Basement Membrane Polarizes Epithelial Cells and Its Loss Can Result in Neoplastic Disorganization (Cell Shape, Cancer, Morphogenesis)

Donald Elliot Ingber, Yale University.

This is an Open Access Thesis


The studies described in this dissertation demonstrate that basement membrane may be required for maintenance of organized epithelial tissue architecture. The structural organization of normal rat pancreatic acinar epithelium is fully characterized in order to analyze its neoplastic disorganization within a pancreatic acinar cell tumor. Transmission electron microscopy and indirect immunofluorescence microscopy of frozen semithin tissue sections are utilized to localize different components of the plasmalemma, cytoskeleton, basement membrane and connective tissue. Normal acinar cells sit on a continuous basement membrane and display a polarized distribution of intracellular organelles, cytoskeletal elements, and distinct membrane domains while these organized cell relations are lost within the parenchyma of the pancreatic acinar carcinoma. This tumor-associated disorganization of normal epithelial cell relations correlates directly with absence of integral basement membrane within the parenchyma of this tumor. Interestingly, pancreatic acinar tumor cells also retain the ability to reorient in vivo when in direct contact with intact basement membrane appears only along the connective tissue boundary.Amniotic basement membrane and stroma are also utilized for studies designed to determine if basement membrane is sufficient to trigger pancreatic epithelial tumor cell polarization in vitro.Thus, basement membrane is necessary and sufficient for reorientation of independent epithelial tumor cells in vitro and so the organization of a polarized epithelium may be directed by forces from outside the cell via basement membrane. Stability of epithelial form may require continued presence of intact basement membrane and its dissolution could be responsible for neoplastic disorganization of epithelial architectural relations as observed within the pancreatic acinar cell carcinoma. A model for architectural regulation of tissue structures with basement membrane as a transducer of physical forces is presented. (Abstract shortened with permission of author.)