On Viral Infectivity and Carcinogenesis

BRIEF PROPOSAL ON VIRAL INFECTIVITY AND CARCINOGENESIS THEOHARIS CONSTANTIN THEOHARIDES* Recent years have witnessed much research investigating cell surface constituents of normal and malignant cells in search for the etiology and possible prevention of cancer [1, 2]. In many instances, this work has focused on cases where a viral etiology has been suspected [3-9]. If viruses are the etiologic agents of cancer in humans [10, 11], then genetic differences among human subpopulations which manifest themselves in changes in surface membranes of target cells would enhance or reduce absorption and penetration of virus and thus influence the rate of tumorogenesis. It is proposed that in sickle-cell disease, blood cells might exhibit cell-surface membrane alterations which would lend these cells inaccessible to penetration and infection by carcinogenic viruses; these alterations, which would be in addition to the known hemoglobin abnormality, would be coded by a gene closely associated with the sickle hemoglobin gene. There is now increased evidence to support the premise that sickle erythrocytes exhibit several alterations in the structure of their surface membrane: Comparison of normal and sickle cells using phase microscopic, cinematographic , and scanning electron microscopic techniques show that sickle cells derive from normal cells with membrane loss [12]. Irreversibly sickled cells appear to involve an alteration of their surface membrane which enhances the extent of binding of hemoglobin to the membrane [13]. When irreversibly sickled cells are oxygenated, the fibrillar fine structure of deoxygenated hemoglobin SS is no longer seen on electron microscopy although the cells remain distorted [14]; in addition, reoxygenation of sickle SS cells results in the formation of membrane spherules which break off the cell surface resulting in extensive membrane loss [15]. Ghosts prepared from irreversibly sickled erythrocytes remain sickled [16]. If normal and sickle erythrocytes are treated with sublytic quantities of lysolecithin, the normal erythrocytes are converted to spheres while irreversibly sickled cells are not [17]. Hemoglobin SA or SS dissociation curves exhibit reduced oxygen affinity only inside the intact erythrocyte [18, 19]. The viscosity of oxygenated SS cells is greater than AA cells even though the viscosities of comparable cell-free solutions are the same [20, 21]. The freedom of rotational ?Address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510. Perspectives in Biology and Medicine ¦ Summer 1977 | 603 motion, on a molecular level, of hemoglobin molecules is smaller in oxygenated SS cells than in the equivalent cell-free solutions [22]. Sickle cells exhibit increased plasma membrane rigidity [20] as well as alterations either in the amount or in the arrangement of surface membrane phospholipids [23]. Sickle-cell membranes are also found to contain a process of polypeptide phosphorylation which is entirely absent in normal erythrocytes [24]; this altered phosphorylation might be involved in the increased cation transport observed in sickle erythrocytes [25]. It has been suggested that unavailability ofsurface membrane "dock" antigens in sickle erythrocytes might play a role in hampering parasitic infections [26]. Certain experimental data have been accumulating in support of such a thesis. In the case of a simian malaria it was shown that erythrocytes lacking Duffy a and b blood group antigens from their surface membrane are resistant to invasion by Plasmodium knowlesi. Resistance to infection in these studies was directly related to the enzymatic removal of the Duffy blood determinants from the erythrocyte surface [27]. Altered cell-surface membranes of the aberrant erythrocyte (i.e., sickle erythrocyte ) could be expected to reflect a modified genetic constitution of the cell [28]. It might also be reasonable to expect that this genetic defect would appear throughout the stem-cell population. Since carcinogenic viruses are known to affect the blood-stem population [29], a defect leading to the disappearance or masking of such surface-membrane "dock" antigens might prevent viral penetration and reduce the rate of carcinogenesis. A case in point could be Burkitt's lymphoma for which Epstein-Bar virus is suspected as the causative agent. Burkitt's lymphoma, the distribution of which correlates well with that of endemic malaria [30], exhibits a decreased rate of incidence in children with sickle-cell trait in Uganda [31]. It might also be of interest to note that the incidence of acute lymphoblastic...