Prostate-specific Membrane Antigen Expression in Normal

Vol. 3, 81-85,

January

Clinical

1997

Prostate-specific

Membrane

Malignant

Human

David

Inmaculada

A. Silver,

William

R. Fair,

Carlos

Antigen

Service,

tion.

Pellicer,

Warren

D. W.

Heston,

The

neoexpression

capillary

and

beds

angiogenesis of Surgery

Department of Cancer Center,

prostatic also

folate

epithelium.

been

small

membrane with

The

documented

bowel

and

PSMA3

define

antigen

(PSMA)

the

II mem-

produced

by

expression

of this

molecule

has

In the

tissues,

present

study,

including an

pattern

PSMA duodenal

levels

of prostate-specific

membrane

identified

in prostatic

a subset

of

were

mucosa,

of to

primary

node

prostate

metastases

and

adenocarcinomas displayed

intense

staining

vessels

in peritumoral

was

and

tumor

malignancies, transitional

cell

7 of

8 lymph

PSMA

cell

implies

immuno-

carcinomas,

a broader

molecule

and

PSMA

cells

endotumoral

8 of 17 renal

Nevertheless,

suspected. in advanced

in endothelial

and

including

Extraprostatic restricted.

observed

its diverse

to bone

is a Mr

be linked

appears anatomical

significance

to the degree

7 of 13

and

conjugate use

an

‘

This

accordance

with

I 8 U.S.C.

Section

tissues.

A selected

solely

work

was

supported

in part

by

NIH

Grant

DK/CA

epithelial

bladder

transitional

47650,

I-CS

the

in vitro

for

of

utilized

(7,

prostate vivo.

in

and

carcinoma,

primary

and

as

to bone.

of these

tumors

metastatic

colon

7E1 1-CS) antibody. reported

of each

cohort

cell carcinoma,

specimens

of pathological tumors

Mouse

monoclonal Princeton,

and and

prior

17 renal

cell

carcinomas,

and

antibody NJ)

was

18

character-

stage

included cell

were

nodes

the clinical

primary

transitional

paraffin-

the Department of Cancer Center.

lymph

in terms

19

CYT-35 used

as

I the

This clone is derived from the original hyby Horoszewicz et a!. (7). Secondary antibod-

of biotinylated

prior

to

(Cytogen,

Laboratories,

centration

prostate

carcinoma.

adenocarcinoma I summarizes

carcinomas, 13 bladder colon adenocarcinomas.

Antibodies.

charhuman

formalin-fixed,

8 metastases

Table

Additional

The

normal

renal

and

neoplastic

prostate

well

is in

METHODS

Normal

as

356)

as a representative

including

its

9-12).

to further

expression as we!!

for

disease deAn extensive

was performed

malignancies,

AND

CYT

tissues

of primary

anti-

a radioimmuno-

(designated

in

been

an intracellular

previously

for

not

Monoclonal

tissue samples were obtained from at the Memorial Sloan-Kettering

evaluated

ments

(6).

prostate

PSMA

cell

has

vivo

recognizes

been

antibody

panel

MATERIALS

to

S. was supported

consist-

exhibits

(6, 8). In addition,

was also evaluated

of other

(Vector

351)

has

agent

pattern

carcinomas

identified

evaluation

the

(clone

this fact.

Koch Foundation, and the CaPCure Foundation. D. A. in part by NIH Training Grant CA09501. 2 To whom requests for reprints should be addressed, Pathology, Memorial Sloan-Kettering Cancer Center, nue, New York, NY 10021. Phone: (212) 639-7746; 3186.

1734

and

in

of PSMA as a marker pattern of its expression

acterize

treatment.

differentia-

been CYT

(7)

imaging

utility on the

istics

noted of this

protein

PSMA

its function

detection

of the 7El

as

to be highly distribution

Received 5/22/96; revised 9/I 2/96; accepted 10/9/96. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked in

(3),

have

of PSMA

carcinomas.

previously

II membrane

type

(1, 2). Although

(designated

immunochemical

ies consisted

indicate

100,000

acids

PSMA’,

7E1 1-CS

metastases

than

of tumor

PSMA body

primary bridoma

advertisement

for specific

The PSMA gene is located on chromosome I1 two molecular forms of the protein, designated

Thirty-five

of certain

The decrease in PSMA immunoreactivity prostate cancer suggests that expression

may

mechanism

of

fully elucidated. (4, 5). To date,

embedded Pathology

of capillary

cell carcinomas,

amino

Tissues.

primary However,

areas

3 of 19 colon

expression

functional

cells to tumor

neovasculature.

immunohistochemical

proximal

Eight of 18 prostate tumors metastatic PSMA. All of the other nonprostatic studied had undetectable PSMA levels.

staining. expressed tumors

a potential

endothelial be related

activity

clinical pends

renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35

in may

neuropeptidase

epitope

extensive

expression.

Detectable epithelium,

is a type

activity

analysis was performed on a panel normal and malignant human tissues

immunohistochemical well-characterized

further

antigen

hydrolase

in extraprostatic

brain.

and

INTRODUCTION

ABSTRACT protein

PSMA

tumors

suggests

of tumor

ing of 750

Prostate-specific

81

[D. A., W. R. F.,

W. D. W. H.] and Division of Molecular Pathology, Pathology [I. P., C. C. C.], Memorial Sloan-Kettering New York, New York 10021

brane

of

in certain and

targeting

Department

in Normal

Research

Tissues’

Cordon-Cardo2

Urology

Expression

Cancer

horse

Inc., reagent

anti-mouse

Burlingame, was

polyclonal

CA).

determined

The

proper

by titration

IgG conexperi-

to staining.

method

Immunohistochemistry. was used. Sections

nous

peroxidase

activity

An were was

blocked

avidin-biotin deparaffinized, in I .0%

peroxidase and endogehydrogen

perox-

membrane

antigen.

at Department of 1275 York AyeFax: (212) 7943

The abbreviation

used is: PSMA,

prostate-specific

Downloaded from clincancerres.aacrjournals.org on January 24, 2018. © 1997 American Association for Cancer Research.

82

PSMA

in Normal

Table

Stage

I

Primary

ADT”

P,N0 P3N0

I 1

P4N() N+ M+

1 2 3

and Malignant

prostate

RT

tumors:

ADT/ RT

Chemo

2

1

ADT/ Chemo

citric

(pH

acid

5

6.0)

Sections

for

were

mmto

15

antigen

(Organon

Teknika

in 2%

PBS-BSA

washed

plied

for

applied antibody removal

overnight and

30

biotinylated

( 1 :500

mm

avidin-biotin I :25

in PBS

immersed

applied

in a solution

0.01%

hydrogen

mounted.

Cases

were

for 30 mm.

Sections

diaminobenzidine

peroxide

in 0.5%

positive

if at least

diluted

I :500

Corp.) diluted were conducted immune

in 2% PBS-BSA

and

and

to

glands,

staining

several

tissues,

was

utilized to avoid

was modified false-positive

display

intense

the

patterns

with

and

negative

controls

controls with non-

in the

either

weak

the

to include reactions.

and

(Fig.

that

was

(Fig.

gastrointestinal

lb). tract,

in the

hyperplastic luminal

prostate

or

absent.

procedure

exhibited

primary !a).

Blocking

in serial docrine

staining restricted

A similar

situation

intense

and

reac-

crypts and

(Fig.

lc).

were distribution

Rare

cells

immunoreactive similar

in the

deepest

of

was encountered of the

(Fig. to those

ld);

portions these

had

-

-

Cortex

-

Medulla

-

cortex

sections

-

ganglion

duodenal

of the colonic a morphology

of chromogranin-positive

cells

(data

studied.

with

-

not shown),

the

a possible

immunoreactivities

Significant

PSMA

prostate

degree

implying

identified

expression

tumors.

The

of differentiation,

neuroen-

was

pattern

with

in the

detectable

of staining

the

most

in varied

intense

and

homogeneous reactivity located at the luminal site of the glands in well-differentiated tumors (Fig. 2a). Immunoreactivity was heterogeneous

Considerable was noted prostatic

in less

heterogeneity in most cases. stromal

seven

nodes

expressed

observed noticeable

of cases,

was

Staining

within

present

The

staining

with

PSMA pattern

cases

was

reactivity

was

metastases with

and

metastatic

of

2c). In the

reminiscent

of that

at the

without any pseudogland luminal

less heterogeneous

prostate

without

to

(Fig.

primary tumors, In one case,

deposit

2b).

vessels. levels

intense

(Fig.

the same tumor was present in

carcinomas

tumors, with cells virtually elements did not exhibit

18 osseous between

blood

prostate

detectable

a metastatic

that in the primary negative. Lymphoid ties.

including

of eight

the

lesions

of expression within No immunoreactivity

in poorly differentiated subcellular orientation.

formation

divided

well-differentiated

elements,

Similarly, majority

revealed

and colonic mucosa. Blocking of endogenous biotin revealed persistent immunoreactivity limited to the duodenal brush border

-

system

origin. Table 3 summarizes

lymph

biotin

to a subset

staining

-

of 35 primary

substitution

of endogenous

cytoplasmic

+

Eye Peripheral

more

biotin noted to

identical

antibody

reproducibly with

In

routinely

blocking of endogenous Renal tubules, initially

staining,

background

tubules

identified

and

immunohistochemical

class-matched

immunoreactivity proximal

normal

cytoplasmic

tion

abolished

In

-

(DAKO

Negative antibodies

immunoreactivities

studied.

+

Cerebellum

33

2 summarizes

-

Frontal

of the

RESULTS tissues

-

Pancreatic islets Nervous system

tumors Table

-

system

Adrenal

serum.

normal

-

Thyroid

then

Positive present in Carpinteria,

chromogranin

1:20,000 in 2% PBS-BSA. by substitution of primary

-

Lymph node Bone marrow Skin Skeletal muscle Endocrine organs

di-

20%

+

Hematological

reaction. After extensive washing, with hematoxylin, dehydrated, and

considered

-

Ileum Colon Liver Pancreas

ap-

X-!00-PBS

-

Duodenum

tetrachloride

Triton

+

Parotid Stomach

Ches-

were

malignant component demonstrated immunoreactivity. control antibodies to normal antigen components specific cell types included CD4S (DAKO Corp., CA)

and

Laboratories)

-

-

Digestive

blocked Nor-

washed

PSMA

organs

Cervix Breast

0.01%

were

were

(Vector

tissues

Prostate Epithelium Stroma Testis

Chemical

antibodies

of 0.05%

accomplish the chromogen sections were counterstained

therapy;

at 4#{176}C. Sections

Sections

complexes

were

18

West

(Sigma

secondary

dilution).

peroxidase

2

retrieval

Corp.,

chamber

in no row!

Tubules Bladder Transitional epithelium Smooth muscle

for 30 mm to minimize backat 2 .ag/ml in 2% PBSIBSA of horse serum, and sections

in a wet

expression

Glomeruli

8

biotin was Laboratories).

serum

were

and

enhance

PSMA

Genitourinary Kidney

35

3 6

in boiling

endogenous kit (Vector

dilution

incubated

Totals

radiation

immersed

blocking

Co., St. Louis, MO) was ground staining. Primary was applied after suction

luted

RT,

2

Tissue

None

2

at a 1:10

were

Table

treatment

ADT/RT/ Chemo

therapy;

allowed to cool. In some cases, with an avidin-biotin blocking PA)

prior

3

deprivation

for IS mm.

ter,

and

14 14

ide in PBS

ma! horse

stage

1

ADT, androgen chemotherapy.

“

Chemo,

Tissues

site.

than

all positive or all immunoreactivicarcinoma

detectable

PSMA


were ex-

Clinical

‘

-

Research

83

0

-

0,

Cancer

#{182}#{149}

-

‘_. l;’

.

..

.

.

lb

--‘.

-

.,.

, %

.,.

;

“:‘‘

.

c.’

#{149}

#{149} ..

--

,.

#{149}r

,

#{149}#{149}##{149},.4

I,’,

%-

,

.

.;:#AaJ

:!..:

II

.

-.,-

.

.

..‘.

-

.-

‘!$

;.

.

,i Table

3

i:’.

‘-

#{149},UjC

‘.:‘

‘-

P SMA expressio

s.,,

1

.

:

A

..f/1’I’, )

.

S

regarded

No.

studied

immunopositive

primary

Tumor

35

Prostate, metastatic Lymph node Bone Renal cell Bladder transitional Colon

cells

cell

Neovascularity

33

8 18 17 13 19

as artifactual,

confirm ing

Carcinoma

this

cells

cells

in the

al.

eight

cases

staining of osseous None of the

with

immunostaining

within

each

demonstrated

specimen

or hematopoietic elements 17 renal cell carcinomas,

(Fig.

19 colon adenocarcinomas levels in the tumor

components were similarly vessels. Capillary endothe!ial

negative, except cell immunoreactivity

the region mas (Fig.

No

cells.

for

in norma!

tissue

tumors

adjacent

(Fig.

evaluated Stromal

(13)

were

tive. Considerable heterogeneity virtually all peritumor capillaries

of expression positive

only

a few

capillaries

in others.

nous

biotin

did

sections

not

positive change

utilizing

this

result,

a class-matched

not

located

and

was evident, in some cases

and

with and

of endoge-

it was

primary

not

seen

in

antibody.

present

study

is supportive

of previous

evaluations

PSMA expression in normal tissues, with several distinctions. Expression of PSMA by a subset of renal tubules cannot

from prostate parallels the

finding.

The

of these

significance report

in central

remarkable

of PSMA

of this

by Carter

nervous

homology

in small

bowel

antibody

7E1 1-CS

a molecule

with

protein

folate

carcinoma cell line extracts known high level of folate

possible

function

of PSMA

duodenum and in the prostate PSMA mRNA transcripts were system

(13).

PSMA

However,

expression

cerebellum

specific

et

system

to PSMA.

has

extracts

not

in the present

present

respect

activity

(15), a finding which hydrolase activity in

as a folate

including prostatic

seen

hydrolase

in the

study.

detectable

in either This

or gangionic study

locus

confirms

cerebra!

may

cortex

represent

or

expression

not analyzed.

results

from

immunohistochemical

nine

of nine

carcinomas,

be

7El 1-CS and the radionuclide-labeled 356 in frozen prostate tissues. They

et

a!.

(8)

noted

of two staining

analyses of PSMA

cancer. in frozen

prostates,

and two compared

metastases.

previous detection

normal

of

Lopes

and, product.

is currently under investigation. also identified in central nervous

expression in primary and metastatic prostate wicz et a!. (7) described immunoreactivity primary

been

hydrolase

spliced molecular form of PSMA (PSMA’) recognized by 7El I-CS or expression at a

to the

tissues,

(14).

recently

immunohistochemically

was

brainstem

The with

DISCUSSION The

The

the recent

involved

monoclonal

of the alternatively lacking the epitope

immunoreac-

Blocking

origin.

with

to precipitate

The

some blood restricted to

3, c and d). Capillaries

to the tumors

a new characteristics

but it parallels

metabolism

sections

PSMA-express-

duodenal mucosa. Folate hydrolase is a carboxypeptidase like the brain enzyme, liberates glutamate as a reaction

of the tumor was noted in 8 of 17 renal cell carcino3a), in 7 of 13 transitional cell carcinomas (Fig. 3b),

and in 3 of 19 colon

control

2d).

was observed. 13 bladder transi-

tional cell carcinomas, and showed detectable PSMA

of rare

The finding of PSMA expression in the duodenum is consistent with the previous detection of PSMA mRNA transcripts in small

shown heterogeneity

in biotin-blocked

represents

a neuroendocrine

Additionally, The

crypts

of a carboxypeptidase

(3)

bowel

considerable

controls

identification

immunohistochemica!

is not clear,

glutamate

8 7 3

The

colonic

and

indicate

finding

since

finding.

morphology

0

7 8 0 0 0

staining of a neuroendocrine cell in a colonic crypt (d). a, b, and d, X400; c, X200.

‘v

_4_.

tissues

No.

,.

,

,, dI

of epithelial

stricted to the luminal site in a subset of proximal renal tubules (b). Biotin-blocked section of duodenum showed strong PSMA immunoreactivity at the mucosal brush border (c). PSMA immuno-

I

,-

:--#{149}.-

n in tumor

r,

,

#{149}e .

staining

tin removed the nonspecific cytoplasmic staining and revealed a persistent immunoreactivity re-

-“

:4;:(i

S

pression.

:

-....-

‘

expression in Setissues. Granular

cells of proximal renal tubules in nonbiotin-blocked tissue sections (a). Blocking of endogenous bio-

>.

!

Prostate,

cytoplasmic

,.

#{149}

I

V

!:_,I

.

‘

.

.

.‘.

I

:#{231}

‘_;:;.-

h%#

.0’s

#{149}

:

#{149}

.

#{149}3

‘

Fig. I PSMA lected normal

a

s’-.

b#{149} #{149}.

. ,-

;M

.4

er-,,

#{149}

,...

.

*

‘

.

#{246}-

..p’

,

Horoszeprostate

nine

of nine

lymph node patterns of

immunoconjugate immunohistochemical

CYT-


84

PSMA

in Normal

and Malignant

Fig. 2 prostatic

PSMA

PSMA

immunoreactivity

Tissues

expression

carcinoma.

in Intense

in the

glandular epithelium located mainly at the luminal site of a well-differentiated primary tumor (a). More homogeneous cytoplasm and membrane immunostaining of a poorly differentiated

primary

tumor

pression

by tumor metastasis.

(b).

PSMA

cells Note

cx-

of lymph the ab-

node sence of staining in lymphoid elements (c). Osseous metastasis showing

a heterogeneous

pattern

of PSMA immunoreactivity a-c, X200; d, X400.

(d).

S (

“4_

r

Il,

:;i

:

,,‘(: ‘4:

-::

r

-

.

1#{149}

?%

‘

,#{149},%

2J

.

‘

:

“A.,.-..

:‘)k.’

‘.

5,.

.

,#{149};tr

5:

‘‘

3 PSMA expression by neovascular capillary endothe!ial cells in peritumora! areas of selected primary epithelial malig-

.j

-.

Fig.

#{149}J.. , -‘..-

‘-.

#{149}SS.,

‘

5’

.5,’

S,

.:

..

S.,

.-

‘

#{149}

..

-

.1.

-

nancies. ,‘

;.-.

I

Renal

cell carcinoma

(a),

transitional cell carcinoma of the urinary bladder (b), and colonic adenocarcinoma (c and d). Note the intense immunostaining of endothelial cells, whereas tumor

S

‘SI,

cells

had undetectable PSMA X400;bandc,

1ev-

els.aandd, X200.

:#{149}. 51 .

..

S

‘C,

of PSMA

normal

prostates

analyzed, metastases. With

1-CS

PSMA

respect

(9) noted

PSMA.

This

in an unspecified

expression

metastases

(Table

or it may

be related

cancer

all of the

is at variance

be detected

2). This

difference

to the degree

cases the

could

and

study,

in only

8 of

be due

of differentiation

node Wright

expressed

current may

prostates

to bone, examined

of

Wright

72 of 79 lymph

metastatic

seven with

number

carcinomas. in all normal

tumors,

to prostate that

prostatic

immunoreactivity

1 57 of I 65 primary

et a!.

PSMA

by 7E!

and in 10 primary

et al. (9) found

‘

*5’

4

detection

#{149}, ,,T:

5;

in which I 8 osseous

to sample

size

and extensive

prior

treatment

(androgen

of the lesions analyzed. metastases express the (PSMA’)

lacking

deprivation, It is also alternatively

the epitope

recognized

ally, although down-regulation response to androgen has been greatest

expression

PSMA

detection

patients

failing

noted

study

deprivation.

those with tumor progression hormonal manipulation. These

chemotherapy) that some bone form of PSMA

by 7E1 1-CS.

Addition-

of PSMA mRNA expression demonstrated in vitro, with

at castrate

in the present androgen

radiation, possible spliced

levels was

of androgen

lowest

These

in the (13),

in the group

patients

represent

to osseous metastases despite findings support the hypothesis


of

Clinical

that the interaction on tumor PSMA

tumors.

of interest, tubules.

was

The that

granular

tumors

cells

displaying

not

the cells

cell carcinomas,

the

docrine

derivation.

colonic

adenocarcinomas,

function

PSMA

Since

these

of PSMA

protection

expression

by

for both In summary,

normal

from

static

normal tissues hum, duodenal

revealed mucosa,

neuroendocrine the bladder, PSMA.

cells kidney,

PSMA

examined

the presence prostate

prostate to be

highly and

present

study,

expressed

by

(13).

expressed nodally

40%

PSMA.

in colonic crypts. and colon do

malignancies

of

tissue

diseases.

as primary

PSMA expression a subset of renal

expression

in other

to with

gene’s control mechanisms of promoter-driven gene

appears In the

toxins

analysis

demonstrated

malignant

to bone

have

antibodies at destroying

cellular

of prostate

in prostate tubules, and

Carcinomas not appear

peritumor

in meta-

Examination

to

of epithecertain

arising in express

capillaries

to establish

must

the range

be

of this

phenomenon.

The

Memorial

Sloan-Kettering

M. O’Brien

Urology

Cancer

Research

Center

is an

NIH-desig-

Center.

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A.,

Meredith,

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W. R., Powell,

J. S., Kawinski,

R. S.,

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and

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E., and Murphy,

S.,

M.,

evidence

spliced variants of prostate-specific RNA: ratio of expression as a potential measurement Cancer Res., 55: 1441-1443, 1995.

7. Horoszewicz,

G. L., Gulfo,

C. E., Texter, J. E., Begun, F. P., Tyson, Purnell, G., and Harwood, S. J. Monoclonal noconjugates in the diagnosis and treatment Urol., 10: 45-54, 1992.

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K.

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I-P.,

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MacLennan,

1993.

W. D. W. Localization

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N., Maraj,

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a prostate-

J. T. Prostate-specific

C. W.,

A. F. Prostate-specific

existence 1995.

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encoding

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neovascular

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Further understanding of the PSMA may be useful in the development therapy

of PSMA

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techniques in both

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cells

the

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RNase

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indicate

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endothelium malignancies.

are

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Prostate-specific membrane antigen expression in normal and malignant human tissues. D A Silver, I Pellicer, W R Fair, et al. Clin Cancer Res 1997;3:81-85.

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Prostate-specific Membrane Antigen Expression in Normal

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