Body Mass Index Is More Predictive of Progenitor Number in Bone Marrow Stromal Cell Population Than Age in Men: Expanding the Predictors of the Progenitor Compartment

Research has focused on in vitro expansion of bone marrow stromal cells with the aim of developing cell-based therapies or tissue-engineered constructs. There is debate over whether there is a reduction in stem cells/osteoprogenitors in the bone marrow compartment with increasing age. The aim of this study was to investigate patient factors that affect the progenitor pool in bone marrow samples. Six milliliters of marrow aspirate was obtained from the femoral canal of 38 primary hip replacement patients (aged 28-91). Outcome measures were total nucleated cell count, colony-forming efficiency, alkaline phosphatase expression, and expression of stem cell markers. There was a nonsignificant negative correlation between age and both colony-forming efficiency and stem cell marker expression. However, body mass index showed a positive, significant correlation with colony area and number in men-accounting for up to 75% of the variation. In conclusion, body mass index, not age, was highly predictive of the number of progenitors found in bone marrow, and this relationship was sex specific. These results may inform the clinician's treatment choice when considering bone marrow-based therapies. Further, it highlights the need to widen research into patient factors that affect the adult stem cell population beyond age and reinforces the need to consider sexes separately.

In vitro testing of Advanced JAX (TM) Bone Void Filler System: species differences in the response of bone marrow stromal cells to beta tri-calcium phosphate and carboxymethylcellulose gel

The Advanced JAX (TM) Bone Void Filler System (AJBVFS) is a novel bone graft material manufactured by Smith and Nephew Orthopaedics Ltd. and comprises beta tri-calcium phosphate granules with carboxymethylcellulose (CMC) gel as a handling agent. This study investigated the potential, in vitro, of the AJBVFS to function as a delivery system for cell therapy to enhance healing of bone defects. The attachment of rabbit bone marrow stromal cells (rbBMSCs), human BMSCs (hBMSCs) and human bone-derived cells (hBDCs) to JAX (TM) granules and the effect of CMC gel on cell proliferation and differentiation were investigated. There were slight species differences in the number and morphology of cells attached on the JAX (TM) granules with less rbBMSC attachment than human. All cells tolerated the presence of CMC gel and a reduction in cell number was only seen after longer exposure to higher gel concentrations. Low concentrations of CMC gel enhanced proliferation, alkaline phosphatase (ALP) expression and ALP activity in human cells but had no effect on rbBMSC. This study suggests that AJBVFS is an appropriate scaffold for the delivery of osteogenic cells and the addition of CMC gel as a handling agent promotes osteogenic proliferation and differentiation and is therefore likely to encourage bone healing.

Comparative validation of c-kit exon 11 mutation analysis on cytology samples and corresponding surgical resections of gastrointestinal stromal tumours

Objective:

Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours

A tissue microarray analysis of 22 proteins in gastrointestinal stromal tumours ( GIST), followed by an unsupervised, hierarchical monothetic cluster statistical analysis of the results, allowed us to detect a vascular endothelial growth factor ( VEGF) protein overexpression signature discriminator of prognosis in GIST, and discover novel VEGF-A DNA variants that may have functional significance.

Targeting Human Gastrointestinal Stromal Tumor Cells with a Quadruplex-Binding Small Molecule

Most of human gastrointestinal stromal tumors (GIST) are driven by activating mutations in the protooncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumor regrowth occurs as a result of them development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus, kinase resistance may be circumvented. A naphthalene diimide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilizes both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (similar to 1 mu M) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modeling studies with a telomeric quadruplex have been used to rationalize aspects of the experimental quadruplex melting data.

The expression and prognostic impact of CXC-chemokines in stage II and III colorectal cancer epithelial and stromal tissue

BACKGROUND: The CXC-chemokine expression is linked with colorectal cancer (CRC) progression but their significance in resected CRC is unclear. We explored the prognostic impact of such expression in stage II and III CRC.

Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion

Stromal-derived growth factors are required for normal epithelial growth but are also implicated in tumour progression. We have observed inactivation of the retinoblastoma protein (Rb), through phosphorylation, in cancer-associated fibroblasts in oro-pharyngeal cancer specimens. Rb is well known for its cell-autonomous effects on cancer initiation and progression; however, cell non-autonomous functions of Rb are not well described. We have identified a cell non-autonomous role of Rb, using three-dimensional cultures, where depletion of Rb in stromal fibroblasts enhances invasive potential of transformed epithelia. In part, this is mediated by upregulation of keratinocyte growth factor (KGF), which is produced by the depleted fibroblasts. KGF drives invasion of epithelial cells through induction of MMP1 expression in an AKT- and Ets2-dependent manner. Our data identify that stromal fibroblasts can alter the invasive behaviour of the epithelium, and we show that altered expression of KGF can mediate these functions. © European Molecular Biology Organization.