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Glucocorticoid Receptors and Steroid Sensitivity in Normal and Neoplastia Human Lymphoid Tissues: a Review1

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Glucocorticoid Receptors and Steroid Sensitivity in Normal and Neoplastia Human Lymphoid Tissues: a Review1 [CANCER RESEARCH 44, 431-437, February 1984] Glucocorticoid Receptors and Steroid Sensitivity in Normal and Neoplastia Human Lymphoid Tissues: A Review1 FrançoiseHomo-Delarche INSERM U7, Physiology and Pharmacology, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France This paper presents a critical review of GR2 determination as Abstract an index of steroid sensitivity in normal and leukemic human The determination of estrogen and progesterone receptors in lymphoid tissue. breast cancer has been shown to be useful in predicting the response to endocrine therapy. Given their well-known inhibitory Normal human lymphoid cells effects on lymphoid tissue, glucocorticoids have been used widely in the treatment of leukemia. Given these facts, over the Although many studies have attempted to determine the ef last 10 years, several investigators have measured the number fects of glucocorticoids on leukemic lymphoid tissues, only a few of glucocorticoid receptors in normal and neoplastic lymphoid have actually related the extent of steroid action in normal human tissue to see whether their number correlated with glucocorticoid lymphoid cells to the level of GR. responsiveness in vitro or in vivo. No clear correlation could be As shown in Table 2, the number of GR was determined by whole-cell assay in children's thymocytes and bone marrow as established between the level of glucocorticoid receptor and the in vitro action of steroids in normal and neoplastic lymphoid well as in adult blood and lymph node lymphocytes in a number tissue. In contrast, attempts to correlate glucocorticoid receptor of studies (5,13,31,32,36,43,46, 56,58,63,70). It is apparent levels in acute lymphocytic leukemia to in vivo steroid respon that the number of binding sites found in blood lymphocytes is siveness and immunological type using the whole-cell-binding very similar in the various reports and ranged from 3 to 7000 sites per cell with a «<,ofaround 10~8 M. No significant difference assay for receptor determination and selecting the patients ac cording to age and immunological criteria have been more suc could be seen between normal T- and B-cells, but it has been cessful. suggested that T-cells are heterogeneous with respect to their quantity of GR (17). On the other hand, the number of receptors measured in either human thymus cells or lymph node lympho Introduction cytes was comparable to that of blood lymphocytes. In contrast, It has been known for a long time that glucocorticoids exert GR levels in normal bone marrow were 3 to 5 times higher than in other lymphoid tissues (13). Monocyte depletion prior to the many physiological and pharmacological effects on mammalian lymphoid tissues. In vivo administration of corticosteroids or determination of blood lymphocyte receptors appeared to be adrenalectomy has been shown to induce marked changes in necessary, since monocytes contain approximately 2 times more the size of lymphoid organs as well as in lymphocyte circulation receptors than lymphocytes (17, 46). and to alter many immunological reactions (11). In vitro, gluco If we consider the effect of steroids on cell viability, it appears corticoids are generally considered as catabolic agents that that human lymphoid cells are extremely resistant to them when compared to rodent lymphoid cells. Mouse thymocytes undergo induce an inhibition of membrane transport and macromolecular a 50% cell lysis after 6 hr incubation in the presence of 10"6 M synthesis leading to an arrest of cell growth, sometimes accom panied by cell lysis (54). These compounds are also able to dexamethasone (12, 34), whereas human lymphocytes are not modify several immunological functions in vitro (1). killed even during longer incubation (Table 3) (5, 26, 65). In These widespread effects on lymphoid cell metabolism and contrast, when another method to determine steroid action in function constitute the basis for the use of glucocorticoid hor vitro, i.e., its effect on nucleoside incorporation into RNA and mones in the treatment of a wide variety of immunological and DNA, is used, it is apparent that the glucocorticoid effect can be inflammatory diseases as well as in the treatment of lymphoid very different from one cell population to another (Table 3). cell neoplasias. Human thymocytes appeared to be extremely sensitive to the According to the classical mechanism of steroid hormone inhibitory action of steroids (32), whereas peripheral and lymph action, which includes a preliminary step of interaction of the node lymphocytes were less affected (5, 36). These differences steroid with cytoplasmic receptors (53), numerous studies have observed between thymocytes and peripheral lymphocytes are been devoted to the question of whether or not the receptor probably related to the stage of cell proliferation. Claman (11) content of lymphoid cells may be representative of the in vitro or postulated that the in vivo shrinkage of the infant thymus after in vivo sensitivity. The different methods used to measure steroid hydrocortisone administration could be explained in terms of receptor levels as well as in vitro and in vivo sensitivity are listed growth inhibition. Since the rate of cell division in infants is very in Table 1. high, any agent which blocks cell proliferation without changing intrathymic cell death would cause a decrease in thymus size (10-12). 1Part of this work was supported by Grant 76-7-1669 from DGRST, by Grant 58-78-90 from INSERM, and by the National Cancer Institute-INSERM Collaborative 2The abbreviations used are: GR, glucocorticoid receptor; ALL, acute lympho Agreement on Hormonal Regulation and Cancer (1976/1977). cytic leukemia; CLL, chronic lymphocytic leukemia; PBL, peripheral blood lympho Received May 5,1983; accepted October 6.1983. cyte. FEBRUARY 1984 431 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1984 American Association for Cancer Research. \ F. Homo-Delarche Table 1 receptors for the steroid were comparable to those determined Different experimental procedures for the determination of glucocorticoid in normal humans. It was recently demonstrated that the use of sensitivity a cytosolic assay instead of the whole-cell assay leads to a Receptor content Cytosol assay Whole-cell assay marked underestimation of the number of binding sites (up to Total binding (cytoplasmic + nuclear) 80%) (38, 49). Several reasons may account for this difference, Nuclear binding mainly the failure to measure the receptor in the nuclear com In vitro sensitivity Steroid effect on glucose and amino acid transport Steroid effect on precursor incorporation into proteins, partment, but also the release of proteolytic enzymes that par RNA, and DMA tially inactivate the receptor during cytosol preparation or even In vivo sensitivity Short-term response to glucocorticoids alone (variation in the failure to break some cells during homogenization. blast cell count) Response to combined chemotherapy It is now widely recognized that ALL is a strongly heteroge Achievement of complete remission neous disease with regard to its clinical and immunological Duration of complete remission Survival aspects. Several groups have thus attempted to establish a relationship between the number of receptors and the immuno logical markers. It appears that in the childhood form, "null" cell With regard to the in vivo action of glucocorticoids in normal leukemia tends to contain more receptors than T-cell leukemia (15, 42, 57).3 The correlation with the immunological type ap humans, it has been shown that steroids induce in vivo a transient lymphopenia (20). Although both T- and B-lymphocytes peared less striking in adults (7, 36). Few data are available are removed from the circulation and sequestered in the bone concerning B-cell lineage, but pre-B-cells have been shown to possess as many receptors as "null" cells (15, 57).3 In a recent marrow, there is a proportionally greater depletion of circulatory T-lymphocytes, more precisely of a functionally defined T-cell study, GR levels were measured in bone marrow aspirates of subpopulation (19, 21). However, this selective lymphodepletive 174 children with newly diagnosed ALL (13). Bone marrow effect of glucocorticoids could not be explained on the basis of samples were selected with more than 90% of blast cells be detectable differences in GR levels in the different T-cell subpop- cause, as mentioned above, normal bone marrow exhibits a high ulations(21). level of GR. The number of binding sites ranged from 2,248 to 79,664 per cell (median, 18,123) and was higher than that reported previously in blood samples. The authors suggested Neoplastia human lymphoid tissue that this discrepancy may result either from cell storage (GR are Glucocorticoids have been used for more than 20 years in the relatively labile) or from a true difference between blood and treatment of leukemia, first alone and now as a part of combined bone marrow receptor content. Extensive comparative studies chemotherapy (4). It appears, however, that some patients either of GR levels in blood and bone marrow samples need to be are resistant to them at the outset or cease to be responsive performed, to give a definite answer (8, 13). As in blood, GR during the course of the treatment. Since determination of estro content is lower in the bone marrow of T-cell leukemia than in gen and progesterone receptors in breast cancer represents an that of common leukemia (13). In studies with a limited number important element in the therapeutic management of the disease of patients, no significant correlation has been found between (52), similar studies were carried out in cases of leukemia, in GR content of circulating cells and WBC or sex (33, 37, 42, 49). order to select in advance the patients who are likely to respond However, after studying a large number of cases, Costlow ef al. to steroid therapy. related low GR levels in bone marrow to ages <2 or >10 years, black race, high leukocyte count, central nervous system dis Acute Lymphocytic Leukemia ease, and mediastinal mass; all these parameters are recognized as high-risk features in the diagnosis of leukemia (13).
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