glucocorticoid receptors and steroid sensitivity in normal ...fects of glucocorticoids on leukemic...

[CANCER RESEARCH 44, 431-437, February 1984]

Glucocorticoid Receptors and Steroid Sensitivity in Normal and NeoplastiaHuman Lymphoid Tissues: A Review1

FranÃ§oiseHomo-Delarche

INSERM U7, Physiology and Pharmacology, HÃ´pital Necker, 161 rue de SÃ¨vres, 75015 Paris, France

Abstract

The determination of estrogen and progesterone receptors inbreast cancer has been shown to be useful in predicting theresponse to endocrine therapy. Given their well-known inhibitory

effects on lymphoid tissue, glucocorticoids have been usedwidely in the treatment of leukemia. Given these facts, over thelast 10 years, several investigators have measured the numberof glucocorticoid receptors in normal and neoplastic lymphoidtissue to see whether their number correlated with glucocorticoidresponsiveness in vitro or in vivo. No clear correlation could beestablished between the level of glucocorticoid receptor and thein vitro action of steroids in normal and neoplastic lymphoidtissue. In contrast, attempts to correlate glucocorticoid receptorlevels in acute lymphocytic leukemia to in vivo steroid responsiveness and immunological type using the whole-cell-binding

assay for receptor determination and selecting the patients according to age and immunological criteria have been more successful.

Introduction

It has been known for a long time that glucocorticoids exertmany physiological and pharmacological effects on mammalianlymphoid tissues. In vivo administration of corticosteroids oradrenalectomy has been shown to induce marked changes inthe size of lymphoid organs as well as in lymphocyte circulationand to alter many immunological reactions (11). In vitro, glucocorticoids are generally considered as catabolic agents thatinduce an inhibition of membrane transport and macromolecularsynthesis leading to an arrest of cell growth, sometimes accompanied by cell lysis (54). These compounds are also able tomodify several immunological functions in vitro (1).

These widespread effects on lymphoid cell metabolism andfunction constitute the basis for the use of glucocorticoid hormones in the treatment of a wide variety of immunological andinflammatory diseases as well as in the treatment of lymphoidcell neoplasias.

According to the classical mechanism of steroid hormoneaction, which includes a preliminary step of interaction of thesteroid with cytoplasmic receptors (53), numerous studies havebeen devoted to the question of whether or not the receptorcontent of lymphoid cells may be representative of the in vitro orin vivo sensitivity. The different methods used to measure steroidreceptor levels as well as in vitro and in vivo sensitivity are listedin Table 1.

This paper presents a critical review of GR2 determination as

an index of steroid sensitivity in normal and leukemic humanlymphoid tissue.

Normal human lymphoid cells

Although many studies have attempted to determine the effects of glucocorticoids on leukemic lymphoid tissues, only a fewhave actually related the extent of steroid action in normal humanlymphoid cells to the level of GR.

As shown in Table 2, the number of GR was determined bywhole-cell assay in children's thymocytes and bone marrow as

well as in adult blood and lymph node lymphocytes in a numberof studies (5,13,31,32,36,43,46, 56,58,63,70). It is apparentthat the number of binding sites found in blood lymphocytes isvery similar in the various reports and ranged from 3 to 7000sites per cell with a Â«<,of around 10~8 M. No significant difference

could be seen between normal T- and B-cells, but it has beensuggested that T-cells are heterogeneous with respect to their

quantity of GR (17). On the other hand, the number of receptorsmeasured in either human thymus cells or lymph node lymphocytes was comparable to that of blood lymphocytes. In contrast,GR levels in normal bone marrow were 3 to 5 times higher thanin other lymphoid tissues (13). Monocyte depletion prior to thedetermination of blood lymphocyte receptors appeared to benecessary, since monocytes contain approximately 2 times morereceptors than lymphocytes (17, 46).

If we consider the effect of steroids on cell viability, it appearsthat human lymphoid cells are extremely resistant to them whencompared to rodent lymphoid cells. Mouse thymocytes undergoa 50% cell lysis after 6 hr incubation in the presence of 10"6 M

dexamethasone (12, 34), whereas human lymphocytes are notkilled even during longer incubation (Table 3) (5, 26, 65). Incontrast, when another method to determine steroid action invitro, i.e., its effect on nucleoside incorporation into RNA andDNA, is used, it is apparent that the glucocorticoid effect can bevery different from one cell population to another (Table 3).Human thymocytes appeared to be extremely sensitive to theinhibitory action of steroids (32), whereas peripheral and lymphnode lymphocytes were less affected (5, 36). These differencesobserved between thymocytes and peripheral lymphocytes areprobably related to the stage of cell proliferation. Claman (11)postulated that the in vivo shrinkage of the infant thymus afterhydrocortisone administration could be explained in terms ofgrowth inhibition. Since the rate of cell division in infants is veryhigh, any agent which blocks cell proliferation without changingintrathymic 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 Grant58-78-90 from INSERM, and by the National Cancer Institute-INSERM CollaborativeAgreement on Hormonal Regulation and Cancer (1976/1977).

Received May 5,1983; accepted October 6.1983.

2The abbreviations used are: GR, glucocorticoid receptor; ALL, acute lympho

cytic leukemia; CLL, chronic lymphocytic leukemia; PBL, peripheral blood lymphocyte.

FEBRUARY 1984 431

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\F. Homo-Delarche

Table 1

Different experimental procedures for the determination of glucocorticoidsensitivity

Receptor content Cytosol assayWhole-cell assay

Total binding (cytoplasmic + nuclear)Nuclear binding

In vitro sensitivity Steroid effect on glucose and amino acid transportSteroid effect on precursor incorporation into proteins,

RNA, and DMAIn vivo sensitivity Short-term response to glucocorticoids alone (variation in

blast cell count)Response to combined chemotherapy

Achievement of complete remissionDuration of complete remissionSurvival

With regard to the in vivo action of glucocorticoids in normalhumans, it has been shown that steroids induce in vivo atransient lymphopenia (20). Although both T- and B-lymphocytesare removed from the circulation and sequestered in the bonemarrow, there is a proportionally greater depletion of circulatoryT-lymphocytes, more precisely of a functionally defined T-cell

subpopulation (19, 21). However, this selective lymphodepletiveeffect of glucocorticoids could not be explained on the basis ofdetectable differences in GR levels in the different T-cell subpop-

ulations(21).

Neoplastia human lymphoid tissue

Glucocorticoids have been used for more than 20 years in thetreatment of leukemia, first alone and now as a part of combinedchemotherapy (4). It appears, however, that some patients eitherare resistant to them at the outset or cease to be responsiveduring the course of the treatment. Since determination of estrogen and progesterone receptors in breast cancer represents animportant element in the therapeutic management of the disease(52), similar studies were carried out in cases of leukemia, inorder to select in advance the patients who are likely to respondto steroid therapy.

Acute Lymphocytic Leukemia

Ten years ago, Lippman ef al. (47) first presented promisingresults. They showed, using a cytosolic assay, that the cells ofpatients with previously untreated ALL contained high levels ofreceptors. These cells were also sensitive to steroid action invitro as well as in vivo. They showed also that patients previouslytreated with corticosteroids who failed to respond to additionaltreatment had barely detectable levels of receptors. In addition,the cells of these patients were insensitive to steroids in vitro.The potential clinical implication of this correlation between receptor content and the in vitro or in vivo response to chemotherapy has prompted several groups to undertake comparablestudies.

It soon appeared that, when assayed by the whole-cell

method, all peripheral leukocytes isolated from patients with ALLcontain specific receptors for glucocorticoids (Table 4). Thenumber of binding sites ranged from 1,000 to more than 20,000(8, 15, 30, 33, 37, 42, 49, 56, 57).3 The affinities of these

3F. F. Quddus, S. H. Kauffmann, M. Roper, B. Dowell, J. Pullen, and B. G.

Leventhal. Glucocorticoid receptor (GR) level in pediatrie leukemia cells, personalcommunication.

receptors for the steroid were comparable to those determinedin normal humans. It was recently demonstrated that the use ofa cytosolic assay instead of the whole-cell assay leads to amarked underestimation of the number of binding sites (up to80%) (38, 49). Several reasons may account for this difference,mainly the failure to measure the receptor in the nuclear compartment, but also the release of proteolytic enzymes that partially inactivate the receptor during cytosol preparation or eventhe failure to break some cells during homogenization.

It is now widely recognized that ALL is a strongly heterogeneous disease with regard to its clinical and immunologicalaspects. Several groups have thus attempted to establish arelationship between the number of receptors and the immunological markers. It appears that in the childhood form, "null" cell

leukemia tends to contain more receptors than T-cell leukemia(15, 42, 57).3 The correlation with the immunological type ap

peared less striking in adults (7, 36). Few data are availableconcerning B-cell lineage, but pre-B-cells have been shown topossess as many receptors as "null" cells (15, 57).3 In a recent

study, GR levels were measured in bone marrow aspirates of174 children with newly diagnosed ALL (13). Bone marrowsamples were selected with more than 90% of blast cells because, as mentioned above, normal bone marrow exhibits a highlevel of GR. The number of binding sites ranged from 2,248 to79,664 per cell (median, 18,123) and was higher than thatreported previously in blood samples. The authors suggestedthat this discrepancy may result either from cell storage (GR arerelatively labile) or from a true difference between blood andbone marrow receptor content. Extensive comparative studiesof GR levels in blood and bone marrow samples need to beperformed, to give a definite answer (8, 13). As in blood, GRcontent is lower in the bone marrow of T-cell leukemia than in

that of common leukemia (13). In studies with a limited numberof patients, no significant correlation has been found betweenGR content of circulating cells and WBC or sex (33, 37, 42, 49).However, after studying a large number of cases, Costlow ef al.related low GR levels in bone marrow to ages <2 or >10 years,black race, high leukocyte count, central nervous system disease, and mediastinal mass; all these parameters are recognizedas high-risk features in the diagnosis of leukemia (13).

Attempts to correlate the level of GR in ALL with most of theparameters of the in vitro sensitivity were unsuccessful in mostof the studies (14, 30, 33, 37, 50). It may be possible to explainthe absence of correlation between the number of receptors andthe in vitro effects of steroids by the heterogeneity of the cells.For this reason, we separated our patients into 2 groups on thebasis of the absence or presence of blood cells in the S phaseof the cell cycle, using pulse cytophotometry analysis (33). Itappeared that the in vitro inhibitory effect of dexamethasonewas 2 times higher in the group of patients with cells in S phasethan in the group of patients without detectable cells in S phase.The cytotoxic effect of cortisol was recently studied in differenttypes of ALL defined by monoclonal antibodies and rosettes(25). Lymphoid cells from 20 patients with common ALL werefound to be resistant to cortisol, whereas the cells from 10patients with pre-B-leukemia were readily lysed. Cells from 5patients with "early" T-cell leukemia were sensitive, whereas

cells from 2 patients with a more mature T-cell phenotype were

found to be resistant. This suggests that the in vitro effect ofglucocorticoids in terms of cell lysis may be linked to cell differentiation.

432 CANCER RESEARCH VOL. 44



GR and Sensitivity in Human Lymphoid Tissues

Tabte2Number of GR in normalhuman lymphoid cells (whole-cell assay)

No.ofCelltypeChildren's

bonemarrowChildren'sthymocytesAdult

peripherallymphocytesPBL(

Non-T-celltT-cellPBLJ

T +null|B-cellPBLPBLPBLPBLAdult

lymphnodes*Median.6

Mean Â±S.D.GR13,929a3,1002,700a2,892

Â±1,068*3,130Â±

1,3163,151Â±7264,6803,6503,8754,850

+1,3407,069Â±6826,617Â±9792,082aTable

3K,,

(M) patientsRefs.5

x10-'5.5

x10-"4x10-'3.5xIO'87.1x10-"5.6x10~e5.1xIO"'4.8

x10-"9910457551814189111332584646703636433156635Glucocorticoid

sensitivity of normal human lymphoid cells invitroThymocytesPeripheral

lymphocytesLymph

node lymphocytesExperimental

conditionsCortisol

Buccinate,1mg/ml,20hrCortisol

succinate, 10Â»ig/ml,4daysDexamethasone,

4 x 10~7M,4

daysCellviability(%)

Refs.>90

26*60

65Â»80

5Experimental

conditionsDexamethasone,10"6M,24

hrDexamethasone,10~Â°M,24

hrDexamethasone,10~7M,20

hrInhibition

of Inhibitionof[3Hluridine[^Ithymidineincorporation

incorporation(%)(%)70.1

Â± 8.1s 95.9 Â±3.920.4

Â±12.9 23.8Â±19.328

21Refs.32365

a Mean Â±S.D.

Table 4Number oÃGR in ALL (whole-cell assay)

PatientsBlood

ChildrenChildren

+adultsChildrenChildrenChildren

+adultsChildrenAdultsChildren

+adultsChildren

+adultsChildrenBone

marrowChildrenType

ofleukemiaNullTNull

+ B +TNull

TBNull

T +BPre-B

NullTNull

+TCommon

+ B +1Null

+ B +TCommon

Pre-BTCommon

TBUndifferentiatedSites/cell2,936-21,869

0-5,8872,560-19,160688-20,79119,768

4,0772,85013,579

Â±11,434a

4,171.6 Â±2,517.321

,00014,0002,5001,348-18,6971

,433-26,8588,495

Â±1,6219,100

Â±7,5008,000 Â±5,4004,200Â±3,1002,480-79,364(21,329Â°)

9,016-37,072 (9,016C)1,115-8,872 (5,897e)9,265-29,574 (20,992e)No.

ofKÂ«(M)patients3.9x10-'

273.9x10-*183.9

x 10-"235

x 10-" 1912

1229

810

149147.7-46.1

x 10-"1910-9

887

3320122

355

11Refs.423337574915830566133 Mean Â±S.D.0 See Footnote 3.0 Numbers in parentheses,median.

FEBRUARY 1984 433



\F. Homo-Delarche

Antileukemic therapy usually includes, in addition to glucocor-

ticoids, 2 or 3 other cytotoxic agents, and it is therefore difficultto ascertain the clinical efficiency of one of these drugs and torelate an in vivo response to the level of GR. To overcome thisdifficulty, several groups have attempted to correlate the level ofreceptors with the short-term response to glucocorticoid therapy.

By selecting the responsive patients on the basis of at least a50% decrease in the number of circulating blast cells, the numberof receptors appeared to be slightly higher in the sensitivepatients (8, 30, 33, 37, 49).

On the other hand, Lippman ef al. (48) were the first to comparein children the levels of receptors at diagnosis before any treatment with long-term combined chemotherapy. They showed thatpatients with high receptor levels tend to have "null" cell ALL

and a long remission duration. Patients with low receptor levelshave T-lymphoblasts and a short remission duration. Patients

with intermediate receptor levels had an intermediate and identical remission duration, regardless of the cell type. They concluded that GR levels appear to have clinical significance independently of age, WBC, or cell type and may represent abiological marker associated with other factors, which are relatedto chemotherapy response, such as rate of growth or biochemical differentiation. More recent studies in children confirmed thatlow GR levels are associated with earlier and more frequentrelapse (13, 31, 49). In contrast, GR levels did not correlate withresponse to combined chemotherapy, duration of remission, orsurvival in adults (8).

Chronic Lymphocytic Leukemia

Determinations of GR have now been performed by severalgroups in more than 100 patients with CLL (24, 31, 35, 43, 56,67, 69, 71, 72, 74). In the early studies performed by cytosolicassay, the receptors were detected in only one-half to one-thirdof the patients. Again, when assayed by whole-cell assay, thepresence of glucocorticoid-binding sites was detected in allcases. The number of these receptors was on an average similarto or even slightly lower than that measured in normal PBL (Table5). More recently, Ho et al. (31 ) have demonstrated that the cellsfrom patients who were treated for 3 to 5 years with a combination of corticoids and chlorambucil and became resistant tothis treatment contain lower receptor content than did cells fromnewly diagnosed patients.

Attempts made to correlate the amount of receptors with invitro steroid sensitivity were unsuccessful (14, 31, 35, 71). Itappears, however, that the extent of dexamethasone-induced

inhibition of uridine incorporation was generally more importantin cells from CLL patients than in normal PBL and that this invitro steroid sensitivity increased significantly with the severity

Table 5Number of GR in CLL (whole-cell assay)

TotalbindingNuclear

bindingSites/cell4000-60003423

Â±666a3850

Â±7734500291

2Â±8842032

Â±692119No.

ofpatients211761161412Rets.35694331567214

1Mean Â±S.D.

of the illness (35). Similarly, it was shown that CLL lymphocytes,in contrast to normal PBL, were in vitro very sensitive to thecytotoxic action of glucocorticoids (26, 66).

Hairy Cell Leukemia

GR were measured by whole-cell assay in leukemic cells from

5 patients with hairy cell leukemia (44). GR sites ranged from5,710 to 11,400 sites per cell, with a Â«<,of about 10~8 M.

Glucocorticoid sensitivity studied in a cell line derived from oneof the patients showed, in fact, a stimulation of DMA synthesis.

Non-Hodgkin 's Malignant Lymphoma

Investigations of malignant lymph nodes were carried out incell suspensions containing at least 50% malignant cells (5-7).The number of binding sites measured by whole-cell assay varied

greatly from one patient to another but was on an average higherin cells from patients with non-Hodgkin's malignant lymphoma

than in cells isolated from control lymph nodes [median valuesare 4110 (n = 42) and 2082 (n = 11) sites per cell, respectively]. In addition, "null" cell lymphomas, as in ALL patients,

usually contained more receptors than did T-cell lymphomas.

Finally, sequential investigations (at diagnosis and at relapse)showed a decrease of the number of GR after treatment.

Despite the high sensitivity of lymphoma cells to the cytotoxicaction of glucocorticoids in vitro (almost 50% of cell lysis after96 hr incubation in the presence of 4 x 10~7 M dexamethasone),

no correlation could be found between the level of these GR andany parameters of in vitro sensitivity.

On the other hand, Bloomfield ef al. (5) have studied in 20patients the response to therapy with corticosteroids as a singleagent. They showed in the group of responders (with a 50% ormore decrease in measurable tumor after corticotherapy) thatthe number of GR was significantly higher than in nonresponders(5600 versus 3300 sites, p < 0.01, n = 10, in each group).

Thymoma

Ranelletti et al. (37, 60, 61) have studied the level of GR invarious forms of thymus dysplasia. Using a cytosolic assay, theyshowed that the level of specific receptors was significantlyhigher in lymphoepithelial thymoma than in pure epithelial form,in thymus hyperplasia, or even in normal thymus. However,despite this high level of GR, the in vitro sensitivity of thymomacells to glucosteroids was comparable to that of normal thymuscells either in terms of inhibition of precursor incorporation or interms of steroid-induced cell lysis.

SÃ©zarySyndrome

Schmidt and Thompson (64) have studied the binding oftritiated dexamethasone in the circulating lymphocytes of 7patients with SÃ©zarysyndrome. Using a cytosolic assay, theyshowed the presence of detectable specific receptors in 5 cases.Although one patient with very high levels of receptors wasshown to be dramatically improved by prednisone treatment,whereas one patient with no detectable receptors was refractoryto combined chemotherapy, it also appears that 2 patients withnonnegligible levels of receptors were not sensitive to combinedchemotherapy including glucocorticoids. These authors also proposed that the determination of the activity of the steroid-





inducible enzyme glutamine synthetase might represent a usefultest for functional glucocorticoid action.

Discussion

After 10 years of research in GR and leukemia, it appears thatthe discrepancies seen among the results of the various studiesmay be in part accounted for by differences in the selection ofthe patients and the experimental procedures used to determinereceptor levels.

Selection of the Patients and Target Tissue

For experimental convenience, most of the studies have beenperformed using peripheral leukocytes, although it is now wellrecognized that blood cells do not entirely reflect the proliferativeactivity of the bone marrow (51). Indeed, comparative studiesperformed in the same patients may show differences in GRlevels between blood and bone marrow samples (8, 13). Bonemarrow, which is usually the main focus of tumoral proliferation,may thus represent a more appropriate tissue for the study ofglucocorticoid action, particularly in leukopenic patients. Whenthe patients have been selected on the basis of more than 80 to90% of circulating or bone marrow blast cells, attempts tocorrelate GR levels with some other parameters (immunologicaltype, response to combined chemotherapy) have been moresuccessful.

Problems of Receptor Determination

Besides the technical problems of receptor determination,which have already been underlined (storage of the cells, cytosolversus whole-cell assay), it should be kept in mind that receptor

concentration in a given target cell is not constant. It may varyunder the influence of several factors, as reviewed elsewhere(18, 45), and in particular as a function of the extracellularconcentration of glucocorticoids (2,22,28,34,63,73). It appearsthat the patients to be investigated should be examined atdiagnosis before any corticoid therapy. Indeed, the level of GRin the previously treated patients, even if they have been withdrawn from steroid treatment 1 to 2 weeks before, is lower thanthat of patients at diagnosis (5, 31).

Determination of Steroid Sensitivity

Studies performed in mouse lymphoma cell lines have demonstrated a fairly good correlation between the level of GR andthe in vitro action of steroids (40, 62). Similar investigationscarried out on cells taken from patients failed to show such acorrelation, as mentioned above. Furthermore, it was demonstrated that the increase in receptor levels following mitogentreatment was not associated with any significant alteration ofin vitro steroid effect (70). On the other hand, despite the generalassumption that steroid-induced cell death represents a conse

quence of the catabolic actions of the drug, there is no relationship between the extent of cell lysis and the metabolic inhibition(34, 59). It should, however, be noted that the in vitro inhibitoryaction of glucocorticoids was more marked in lymphoid populations characterized by a high level of proliferative activity (32, 33,35).

Recent investigations have also shown that the in vitro actionof steroids on lymphoid cells may be more complex than previ

ously believed. Gillis e? al. (27) demonstrated that inhibition ofmitogen-induced cell proliferation by steroids represents an indirect action (suppressing the production of a T-cell growth factorby a small subset of cells) rather than a direct action at the levelof activated lymphocyte. Moreover, the in vitro sensitivity ofleukemic blasts may not always reflect the in vivo response tocombined chemotherapy. We have already seen that the response to treatment as well as the number of GR appears moreprobably dependent on the immunological type of the cells.

It was recently demonstrated that high levels of GR wereusually associated with the presence of terminal deoxynucleoti-dyl transferase activity in lymphoid as well as in myeloid leukemiccells (55, 68). Although these results should be confirmed inmore extensive studies, including careful choice of patients andinvestigation of immunological markers, they suggest a relationship between the level of receptors and cell differentiation.

Evaluation of the in vivo response to corticoid therapy is evenmore complex because it represents a combination of differentmechanisms including, among others, inhibition of cell proliferation and cell lysis, but also cell recirculation and sequestration.In addition, it is obvious that in vivo the perturbations caused bysteroid treatment on the general hormonal balance, on vascularfunction, and on immunological reactions may influence considerably the evolution of leukemia (4). Nevertheless, there are nowsome indications suggesting that the cells of ALL sensitive tosteroid therapy and/or chemotherapy tend to contain more receptor than do cells of nonresponders or patients who willrelapse.

Finally, there are several aspects of steroid action which havenot been fully explored but may play an important role in neo-

plastic lymphoid tissues. Recent findings have shown the existence of a high level of transcortin in patients with lymphaticleukemia and non-Hodgkin's lymphoma (16). This abnormality

was associated with HLA antigens of the ÃŸand C loci. Theseresults, together with the indications suggesting that GR andsteroid response may be under the control genetic influence (3,9, 29), raise the question of the possible role of transcortin in themodulation of GR and steroid sensitivity.

In addition, several authors have described an increased metabolism of cortisol in malignant lymphoid cells (23, 39). Othershave shown a relatively higher metabolism of cortisol by B-lymphocytes than by T-lymphocytes and suggested that thismay explain the greater resistance to cortisol of B-cells (41). Itremains to be determined whether this phenomenon may play arole in the expression of GR and/or in the control of cell response.

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1984;44:431-437. Cancer Res Françoise Homo-Delarche Neoplastic Human Lymphoid Tissues: A ReviewGlucocorticoid Receptors and Steroid Sensitivity in Normal and

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