Bone Morphodifferentiation and Tumorigenesis

BONE MORPHODIFFERENTIATION AND TUMORIGENESIS* MARSHALL R. URISTf By means of correlated observations on the roentgenographic and histological structure, in an article written over 50 yr ago, Phemister [1] demonstrated diat osteosarcomas contain tumorous and normal nontumorous bone. Normal growing bone has a trabecular pattern that is specific for each bone and part of a bone as well as a characteristic microscopic palisade of cuboidal basiphilic cells named osteoblasts. Tumorous bone has a disoriented structure widi trabeculae enveloped in a random arrangement of bizarrely shaped anaplastic cells. Tumorous bone grows by proliferation of transformed osteoblasts. The alterations in gene structure and function in the transformed state are obscure, but the involvement is comparable to a mutation. The criteria for cell transformation generally include: loss of cell contact inhibition; altered morphology ; increased growdi rate; increased capacity to persist in serial subcultures; chromosomal abnormalities; increased resistance to reinfection by die transforming virus; emergence of new antigens; capacity to form neoplasms [2]. Viral-induced malignant transformation constitutes a heritable change and is accompanied by the loss of regulatory controls of cell growdi. Present knowledge ofnonmalignant morphodifferentiation, as well as malignant transformation, is chiefly descriptive. Data on the biochemical controls of morphodifferentiation are lacking. The process beginning widi the fertilized ovum and ending widi the mechanics of unfolding of die structural characteristics, form, and size of functional tissues defies present understanding. The problem is the prerogative of students of dieoretical, as distinguished from experimental, biology. ?The 27th Dallas B. Phemister Lecture, November 15, 1977. tDirector, UCLA Bone Research Laboratory, 1000 Veteran Avenue, Los Angeles, California 90024. 1 am deeply indebted to my collaborators, D. H. Hanamura, N. Nakata, J. Felser, G. Styfestad, M. Miki, J. Mirra, K. Tibone, and G.A.M. Finerman and to S. Kirkpatrick, S. Uyeno, and E. King for technical assistance in securing die information presented in this paper. The research was supported by a grant-in-aid from USPHS, National Institutes of Health, NIDR, DE-02103-14.© 1979 by The University of Chicago. 0031-5982/79/2222-0008$01.00 Perspectives in Biology andMedicine ¦ Winter 1979 ¦ Part 2 | S89 Bone morphodifferentiation can be consistently initiated in postfetal life in muscle, a tissue that in die lifetime of the animal does not spontaneously differentiate into any odier organ structure [3]. As in development in embryonic life, the process can be arbitrarily divided into morphogenetic and cytodifferentiation phases [4]. The morphogenetic phase begins by a chain of reactions of proliferating cell populations to chemical agents collectively termed morphogens [5-8]. Every new generation of cells synthesizes and transfers morphogen in minute quantities to a succeeding generation ofresponding tissue cells. Theoretically, morphogens have as low molecular mass as hydrophobic peptides or polypeptides [7], which are chiefly bound to proteins and only partly free or diffusible. The concentration of free morphogen in developing tissues may be as low as ??-10 M [9]. The morphogen concept is a modification of die Spemann theory of embryonic inducer substances and die Waddington tiieory of embryonic evocators [5]. Cells exposed to the critical concentration of free morphogen in the extracellular fluid differentiate or adopt a new padiway of development of a specialized form [7]. Covert stages of differentiation of skeletal tissues are observed by accumulation of biosyndietic products such as hyaluronate, collagen, and enzymes (e.g., hyaluronidase, alkaline phosphatase ). Overt stages are recognized by deposition of extracellular hyaline matrix or calcifiable bone collagen matrix. Nodiing is known about die biochemical reactions leading to the development of a concentration gradient between die source of die morphogen and its disposition in a population sink of competent responding cells. For a true comprehension of the mode of action of morphogens, present concepts of the action of hormones on specialized target cells are inadequate. Morphogens are much lower in concentration in interstitial fluids than hormones. Morphogens are surface oriented in highly compartmentalized intra- and extracellular fluids and released from protein-protein complexes. Transfer of morphogen from a transport system to a plasma-membrane morphogen receptor molecule would release a gene regulator molecule which in turn could de-repress a specific form of gene expression. An effective concentration ofmorphogen develops when a population of proliferating competent cells reaches a critical mass. The population...