Biomedical subjects

Ian C Mackenzie

Publications and source records attributed to Ian C Mackenzie.

4 recordsLinked to original sources

PubMed2006

Stem cell properties and epithelial malignancies.

The growth and repair of normal tissues depends on a small sub-population of cells termed somatic stem cells whose primary characteristic is an ability for indefinite self-renewal. Epithelial stem cells divide to produce cells, termed transient amplifying cells, that undergo a few rounds of more rapid division before they terminally differentiate. Evidence that the growth of tumours, as for normal tissues, is ultimately dependent on a subpopulation of the proliferatively competent cells was first shown for leukaemias by isolation of small sub-populations of phenotypically distinct 'tumour-initiating cells'. Differing cell surface phenotypes also prospectively identify tumour-initiating sub-populations in solid tumours. Even cell lines derived from tumours retain hierarchical stem cell patterns demonstrable as differing clonogenic abilities related to cellular properties such as size, adhesiveness, dye exclusion, and patterns of gene expression. Malignant stem cells appear to form the primary targets of therapy, but how differences between malignant stem and other cells affect therapeutic responses remains unclear. However, transplantation methods exist for their analysis and the in vitro persistence of stem cell patterns may provide systems for developing new therapeutic approaches.

Carcinoma↗

PubMed2005

Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines.

Recent work indicates that the growth and behavior of cancers are ultimately determined by a small subpopulation of malignant stem cells and that information about the properties of these cells is urgently needed to enable their targeting for therapeutic elimination. A key feature of normal stem cells is their asymmetrical division, the mechanism that allows stem cell self-renewal while producing hierarchies of amplifying and differentiating cells that form the bulk of the tissue. Most cancer deaths result from epithelial malignancies, but the extent to which the hierarchical proliferative stem and amplifying cell patterns of normal epithelia are actually retained in epithelial malignancies has been unclear. Here we show that even cell lines generated from carcinomas consistently produce in vitro colony patterns unexpectedly similar to those produced by the stem and amplifying cells of normal epithelia. From the differing types of colony morphologies formed, it is possible to predict both the growth potential of their constituent cells and their patterns of macromolecular expression. Maintenance of a subpopulation of stem cells during passage of cell lines indicates that the key stem cell property of asymmetrical division persists but is shifted towards enhanced stem cell self-renewal. The presence of malignant epithelial stem cells in vivo has been shown by serial transplantation of primary cancer cells and the present observations indicate that stem cell patterns are robust and persist even in cell lines. An understanding of this behavior should facilitate studies directed towards the molecular or pharmacologic manipulation of malignant stem cell survival.

Breast Neoplasms↗

PubMed2004

Intrinsic patterns of behavior of epithelial stem cells.

The early concepts concerning hematopoietic and epithelial stem cells that were derived from kinetic studies have been greatly enhanced by new information about a range of other properties of somatic and embryonic stem cells. Firstly, the stem and amplifying pattern characteristically established by epithelial lineages has been found to represent an intrinsic pattern that is generated by somatic epithelial stem cells without the need for additional environmental information. Secondly, it is now apparent that somatic epithelial stem cells are plastic and can be directed into a range of new pathways of differentiation by heterotypic interactions. The mechanisms of this plasticity need to be reconciled with the normally stable commitment of these cells to production only of progeny entering a tightly restricted range of phenotypic pathways. The present review discusses the intrinsic properties of epithelial stem cells and how they may be acted upon by connective tissues to generate a wide range of phenotypically different epithelial structures.

Animals↗

PubMed2004

Growth of malignant oral epithelial stem cells after seeding into organotypical cultures of normal mucosa.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is associated both with the local expansion of clones of malignant cells and with their further migration to regional and distant sites. The interactions that occur between normal and malignant cells during these events are not well modelled by standard culture conditions, but organotypical cultures, in which epithelial cells are grown on a matrix containing fibroblasts, provide a suitable environment for such investigations. METHODS: Cells from five cell lines, each derived from OSCC and marked by retroviral transduction with alkaline phosphatase, were incorporated as small subpopulations (0.1-5%) in uniformly differentiating organotypical cultures constructed from normal oral mucosal cells. The patterns of growth of the malignant cells within the normal epithelium were examined for 3 weeks. RESULTS: There was variation between the different cell lines in their rates and patterns of growth, but all cell lines produced clusters of malignant cells that had expanded within 3 weeks to replace the normal epithelium. The appearance and spacing of these clusters suggested that each was derived from a single progenitor cell. The number of malignant cells initially present within a given area of organotypical epithelium was much greater than the number of expanding cell clusters subsequently formed. Cluster-forming cells thus represented only a subpopulation of the tumour cells. CONCLUSIONS: The organotypical model allows examination of interactions occurring between cells derived from OSCC and normal epithelia. The three-dimensional nature of organotypical cultures, together with their more normal patterns of differentiation, provides an environment that more closely mimics the in vivo environment in which tumours develop. The finding that only a subpopulation of tumour cells forms expanding tumour colonies suggests a range of growth potentials within a tumour population and may provide preliminary evidence for some form of stem and amplifying cell pattern.

Carcinoma, Squamous Cell↗