Contact interactions between cells that suppress neoplastic development: can they also explain metastatic dormancy?
A comprehensive listing with accompanying discussions is given for established cases of interactions between normal and neoplastic cells of the same histotype that suppress neoplastic development. General principles that apply to the process are: (a) the requirement for a large excess of normal cells in direct contact with the neoplastic cells; (b) the effectiveness of suppression decreases with the degree of malignant progression of the neoplastic cells; and (c) the transformability of normal cells decreases under long-term negative selection, which also increases their contact suppression of neoplastic cells. Although suppression requires adhesive contact, it does not require gap junction communication, and it represents the first line of defense against tumor development. In contrast, potentially metastatic cells released from primary carcinomas into the circulation are activated to multiply when they form heterotypic adhesions with endothelial and parenchymal cells of distant organs. The great majority of the disseminated cancer cells (DCCs) fail to develop heterotypic cells adhesions in distant organs, and remain metastatically dormant as single cells. The lack of growth factors for the DCC in foreign territory also contributes to metastatic dormancy. The major insights about suppression of neoplastic development by homotypic contact arose from strictly operational experiments with living cells in culture. Molecular characterization of the cell-cell adhesions that underlie neoplastic suppression and metastasis activation has had only limited success, probably because of the complex variety of molecules involved. Hence, a program is outlined for further operational experiments on cell-cell interactions in tumor suppression to deepen our understanding of the neoplastic process, and provide possible avenues for its control.
Rubin
Harry
H
Department of Molecular and Cell Biology, Life Sciences Addition, University of California, Berkeley, CA 94720-3200, USA.
D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D008545:Melanoma / Q000473:pathology; D008648:Mesoderm / Q000502:physiology; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011930:Reaction Time / Q000502:physiology*