Computational Modeling and Analysis of the TGF-β-induced ERK and SMAD Pathways.

TGF-β, an important cytokine that plays a key role in many diseases regulates a wide array of cellular and physiologic processes via several TGF-β-driven signaling cascades, including the SMAD and non-SMAD-driven pathways. However, the detailed mechanisms by which TGF-β induces such diverse responses remain poorly understood. In particular, compared to the SMAD-dependent pathway, SMAD-independent pathways such as the ERK/MAPK pathway, which is critical in cancer progression, are less characterized.

Cell Culture-Based Assessment of Toxicity and Therapeutics of Phytochemical Antioxidants.

Plant-derived natural products are significant resources for drug discovery and development including appreciable potentials in preventing and managing oxidative stress, making them promising candidates in cancer and other disease therapeutics. Their effects have been linked to phytochemicals such as phenolic compounds and their antioxidant activities. The abundance and complexity of these bio-constituents highlight the need for well-defined in vitro characterization and quantification of the plant extracts/preparations that can translate to in vivo effects and hopefully to clinical use.

Experimental integrative muscular movement technique enhances cervical range of motion in patients with chronic neck pain: a pilot study.

Introduction: Neck pain presents a tremendous physical and financial burden. This study compared the efficacy of the complementary and alternative medical treatments of integrative muscular movement technique (IMMT) and Swedish massage on neck pain in women of occupation age, the largest demographic group with neck pain.

Methods: A total of 38 women were assigned to IMMT (n=28) or Swedish massage (n=10) in a blinded manner.

A control engineering approach to understanding the TGF-β paradox in cancer.

TGF-β, a key cytokine that regulates diverse cellular processes, including proliferation and apoptosis, appears to function paradoxically as a tumour suppressor in normal cells, and as a tumour promoter in cancer cells, but the mechanisms underlying such contradictory roles remain unknown. In particular, given that this cytokine is primarily a tumour suppressor, the conundrum of the unusually high level of TGF-β observed in the primary cancer tissue and blood samples of cancer patients with the worst prognosis, remains unresolved. To provide a quantitative explanation of these paradoxical observations, we present, from a control theory perspective, a mechanistic model of TGF-β-driven regulation of cell homeostasis.

A novel massage therapy technique for management of chronic cervical pain: a case series.

Background: Neck pain is a generalized condition resulting from a complex etiology with presentation of a wide variety of symptoms. Neck pain is most often accompanied by decreased range of motion (ROM), muscle and joint stiffness, and limitations in functional capabilities. This condition may result in significant personal and societal burden.

Effect of moderate-to-severe chronic kidney disease on flow-mediated dilation and progenitor cells.

A reduction in progenitor cell populations that help preserve vascular continuity and induce vascularization may accentuate endothelial cell apoptosis and dysfunction, ultimately contributing to organ failure and increased cardiovascular disease in chronic kidney disease (CKD). We hypothesized that CD45+ myeloid and CD34+ hematopoietic circulating progenitor cell (CPC) subpopulations would be reduced, peripheral blood mononuclear cell (PBMNC) colony-forming units (CFU) would be impaired, and flow-mediated dilation (FMD) would be impaired in patients with moderate-to-severe CKD as compared with healthy controls. Eleven moderate-to-severe CKD patients (mean estimated glomerular filtration rate [eGFR]: 36 ± 5) and 14 healthy controls were studied; blood was drawn and FMD was assessed by brachial artery FMD.

Soluble perlecan domain I enhances vascular endothelial growth factor-165 activity and receptor phosphorylation in human bone marrow endothelial cells.

Background: Immobilized recombinant perlecan domain I (PlnDI) binds and modulates the activity of heparin-binding growth factors, in vitro. However, activities for PlnDI, in solution, have not been reported. In this study, we assessed the ability of soluble forms to modulate vascular endothelial growth factor-165 (VEGF165) enhanced capillary tube-like formation, and VEGF receptor-2 phosphorylation of human bone marrow endothelial cells, in vitro.

Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion.

Chemokines and their corresponding receptor interactions have been shown to be involved in prostate cancer (PCa) progression and organ-specific metastasis. We have recently shown that PCa cell lines and primary prostate tumors express CXCR5, which correlates with PCa grade. In this study, we present the first evidence that CXCL13, the only ligand for CXCR5, and IL-6 were significantly elevated in PCa patient serum compared to serum from subjects with benign prostatic hyperplasia (BPH), or high-grade prostatic intraepithelial neoplasia (HGPIN) as well as normal healthy donors (NHD).

Quantitative modeling and analysis of the transforming growth factor beta signaling pathway.

Transforming growth factor beta (TGF-beta) signaling, which regulates multiple cellular processes including proliferation, apoptosis, and differentiation, plays an important but incompletely understood role in normal and cancerous tissues. For instance, although TGF-beta functions as a tumor suppressor in the premalignant stages of tumorigenesis, paradoxically, it also seems to act as a tumor promoter in advanced cancer leading to metastasis. The mechanisms by which TGF-beta elicits such diverse responses during cancer progression are still not entirely clear.

Nonlinear model-based estimates of IC(50) for studies involving continuous therapeutic dose-response data.

We present statistical details for estimating an in vitro 50% inhibitory concentration (IC(50)), based on several models for continuous response data fit to bone-marrow endothelial cell lines replicated in vehicle and at several dose increments. Nonlinear models are fit via maximum likelihood assuming normal errors, and primary attention is given to exponential, Gompertz, and scaled logistic dose-response curves that admit increasing or decreasing monotonic and sigmoidal patterns. Careful consideration is given to dose axis scaling, comparative model fit via mean squared error and graphical assessment, analogues to weighted least squares analysis to address heterogeneity of variance across doses, and potential hormetic effects.

Novel surface expression of reticulocalbin 1 on bone endothelial cells and human prostate cancer cells is regulated by TNF-alpha.

An unbiased cDNA expression phage library derived from bone-marrow endothelial cells was used to identify novel surface adhesion molecules that might participate in metastasis. Herein we report that reticulocalbin 1 (RCN1) is a cell surface-associated protein on both endothelial (EC) and prostate cancer (PCa) cell lines. RCN1 is an H/KDEL protein with six EF-hand, calcium-binding motifs, found in the endoplasmic reticulum.

Rho GTPases in PC-3 prostate cancer cell morphology, invasion and tumor cell diapedesis.

Background: The Rho GTPases comprise one of the eight subfamilies of the Ras superfamily of monomeric GTP-binding proteins and are involved in cytoskeletal organization. Previously, using a dominant negative construct, we demonstrated a role for RhoC GTPase in conferring invasive capabilities to PC-3 human prostate cancer cells. Further, we demonstrated that inactivation of RhoC led to morphological changes commensurate with epithelial to mesenchymal transition (EMT) and was accompanied by increased random, linear motility and decreased directed migration and invasion.

Stepping out of the flow: capillary extravasation in cancer metastasis.

In order for cancer cells to successfully colonize a metastatic site, they must detach from the primary tumor using extracellular matrix-degrading proteases, intravasate and survive in the circulation, evade the immune response, and extravasate the vasculature to invade the target tissue parenchyma, where metastatic foci are established. Though many of the steps of metastasis are widely studied, the precise cellular interactions and molecular alterations associated with extravasation are unknown, and further study is needed to elucidate the mechanisms inherent to this process. Studies of leukocytes localized to inflamed tissue during the immune response may be used to elucidate the process of cancer extravasation, since leukocyte diapedesis through the vasculature involves critical adhesive interactions with endothelial cells, and both leukocytes and cancer cells express similar surface receptors capable of binding endothelial adhesion molecules.

Preferential association of prostate cancer cells expressing prostate specific membrane antigen to bone marrow matrix.

Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed almost exclusively in prostatic epithelial cells. Expression of PSMA is elevated in prostate cancer, with levels closely correlated with disease grade. Although the highest levels of PSMA expression are associated with high-grade, hormone-refractory and metastatic prostate cancer, the significance of elevated PSMA expression in advanced prostate cancer has yet to be fully elucidated.

Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells.

Background: Stromal cell-derived factor-1 (SDF-1 or CXCL12) and CXCR4 are key elements in the metastasis of prostate cancer cells to bone--but the mechanisms as to how it localizes to the marrow remains unclear.

Methods: Prostate cancer cell lines were stimulated with SDF-1 and evaluated for alterations in the expression of adhesion molecules using microarrays, FACs, and Western blotting to identify alpha(v)beta(3) receptors. Cell-cell adhesion and invasion assays were used to verify that activation of the receptor is responsive to SDF-1.

Thalidomide and analogues: current proposed mechanisms and therapeutic usage.

Microvessel density is a prognostic factor for many cancers, including prostate. For this reason, several studies and therapeutic approaches that target the tumor microvasculature have been attempted. Thalidomide has long been recognized as an antiangiogenic molecule.

Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer.

Prostate cancer (PCa) is no exception to the multi-step process of metastasis. As PCa progresses, changes occur within the microenvironments of both the malignant cells and their targeted site of metastasis, enabling the necessary responses that result in successful translocation. The majority of patients with progressing prostate cancers develop skeletal metastases.

The effect of bone-associated growth factors and cytokines on the growth of prostate cancer cells derived from soft tissue versus bone metastases in vitro.

Prostate cancer metastasis to bone may be mediated by preferential proliferation of these cells in the bone's microenvironment. We hypothesize that this preferential proliferation is mediated by bone-associated growth factors (GFs) and cytokines. To test our hypothesis, human prostate cancer cells, derived from both soft tissue (LNCaP, DuCaP, DU145) and bone metastases (PC-3, VCaP, MDA-2a, MDA-2b), were treated with bone-associated GFs and cytokines (PDGF, IGF-1, TGF-beta, EGF, bFGF, TNF-alpha, IL-1, and IL-6) for 48 h, and their growth responses were compared.

Stromal factors involved in prostate carcinoma metastasis to bone.

Background: Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site.

Methods: The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth.

A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines.

Objectives: To identify genes important in prostate cancer metastatic to bone. Bone-specific metastasis is a common feature of prostate cancer and a significant cause of morbidity.

Methods: To identify factors involved in organ-specific metastasis, we used cDNA microarray analysis to compare a bone-derived cell line, VCaP, with a soft tissue-derived cell line, DuCaP.

The role of alpha(v)beta(3) in prostate cancer progression.

Integrin alpha(v)beta(3) is involved in varied cell biological activities, including angiogenesis, cell adhesion, and migration on several extracellular matrix components. Although alpha(v)beta(3) is not typically expressed in epithelial cells, it is expressed in macrophages, activated leukocytes, cytokine-stimulated endothelial cells, osteoclasts, and certain invasive tumors. Interestingly, the adhesion and migration of breast cancer cells on bone matrix are mediated, in part, by alpha(v)beta(3).

The regulation of prostate cancer cell adhesion to human bone marrow endothelial cell monolayers by androgen dihydrotestosterone and cytokines.

A previous study from our laboratory suggested that prostate cancer metastasis to bone may be mediated, in part, by preferential adhesion to human bone marrow endothelial (HBME) cells. Tumor cell adhesion to endothelial cells may be modulated by the effect of cytokines on cell adhesion molecules (CAMs). Tumor necrosis factor-alpha (TNF-alpha) regulates VCAM expression on the endothelium and this effect is enhanced by dihydrotestosterone (DHT).

New discoveries in prostate cancer biology and treatment. 5-9 December 2001, Naples, Florida, USA.

Androgen independence and bone metastasis are lethal complications in patients with advanced prostate cancer. Presently, there is no cure for patients with androgen-independent prostate cancer. In order to develop more effective therapies for this disease, the molecular events involved in the development of androgen independence and bone metastasis must be elucidated and then targeted by therapeutic agents.