The process of development and differentiation are influenced by chemomechanical forces generated by the structural network of the cell, which includes the interconnected extracellular matrix, cell adhesion molecules, cytoskeleton, and nuclear matrix. Multiple studies support the role of these components in development and differentiation. Alterations in the structural components of the cell often accompany neoplastic progression although the significance of these changes to loss of growth controls in neoplastic cells is poorly understood. We have implicated a tumor suppressor gene product in an intrinsic block of cellular growth responses to growth factor signals under conditions that are cell shape- and attachment-dependent. Cells that have lost a tumor suppressor gene (supB-) do not exhibit autonomous anchorage-independent growth but grow in soft agar in the presence of serum and growth factors. Cells that retain tumor suppressing ability (supB+) are growth inhibited in agar even in the presence of growth factors. Although nontumorigenic, the supB- cells display alterations of actin microfilament organization characteristic of tumor cells. mRNA and protein levels of the actin binding protein tropomyosin-1 (TM-1) were down-regulated in subB- compared to supB+ cells. Expression of an antisense cDNA for hamster TM-1 induced an actin microfilament organization in supB- cells that was indistinguishable from that observed in supB- cells. In addition, supB+ clones expressing antisense TM-1 acquired the anchorage-independent growth potential characteristic of supB- clones. These data indicate that TM-1 can regulate microfilament organization and provide direct evidence for cytoskeletal regulation of anchorage-independent growth. Our working hypothesis is that loss of a tumor suppressor gene in the supB- cells result in cell shape- dependent differences in growth and gene expression manifest related to these structural perturbations. The altered cell structure, anchorage- independent growth, and patterns of gene expression that correlate with loss of the tumor suppressor phenotype in these cells may be illustrative of a general mechanism relating cell shape, differentiation, and cancer.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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