Tobacco Documents Online

THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. Memorandum - To: Dr. H.McAllister and Staff From: D.H.Ford (Other site visitor: Dr. A. Eisenberg) Re: Site visit with Dr. E.E.Marcantonio, Columbia University, P&S, July 11,1991. Grant No. 2906 entitled "The role of integrin receptors in targeting of lymphocytes in human disease." Goals: To determine if changes in the molecular structure of the integrins would lead to a change in the targeting of lymphocytes. He further hopes to determine what factors control tumor cell adhesion and integrin receptor function, which may be of significance in the differentiation and migration of normal and malignant cells. Results: Inasmuch as CTR support for this program was only initiated in January, 1991, Dr. Marcantonio's results are so far at a preliminary level. Since Dr. Marcantonio is essentially interested in the role integrins play in normal and abnormal states, one should note that the integrins, of which there are several, each with specific binding characteristics, are a class of membrane receptors which bind matrix molecules such as fibronectin, laminin and collagen. They appear to be impqrtant in cell adhesion, morpho- genesis and possibly in metastasis. Further, they are found in one form or another in every organ of the body. The initial studies have been directed toward analyzing the integrin profiles of circulating T-cells from a small number of patients with cutaneous T-cell lymphomas (CTCL), using fluorescg29 e activated cell sorting analysis and immunoprecipitation of extracts of I-surface-labelled lymphocytes. Preliminary data demonstrated the presence of a high level of alpha6 and alpha5 subunits, but very little of alpha4, a subunit usually expressed on lympho- cytes. This appeared to be due to the presence of small amounts of monocytes, which have much greater amounts of integrins than lymphocytes. Another problem was that several of his preparations of frozen stocks of CTCL cells had a high degree of intra-cellular labelling and integrin degradation, presumably due to cell death. He has modified his methods and believes corrected for the monocyte contamination and cell death problems. Preliminary results with the improved procedures indicated that CTCL cells do seem to actually have a reduced number of alpha4 integrin subunits. This analysis is being repeated to ensure that he is not observing an artifact. If this is a real loss of this subunit, Dr. Marcantonio speculates that this might make sense on CTCL cells, since the alpha4 subunit plays a role in the normal homing of lymphocytes to Peyer's patches and other normal lymphoid areas. The absence of this subunit might then permit the abnormal homing of these lympho- cytes to the skin wherein they collect to form the lesions eventually recog- nized as a lymphocytic malignancy (CTCL). Comment: Dr. Marcantonio is a young enthusiastic investigator who literally explodes with excitement while discussing his research. Since innervation of the thymus is necessary for normal development and maturation of T-cells, we posed the question as to whether or not a deficiency of the muscarinic or adrenergic nerve supply might contribute to abnormal integrin subunit devel- opment. While this had not occured him, he considered it might be a contributing factor. This appears to us to be a basic investigation with ramifications relevent to both immunological and oncologic investigations. Further, since the integrins appear to be important in normal brain development, alterations in subunit composition might be of significance at this site as well. A well developed study which should provide interesting information. DHF