Identification of novel cell components designated “tissue organizing structures”* with potential applications in cancer prevention/therapeutics, tissue bioengineering, and gene therapy

A98

This research describes the identification of a novel cellular structure, approximately 2 microns in diameter, that was isolated from normal and malignant human tumor cell lines, but has also been found to be present in diverse mammalian and even plant species, suggesting that this represents a ubiquitous cellular component of multicellular systems. These unique entities are comprised of membrane bound vesicles that incorporate genetic material that are either “budded” from the surface of the cell, or are released by cell lysis. These novel cell-derived structures have been given the name “Tissue Organizing Structures”* or “TOS” based on their observed properties, which include numerous functions associated with homotypic/heterotypic cell-to-cell and extracellular matrix (ECM) interactions that have been studied using an in vitro system to isolate and assess their biological properties by live imaging photomicroscopy, videography and histological staining procedures.
 >The biological activities of TOS structures documented in this research include:
 >• Central role in solid tumor development in vitro assessed in brain, colon and lung tumor cell lines;
 >• Exchange of genetic material by recombination with cells or other TOS;
 >• TOS/TOS fusions to generate tubular structures as connectors to link separate tumor masses;
 >• TOS fusion to cell membrane associated with rapid morphogenetic changes in host cell, including induction of masses of intracellular TOS , designated “TOS bags”, released by cell lysis;
 >• Cell-free TOS generate complex tissue-like structures in vitro;
 >• Cell-free TOS isolated from lung carcinoma cells induce rapid malignant transformation of normal lung cells in vitro;
 >• Cell-free TOS isolated from normal lung cells induce the rapid reversion of transformed malignant lung cells in vitro to a normal phenotype followed by the induction of cell death.
 >We propose a model suggesting that TOS may play a critical role in the following processes associated with solid tumor behavior:
 >• Role in producing genetic instability in tumors via novel forms of cell fusion and somatic recombination;
 >• Role in tumor spread via formation of tubules enabling tumor spread and increasing tumor network area;
 >• Role in somatic genetic exchange, tissue morphogenesis, intercellular communication;
 >• Role in metastasis as a vehicle of tumor spread and metastatic site tissue transformation;
 >• Role in altering tumor/stromal microenvironmental interactions associated with proposed epithelial-to-mesenchymal transitions (EMTs), and tumor/stem cell interactions.
 >In addition to these properties associated with solid tumor behavior, this research suggests that TOS isolated from normal tissue may have important potential preventive and therapeutic applications in clinical cancer research.
 >*Patent Pending, 2007