represent a unique class of naturally occurring IGF antagonists that bind to and sequester IGF-1 and IGF-2, inhibiting their access to the IGF-1R. Due to their dual targeting of the IGFs without affecting insulin action, the IGFBPs are an untapped “third” class of IGF-1R inhibitors. In this commentary, we highlight some of the significant aspects of and prospects for targeting the IGF-1R and describe what the future may hold.
doi:10.1016/j.bcp.2010.06.013
PMCID: PMC2934757  PMID: 20599789
IGF-1 receptor; receptor tyrosine kinase; targeted therapeutics; resistance
7.  High-yield bacterial expression and structural characterization of recombinant human insulin-like growth factor binding protein-2 
The diverse biological activities of the insulin-like growth factors (IGF-1 and IGF-2) are mediated by the IGF-1 receptor (IGF-IR). These actions are modulated by a family of six IGF-binding proteins (IGFBP-1–6; 22–31 kDa) that via high affinity binding to the IGFs (KD ~ 300–700 pM) both protect the IGFs in the circulation and attenuate IGF action by blocking their receptor access. In recent years, IGFBPs have been implicated in a variety of cancers. However, the structural basis of their interaction with IGFs and/or other proteins is not completely understood. A critical challenge in the structural characterization of full-length IGFBPs has been the difficulty in expressing these proteins at levels suitable for NMR/X-ray crystallography analysis. Here we describe the high-yield expression of full-length recombinant human IGFBP-2 (rhIGFBP-2) in E. coli. Using a single step purification protocol, rhIGFBP-2 was obtained with >95% purity and structurally characterized using NMR spectroscopy. The protein was found to exist as a monomer at the high concentrations required for structural studies and to exist in a single conformation exhibiting a unique intra-molecular disulfide-bonding pattern. The protein retained full biologic activity. This study represents the first high-yield expression of wild-type recombinant human IGFBP-2 in E. coli and first structural characterization of a full-length IGFBP.
doi:10.1016/j.abb.2010.06.006
PMCID: PMC2934857  PMID: 20541521
Recombinant human IGF- binding protein-2 (rhIGFBP-2); E coli Expression; Protein Purification; Protein Structure; Secondary Structure; G-matrix Fourier transform (GFT) NMR
8.  Regulation of Invasive Behavior by Vascular Endothelial Growth Factor is HEF1-dependent 
Oncogene  2010;29(31):4449-4459.
We previously reported a VEGF autocrine loop in head and neck squamous cell carcinoma (HNSCC) cell lines, supporting a role for VEGF in HNSCC tumorigenesis. Using a phosphotyrosine proteomics approach we screened the HNSCC cell line, SCC-9 for effectors of VEGFR2 signaling. A cluster of proteins involved in cell migration and invasion, including the p130Cas paralog, human enhancer of filamentation1 (HEF1/Cas-L/Nedd9) was identified. HEF1 silencing and overexpression studies revealed a role for VEGF in regulating cell migration, invasion, and MMP expression in a HEF1-dependent manner. Moreover, cells plated on extracellular matrix coated coverslips exhibited enhanced invadopodia formation in response to VEGF that was HEF1-dependent. Immunolocalization revealed that HEF1 colocalized to invadopodia with MT1-MMP. Analysis of HNSCC tissue microarrays for HEF1 immunoreactivity revealed a 6.5-fold increase in the odds of having a metastasis with a high HEF1 score compared to a low HEF1 score. These findings suggest that HEF1 may be prognostic for advanced stage HNSCC. They also demonstrate for the first time, that HEF1 is required for VEGF-mediated HNSCC cell migration and invasion, consistent with HEF1’s recent identification as a metastatic regulator. These results support a strategy targeting VEGF:VEGFR2 in HNSCC therapeutics.
doi:10.1038/onc.2010.185
PMCID: PMC2921319  PMID: 20498643
VEGF; Invadopodia; Cell migration; invasion; HEF1; NEDD9; CAS-L; tyrosine phosphorylation
9.  Enhanced Psychosocial Well-Being Following Participation in a Mindfulness-Based Stress Reduction Program is Associated with Increased Natural Killer Cell Activity 
Mindfulness-based stress reduction (MBSR) programs have consistently been shown to enhance the psychosocial well-being of participants. Given the well-established association between psychosocial factors and immunologic functioning, it has been hypothesized that enhanced psychosocial well-being among MBSR participants would be associated with corresponding changes in markers of immune activity.
Objective
To examine changes in psychosocial and immunologic measures in a heterogeneous patient sample following participation in a MBSR program.
Design
A single-group, pre-test post-test design was utilized.
Setting
The intervention was conducted at an academic health center.
Subjects
This pilot study involved twenty-four participants (aged 28–72 years). Inclusion criteria were: ≥18 years of age, English-speaking, no known autoimmune disorder.
Intervention
The intervention was an 8-week MBSR program.
Outcome Measures
Distress and quality of life (QOL) measures included the Brief Symptom Inventory-18 and the Medical Outcomes Survey (MOS) Short-Form Health Survey (SF-36), respectively. Immunologic measures included natural killer (NK) cell cytolytic activity and C-reactive protein (CRP).
Results
Patients completed psychosocial assessments and provided a blood sample at baseline (pre-MBSR) and within 2 weeks post-MBSR. Significant improvements in anxiety and overall distress as well as across multiple domains of QOL were observed from baseline to post-MBSR. Reductions in anxiety and overall distress were associated with reductions in CRP. Patients who reported improvement in overall mental well-being also showed increased NK cytolytic activity from pre- to post-MBSR, whereas patients who reported no improvement in mental well-being showed no change in NK cytolytic activity.
Conclusion
Positive improvement in psychological well-being following MBSR was associated with increased NK cytolytic activity and decreased levels of CRP.
doi:10.1089/acm.2009.0018
PMCID: PMC2921566  PMID: 20455784
mindfulness-based stress reduction; psychosocial functioning; natural killer cell activity; C-reactive protein
10.  Enhanced Psychosocial Well-Being Following Participation in a Mindfulness-Based Stress Reduction Program Is Associated with Increased Natural Killer Cell Activity 
Abstract
Background
Mindfulness-based stress reduction (MBSR) programs have consistently been shown to enhance the psychosocial well-being of participants. Given the well-established association between psychosocial factors and immunologic functioning, it has been hypothesized that enhanced psychosocial well-being among MBSR participants would be associated with corresponding changes in markers of immune activity.
Objectives
The objectives of this study were to examine changes in psychosocial and immunologic measures in a heterogeneous patient sample following participation in a MBSR program.
Design
A single-group, pretest/post-test design was utilized.
Setting
The intervention was conducted at an academic health center.
Subjects
This pilot study involved 24 participants (aged 28–72 years). Inclusion criteria were as follows: ≥18 years of age, English-speaking, and no known autoimmune disorder.
Intervention
The intervention was an 8-week MBSR program.
Outcome measures
Distress and quality of life (QOL) measures included the Brief Symptom Inventory-18 and the Medical Outcomes Survey Short-Form Health Survey, respectively. Immunologic measures included natural killer (NK) cell cytolytic activity and C-reactive protein (CRP).
Results
Patients completed psychosocial assessments and provided a blood sample at baseline (pre-MBSR) and within 2 weeks post-MBSR. Significant improvements in anxiety and overall distress as well as across multiple domains of QOL were observed from baseline to post-MBSR. Reductions in anxiety and overall distress were associated with reductions in CRP. Patients who reported improvement in overall mental well-being also showed increased NK cytolytic activity from pre- to post-MBSR, whereas patients who reported no improvement in mental well-being showed no change in NK cytolytic activity.
Conclusions
Positive improvement in psychologic well-being following MBSR was associated with increased NK cytolytic activity and decreased levels of CRP.
doi:10.1089/acm.2009.0018
PMCID: PMC2921566  PMID: 20455784
11.  Secretion of VEGF by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions 
Human immunology  2009;70(6):375-382.
Patients with oral squamous cell carcinoma (OSCC) have severe defects in anti-tumor immune functions. Endothelial cells are potential regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. The present studies showed that supernatants from endothelial cells exposed to OSCC-conditioned media (EndoOSCC-sup) had elevated levels of the immune suppressive products PGE2 and VEGF as compared to supernatants from endothelial cells treated with media alone (EndoMedia) or with keratinocyte-conditioned media (EndoKer-sup). Antibody neutralization of OSCC-derived VEGF prevented tumor-conditioned media from inducing endothelial cells to increase production of PGE2 and VEGF. Furthermore, treatment of T-cells with supernatants from EndoOSCC-sup resulted in diminished T-cell proliferation and decreased IFN-γ production, when compared to T-cells treated with media or supernatants from EndoMedia or EndoKer-sup controls. T-cell levels of granzyme B and perforin were reduced after treatment with supernatant from EndoOSCC-sup compared to control treatments. Addition of VEGF neutralizing antibody to the OSCC-conditioned media prevented endothelial cells from being skewed to downregulate T-cell proliferation and production of IFN-γ, perforin and granzyme B. Taken together, these studies provide support for the use of VEGF targeting therapies as an immunotherapeutic agent to block induction of immune suppressive endothelial cells in patients with OSCC.
doi:10.1016/j.humimm.2009.01.014
PMCID: PMC2746465  PMID: 19480853
Oral squamous cell carcinoma (OSCC); vascular endothelial growth factor (VEGF); endothelial cell; T-cell; immune suppression
12.  Integrative Medicine Research at an Academic Medical Center: Patient Characteristics and Health-Related Quality-of-Life Outcomes 
Abstract
Objective
To characterize patients seeking care at a university-based integrative medicine practice, and to assess short-term changes in health-related quality of life (HRQoL) associated with integrative medical treatment.
Design
Prospective, observational study.
Setting
This study was conducted at a large U.S. academic medical center affiliated with the Consortium of Academic Health Centers for Integrative Medicine.
Participants
Seven hundred and sixty-three (763) new patients with diverse medical conditions participated in the study. Mean age was 49 years (standard deviation = 16, range = 14–93). Two thirds of patients were women and three quarters were white. The most common International Classification of Diseases 9th Revision medical diagnoses were malaise and fatigue, myalgia and myositis, allergy, anxiety or depression, hypertension, malignant neoplasm of the breast, lumbago, and irritable bowel disease. Over half the sample had two or more comorbid medical conditions.
Outcome measure
The Medical Outcomes Study 36-item Short-Form (SF-36) health survey was used to measure HRQoL at initial assessment and 3-months following integrative medicine consultation.
Results
Baseline SF-36 scores fell below the 25th percentile, indicating substantially compromised HRQoL. Physician-prescribed treatment modalities included anthroposophical medicine, nutritional medicine, Western herbs, homeopathy, nutritional counseling, and acupuncture. Three (3) month follow-up assessment revealed statistically significant improvements on all eight SF-36 subscales among survey respondents. HRQoL effect sizes ranged from 0.17 (Physical Functioning) to 0.41 (Social Functioning), with a mean of 0.30. HRQoL effects were consistent among demographic subgroups.
Conclusions
Integrative medical treatment at a university-based center is associated with significant increases in HRQoL for a medically diverse population with substantial comorbidity and functional limitations. Controlled studies that measure HRQoL and additional outcomes related to whole person health—physical, mental, social, and spiritual—are needed to determine the full therapeutic potential of integrative medicine, and to determine efficacy and cost-effectiveness relative to conventional medical care.
doi:10.1089/acm.2008.0114
PMCID: PMC3153865  PMID: 18620477

Results 1-12 (12)