0022-1554/90/$3.30 Thejournal of Histochemistry

Copyright

© 1990

and Cytochemistry by The Histochemical Society,

Vol. 38, No. Inc.

MASASHI FUKAYAMA,’ NOBUAKI FLJNATA, YUKIKO MORIO KOIKE, JUN-ICHI WATANABE, and TETSURO ofPathology,

Received

of Tokyo

Tokyo

(JW);

for publication

Metropolitan

and

Third

March

23,

Komagome

Department 1989

Hospital

oflnternal

and

in revised

form

July

of brain-associated

(BASCA)

small-cell

in developing lung immunohistochemically with monodonal

and

bronchial tubes were diffusely positive at the pseudoglandular stage. Ciliated cells lost immunoreactivity shortly after their emergence, but non-ciliated cells, induding endocrine cells, lost it at the alveolar stage. The immunoreactivity in mesenchymal cells was reduced in the proximal airway,

Introduction Monoclonal antibodies (MAb) were raised noma of the lung (SCCL) for investigation

against small-cell of this particular

carcitype

oflung cancer (14). Interestingly, many of the MAb also react with normal and neoplastic neural tissues, and the majority of them (4,11,12,15) recognize a common antigen, brain-associated smallcell cancer man brain

antigen (BASCA), which was recently (16). BASCA is a 124 KD cell surface

containing several

three questions

no unequivocal

different about

epitopes the

evidence

in the lung

is tumor in some

sp&ific in the lung. non-SCCL (2,12,17),

neuroendocnine

tissue,

However,

significance

has

BASCA

(18).

been

the question but

differentiation

there

of BASCA

obtained

BASCA

purified antigen,

for

is whether expression

this

fact

in non-SCCL

have

As

presence

of

or not

been

been

in SCCL. the

could

has

from huprobably

BASCA

31,

1989;

but

to: Masashi

Fukayama,

interpreted

August

positivity

ofMedical Tokyo,

(70),

4,

1989

Sciences, Japan.

(9A1651).

remained

period.

All

to be too simplistic for understanding plastic lungs. Therefore, in an attempt first investigated BASCA vealed that the developing pression

undergoes

vation, sion

in its spatial

nificance

microscopy

of BASCA

be difficult

and

lung, which neand that this ex-

temporal

pattern.

this changing pattern with BASCA organs and in fibrotic or neoplastic were based solely on morphological

our immunohistochemical by electron

expression in neothis question, we

expression in developing lung expresses BASCA

changes

then tried to compare sion in other developing Although our findings

ofBASCA to clarify

study will provide

in normal

to obtain

with

and other

defining some

neoplastic

We expres-

lungs. obser-

cell type

expres-

insights

into

the sig-

lungs

which

would

approaches.

as

(2). This view appears

3-18-22

Institute

be observed

MD, Department

Hospital,

MAEDA,

in the distal lung later during the endocrine tumors ofthe lung, defmed by diffuse synaptophysin immunoreactivity, expreased BASCA, but some non-endoaine carcinomas which also laCked densely cored granules ultrastructurally, showed BASCA positivity. The temporal and spatial pattern of BASCA expression in the developing lung suggests that BASCA plays an active role inlung morphogenesis. BASCA may be expressed as an oncofetal substance in some non-endocrine carcinomas of the lung. (J Histochem Cytochem 38:51-57, 1990) KEY WORDS: Brain-associated small-cell lung cancer antigen; Smallcell carcinoma of the lung; Surface antigen; Lung development; Monoclonal antibody; Human; Immunoelectron microscopy.

Materials

of Pathol-

Honkomagome,

and

and

Methods

non-neoplastic

consisted

of fetal

lung lungs

and 28), days and 3 months), and tumors with or without adults, were sampled at 20,

Metropolitan Komagome Tokyo 113, Japan.

YOSHIHARU

of Tokyo

accepted

postnatal

try,

I Correspondence

HAYASHI,

(BASCA)

OKABE

University

Normal

ogy, Tokyo Bunkyo-ku,

Antigen

(MIN1YH,YM,MK);

Medicine,

lung cancer antiin lung tumors was investigated and immunoelectron miaoscopically antibodies recognizing different epitopes of BASCA. In fetal lung, epithelial and mesenchymal cells had different spatial and temporal expression ltterns, in contrast to the consistent ttem in neural cells The cell membranes ofepitheial cells ofthe proximal Expression

gen

1990

USA.

Article

Brain-associated Small-cell Lung Cancer Is Expressed in Developing Lung: An Immunohistochemical and Immunoelectron Microscopic Study

University

51-57,

Printedin

Original

Department

pp.

1,

21,

22,

23,

(n

tissues, =

studied

11; gestational

by immunohistochemisweeks

8,

14,

16,

17,

19,

and infant lungs (n - 3; ages 1 and 8 non-neoplastic portions oflungs resected for lung fibrosis (n = 2 of each). Lung tissues, except for autopsy. To clarify the significance of BASCA in newborn

51

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 15, 2015

52

FUKAYAMA,

fetal differentiation, fetal and adult kidneys (n = 9 and 2, respectively), fetal thymuses (n - 10), and fetal and adult brains (n =2 of each) were also examined for comparison. The neoplastic tissues studied were endocnine tumors Itwo carcinoid tumors, eight SCCL, and one atypical endocrine tumor (5,9)1, and non-endocrine carcinomas (24 squamous cell carcinomas, 29 adenocarcinomas, one adeno-squamous cell carcinoma, and five large-cell carcinomas). To define endocrine and non-endocrine tumors, the tumor tissues were screened using an MAb for synaptophysin, which is a constituent of synaptic vesicles. Diffuse staining for synaptophysin classifled the tumor as an endocrine tumor (8). Tissues were fixed overnight with periodate-lysine-panaformaldehyde (PlY), embedded in OCT compound, frozen in dry ice-hexane, and stored at - 80C until immunohistochemical and immunoelectron microscopic studies were performed. Sections were cut at 5 tm with a cryostat for immunohistochemistry. Immunohistochemistry. Immunohistochemistry was performed by the indirect enzyme method (10), using MAb directed to SCCL for all tissues. The MAb reactive with BASCA included TFS4 (11), TFS6(18), MOC1 (2,4) (Bio-Science Products; Emmenbrucke, Switzerland), and 6H7 (12) (provided by Dr. T Okuda, Biological Science Institute, Nippon Zeon, Kawasaki, Japan and Dr. T Kameya, Department of Pathology, Kitasato University, Sagamihara,Japan). These MAb recognize at least two and possibly three different epitopes (18). All four MAb react with purified BASCA, but TFS6, which was obtained using BASCA as immunogen, did not immunolabel the viable SCCL cells, suggesting that the epitope recognized by TFS6 is not present at the outer side of the membrane. In contrast, the other three MAb reacted with viable cells, but 6H7 showed no interaction with TFS4

Table

1 . BASCA

in fetal

adult

and

HAYASHI,

FUNATA,

MAEDA,

KOIXE,

WAIANABE,

OKABE

or MOC1 in competitive inhibition assay of BASCA. Therefore, BASCA has at least two (6H7 and TFS4/MOC1), and possibly a third (TFS6), epitopes. The MAb for synaptophysin (SY38)was purchased from Boehninger (Mannheim, FRG). The cryostat sections were immunostained with MAb in optimal dilution; 1 ng/ml for l’FS4, 10 ng/ml for TFS6, iSo for cornmercially available MOC1, 1 pg/mlfor6H7, and 3 tg/ml for synaptophysin. Immunoelectron Microscopy (IEM). The pre-embedding method for LEM was applied to representative cases: fetal lungs (n = 7), adult lungs with fibrosis (n = 2), SCCLS (n = 4), carcinoids (n = 2), atypical endocnine rumor (n = 1), squamous cell carcinomas (n - 4), and adenocarcinomas (n 1). Ten-micrometer sections adjacent to those for light microscopy were immunostained with MAb for BASCA as described above. The sections were reacted overnight with Fab fragments of rabbit anti-mouse immunoglobulin conjugated with horseradish percacidase. The sections were post-fixed with 1.0% glutaraldehyde in PBS for 15 mm, washed, and preincubated with 0.02% 3,3’-diaminobenzidine, 10 mM sodium azide, and 1% dimethylsulfoxide

in 0.05

M Tris buffer,

pH

7.6,

for 30 mm.

reaction was developed by adding 0.005% sections were post-fixed with 1.0% osmium tetroxide perature, dehydrated in ethanol, and embedded in sections were viewed with a Hitachi H-7000 electron tification of cell types in detail, adjacent ultra-thin stained with uranyl acetate and lead citrate.

Then

the

H2O2 for 5 mm. The for 1 hr at room ternEpon 812. Ultra-thin microscope. For ideasections were doubly

peroxidase

ControlStudies Controlstudies induded the replacement of MAb with non-immune mouse immunoglobulin and omission of the MAb, applied to all cases for light microscopy and to selected cases (frtal lungs, carcinoid tumors, and two non-SCCL) for electron microscopy.

lunga Epitheium/Non-n

eural

mesendsyme

Neural

Dismi lungb

tissue

e

btonchusb

Kidney

Thymus

Brain

Fiber

Fetus *8c (20)’

I

-

+

+

+

I

+

*14(75)

-/++

++I++

#{149}16(95)

-/++

++/+

+

nae

+

na

++/++

na

+

+

+

-I-

na

++

-I-

++

-/++

na(+)

++/++

-I-

-/++

±1±

++/++

-I-

20

-/++

na(±)

++/++

-I-

na na na na

21

/++

±1-

++I++

-I-

na

++

na(-)

++I++

-I-

na

++

17 #{149}19(120)

22

22(190) 23(155) *28

+

++ ++ ++

-/++

±1-

++/++

-I-

-I++

+1±

++/++

-I-

na

++

-/++

-I-

++I++

±1-

na

++

++

++

Postnatal ldf(42

gw)S

4 -

.

I Large

negative bronchi

+

na na na

+

-1+ -1+

nf4 of ++

-I-

-I-

-I-

na

+

+

+

+

±1staining;

±

,a

are defined

mediate sized bronchi, of epithelial cells of C Gestational I Crown-rump

I

-

8d(3lgw) 3m Adult Fibrosis(-) *Fibrosis(+)

few or several

by the presence

the staining intermediate

week. length

results

positive

cells;

of cartilage

in epithelial

+

except

,

many

cells were nearly

sized bronchi were presented

positive

cells but not diffusely

the case of 8th gestational parallel

with

those

week. of large

positive; DiStal

+

+

lung means

bronchi.

When

,

diffuse

staining

glandular,

large bronchus

in parenthesis.

(mm).

‘ na, tissues were not available. fDays or months after birth. g Gestational weeks of neonates. aS f tissues were not found.

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 15, 2015

in most

canalicular,

was

cells;

,

or alveolar not

available,

IEM

was

performed.

structure.

the staining

In

interresults

BASCA

IN DEVELOPING

53

LUNG

f

.‘

_...

T

‘

#{149}

.

.

,

.

#{149}1

.

‘‘4’

,rI..e

#{149}.

..

.,

s

.

,,

4\

V

:

‘).._

-

.;6,

i:...:

.

.,,.-p’

.

:

#{149} #{149}

,/

-

t

,;e*

%

.

.

-.

.

c

!4

I

;:

#{149},J r

.

F

y-

: .

.

i

:..

#{149}

,

-

,

.

. :-

.

:-

,..

..,

;

. -y

.,.

F’.

‘

,

‘,

.--

,

a’

SI.

.-

,‘.

y

_-k*____

;.

.

,,.

-

.

.

.:

-

.

4 #{149}.:‘:;,

_

‘

________

“..*

Figure 1. BASCA expression in developing lung. Three structures are positive: epithelial cells of the bronchial tubes, mesenchymal cells surrounding the airway, and nerve fibers. 6W, gestationalweek. (A) Pseudoglandular stage(GW8), TFS4. Epithelial cells ofthe proximal part show diffuse positivity at the cell membrane, butthe epithelial cells ofthe glandular portion lack immunoreactivity. Note that mesenchymal positivity is present in both parts (arrowheads indicate distal portions, where only mesenchymal cells were positive). (B) Pseudoglandular stage(GWI4), MOC1. Immunoreactive epithelial cells are slightly reduced in alarge bronchus. Arrow indicates focal aggregation ofpositive mesenchymal cells. (C)Canalicularstage(GW21), TFS4 with counterstaining. Arrows pointto afew positive epithelial cells. Neural tissues are positive (arrowheads indicate ganglions). (0-F) Distal lung atthe pseudoglandular stage (0, GW14, MOCI) canalicular stage (E, GW21, TFS4), and postnatal period (F, 8 days, TFS4). Mesenchymal cells surrounding distal structures show positivity which appears to become sparse as the alveoli develop. Original magnifications: A x 100; B, D-F x 125; C x 250. Bars - 100 tm.

Results In all tissues studied, although the intensity with

others.

four MAb showed similar reaction of reaction with TFS6 was weaker

patterns, than that

Nonneoplastic

Lung

The results of immunohistochemistry lungs are presented in lhble 1.

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 15, 2015

on the fetal

tissues

and

adult

54

FUKAYAMA,

HAYASHI,

FUNAIA,

Pmfile

Developmental Kidney,

MAEDA,

and to the

constant

its absence

in the

thymus,

BASCA

in two specific

sociated

with

ofBASCA

and Mature

fetal

structures

in the

brain

kidney

of BASCA showed

the

presence

(Figure

2). One

of these

formation,

epithelial glomeruli

i.e.

cells with

any positivity.

The

Immunoelectron Cells

other

positive

The youngest fetus Positive immuno-

tial

the airway,

two

and temporal changes At the pseudoglandular

8-17),

epitheial

changed in

lung

stage

and

nerve

fibers.

considerably

along

morphology of fetal

cells in the proximal

BASCA with

spa-

(3).

lung

pseudoglandulan

emerged, the

portion

ofthe

week

bronchial

tubes

showed (Figure

diffuse immunostaining with MAb on their cell membranes 1A). The proximal portion, i.e., future bronchi, was charac-

terized

by undulated

fibers

at the outer

seen in the as a glandular chymal tive.

sheath

epithelial structure

cells of the distal at this stage(Figures

cells surrounding They

surrounded

only the distal immunoreactivity portion

than

and bundles ofdensely positive of the tubes. No immunoreactivity

epitheia

tip

the bronchial both

in the proximal

was

portion, which appeared IA, lB. and 1D). Mesentubes

the proximal

lacked positive in mesenchymal

nerve

were also immunoreacand

distal

portions,

and

cells (Figures 1A and 1D). The cells was stronger in the distal

portion,

and

was reduced

with

focal

immunoreaction

for BASCA

membrane

of ciliated

(Figure

BASCA-expressing the developing Some positive

tive cells drastically decreased There were some foci ofseveral cartilage), small in the respiratory maimed

negative

bronchi, and bronchioles (Figure

showed strong positivity During the alveolar tive

cells

could

cells

in the

adult

lungs

bronchial tree (Figure cells in large bronchi

bronchioles. and the

1E). Mesenchymal

However, canalicular cells

1C). (with

epithelial structures in the distal

for BASCA

(Figure

disappeared

and

filaments, indicating 3F). Immunoreactivity cells at the apposing

Non-ciliated

septal

In the of Schwann

differentia-

cells appeared to stage (Figure 3G).

(Figure

3E) surrounded

especially its distal bronchi had bundles

that they were smooth muscle was observed similar to that membranes where mesenchymal

MAb

portion. of actin

cells (Figure in epithelial cells are in portion had to be fibro-

cells.

nerve

fibers,

BASCA

was expressed

at the

lung

(Figure

membranes

cells.

in Fibrosed

epithelial

cells

cells with prominent

definite

intimate contact. Immunoreactive cells in the distal no bundles of filamentous structures, and appeared blastic

but

lateral

stage, when the imat the points of mem-

cells without

cells

they

3A),

cells were endocrine basal cells with

mesenchymal

at the

when at the

3B).

pat-

cells

in bronchiolized

for BASCA.

Positivity

cells ne-

some non-ciliated and cells with dense-cored

lung

in both

samples

Lung of fibrosed was seen

non-endocrine granules did

of fibrosed

tissue

structures at the

showed lateral

4A),

some

positivity

with

membranes

cells (Figure 4B). not show BASCA

of

Endocrine expression

lung.

demarcating the unstained epithelia. stage and early postnatal period, no posi-

be identified

cells were positive at the diffusely in the alveolar

in the positive

of immunoreac-

3D),

3C),

apparent cells,

(Figure

bronchial structure, cells surrounding the

In one of two specimens

the number

non-ciliated (Figure

This

epithelial

soon

cells

contact.

tion. Among these non-ciliated cells, endocrine be the dominant cell type at the canaliculan

BASCA

completed,

-expressing

used. became

continued to express BASCA at the canalicular munoreactivity appeared to be discontinuous

chial

has been

Ciliated

immunoneactivity

and transient aggregations ofpositive cells. These aggregations appeared to be associated with bronchial cartilage (Figure 1B). At the canalicular stage (gestational week 19-23) when bronbranching

points

stage.

showed

tonofilaments

(gestational

unstained

ofcell-to-cell

along

brane contact. These dense-cored granules

former

comprised

of BASCA

did not differ among the four MAb In the fetal bronchi, cell differentiation

mesenchymal

cells surrounding

structure surrounded

at the cell membranes

surface

in the

nephrogenic and immature glomerulan tufts

Lung

staining for BASCA was first identified in this fetus. Three different components in the lung showed similarly positive immunoreactions with four MAb (Figure 1): epithelia ofthe developing bronchi, expression

of

was as-

positive cells were observed by for BASCA was always seen

late Profile ofBASCA in Lung. a gestational age of 8 weeks.

and

To define BASCA-expressing cells, electron microscopy. Immunoreactivity tern

Developmental in the series had

subcapsular

which

Microscopy

in Fetal

,

in renal tubules fully developed

the mesenchymal cells in the medulla, unetenic buds or urinary tubules.

Figure 2. Fetal kidney also exhibits BASCA (GW14, MOC1). Posftive reaction is seen in glomerulus-forming structures(nephrogenic mesenchyme, renaltubules, and Immature glomeruli; arrows) and in mesenchymal cells surrounding ureteric buds (asterIsks). Note the absence of the reaction in fully developed glomeruli near the axis. Original magnification x 63 Bar - 100 pam.

OKABE

in Brain,

presence

glomerular

did not show

WAIANABE,

Thymus

In contrast

mesenchyme glomeruli.

KOIKE,

in epithelia,

but

the

mesenchymal

bronchioles and the alveolar entrance, and septa (Figure iF). There were no positive except

for

nerve

fibers.

BASCA

in Lung

Consistent with previous diffuse staining reaction synaptophysin

Tumors studies, all ofthe endocrine tumors for BASCA at the cell membrane

in the cytoplasm.

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 15, 2015

However,

in non-endocrine

showed and for carci-

*

.

.

F

.--.

,

Figure a Immuncelectron microscopy for BASCA in developing lung. (A) At GW14, TFS4: cilia emerge at the surface of some epithelial cells of the bronchial tubes. Positivity is present at the lateral membranes and not at the luminal side. (B-D) At the GW16 TFS4, counterstained with uranyl acetate and lead citrate: immunoreactivity is lost in ciliated epithelial cells. At this time, differentiated cells other than ciliated cells were identified, endocrine cells (C) and basal cells (D) (arrows indicate bundles of intermediate filaments or tonofilaments). These non-ciliated cells were reactive. Note absence of positivity at abluminal membranes. (E, F) As in epithelial cells, mesenchymal positivity is observed along the points of cell contact between peribronchial cells without specialized structures (E, GW14, TFS4)and apparent smooth muscle cells(F, GW14, TFS4). Asterisk in E indicatesfetal epithelia. (G)At the canalicular stage(GW21, MOC1), positive epithehal cells are reduced and endocrine cells (asterisks) are the predominating cell type among positive cells. Arrows and arrowheads indicate discontinuous positivity of endocrine cells and non-endocrine cells, respectively. Original magnifications: A x 4000; B x 4200; C x 8500; D x 6000; E x 3500; F x 7200; G x 3400. Bars = 2 pam.

55

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56

FUKAYAMA,

FUNATA,

HAYASHI,

munofluorescence

study

that BASCA probably cell surface (‘ff54 and the outside

MAEDA,

oflive

KOIKE,

small-cell

WATANABE,

lung

has three independent MOC1, and 6H7) and

(TFS6)(18).

BASCA

cancer

OKABE

cells revealed

epitopes, two on the one inaccessible from

is selectively

expressed

on cell mem-

branes of small-cell carcinoma of the lung (SCCL) in lung tumors and of human brain cells among normal tissues (17). However, its

.

C-#{149}

..

.

-

expression in the developing In the present study, using

lung has not yet been fully investigated. MAb recognizing three different epi-

topes

these

of BASCA,

in the same

:

we found

specific

is expressed

structures

in fetal

epitopes

ofthe

non-neural

simultaneously

fetal

tissues,

lung.

present

Therefore,

although

BASCA

some

difference

.

in BASCA

molecules

BASCA

in fetal

neural tissues. and temporal Figure 4. (A) Fibrosis in an adult lung; hematoxylin and eosin. (B) Immunoelectron microscopy in bronchiolized epithelia. sitivity is seen atthe apposing membranes between ciliated and non-ciliated cells; MOC1. Original magnifications: A x 25; B x 2700. Bars: A - 200 pam; B = 2 pam.

nomas,

one

of 24 squamous

munoneactive were negative. four

squamous

for BASCA Furthermore,

cell carcinomas.

tophysin

could

positive identified

cases. Ultrastructurally, in BASCA-expressing

in contrast

cell (Figure some

be identified

to their

relative

Only

of fibroblastic

was

a few positive

in serial sections

diffusely

ofone

frequency

imcells in

cells for synapofthese

no dense-cored granules cells offour carcinomas

types of lung carcinomas did for non-neoplastic mesenchymal Iksitivity was ultnastructunally membranes

carcinomas

5), although keratinizing positive cells were identified

in all endocrine

BASCAcould be examined,

tumors.

Other

not show BASCA expression, except cells in one of 29 adenocarcinomas. present at the contact points between or

myofibnoblastic

cells.

may

in neural

lung

BASCA pattern

cells.

between

be present

is present

in epithelial,

in the former of expression,

and

adult

tissues.

mesenchymal,

and

two tissues has a different spatial in contrast to its consistency

As for the spatial

thelial cells are immature BASCA in mesenchymal

fetal

pattern,

cells in the cells is strongly

BASCA-expressing proximal expressed

epi-

bronchi, whereas in the distal part

of the lung where epithelial cells lack immunoreactivity. This spatial pattern of BASCA expression in epithelial and mesenchymal cells appears to parallel that in the fetal kidney: epithelial cells in the immature glomeruli and mesenchymal cells surrounding unetenic buds. This parallelism suggests that BASCA plays a common role in lung and kidney morphogenesis. In this regard, it is interesting

that

a neural

demonstrated mesenchymal

cell

adhesion

molecule

in fetal epithelial immunoreactivity

(NCAM)

cells of glomeruli, present for BASCA

was

recently

although the is not observed

for NCAM (13). Furthermore, N-cadhenin cell adhesion molecules, which were identified in brain cells of mouse and chicken, are expressed in various tissues of chicken embryos, and this expression seems to be related to a variety ofmorphological velopment (6). BASCA may be also a kind

events during deof cell adhesion mole-

cule, and the ultrastructural finding that BASCA is present at the points of cell membrane contact may further support

Discussion Brain-associated KD, recognized bition

small-cell lung cancer antigen is a molecule by the munine MAb TFS4 (16). Competitive

assay of binding

to affinity-purified

BASCA

and

surface

of 124 inhiim-

assumption. In developing

mouse

of mesenchyme gin and perhaps mesenchyme

lung

appeared

to be two

domains

distinguished on the basis of their embryonic ontheir morphogenic properties (19). The tracheal is derived

bronchial

mesenchyme

cells.

latter

The

there

only this

from shares

promote

mesodermal

mesenchyme,

common

budding

epitopes

and

with

branching

whereas neural

crest

of the bronchial

and tracheal epithelia in vitro, whereas the former lack such capability. Although we do not know the origin of human pulmonary mesenchyme, BASCA expression in mesenchymal cells appears to be related

to branching

and BASCA

expression

ofbronchial

ponent in the pulmonary In fetal epithelial cells, but is retained servation may sion

(5,9).

have

been

but

regarded

not

exclusive,

differentiation

was

immunoreactivity

rare

synaptophysin

cell carcinomas

Downloaded from jhc.sagepub.com at VIRGINIA COMMONWEALTH UNIV on March 15, 2015

with

the fetal

a morphogenic is lost in ciliated

for endocrine

component

period, comcells

stage. This obBASCA exprestumors

and atypical endocrine cells in non-endocrine

as an endocrine

ing the mukidirectional ules in squamous

during

cells at the canalicular with the finding that

lung: carcinoid tumor, SCCL, Although BASCA-expressing

nomas Figure 5. Diffuse immunostaining in a squamous cell carcinoma; MOd with counterstaining. Keratinizing cells are negative. In the adjacent section there was no synaptophysin immunoreactivity. Original magnification x 165. Bar 100 pam.

specific,

represent

mesenchyme. BASCA expression

in endocrine be consistent

is relatively

ofthe

tubes

may therefore

tumors carci-

(2), reflect-

oflung carcinomas (1), there or no dense-cored granBASCA-positive cells. BASCA

BASCA

can

IN DEVELOPING

be expressed

57

LUNG

without

accompanying

endocrine

cell

Funata

differen-

tiation, as it occurs in the bronchial epithelia at the pseudoglandular stage. Therefore, BASCA expression in non-endocrine carcinoma of the lung may represent an oncofetal form of expression. It is interesting to note that BASCA expression was found in the non-ciliated

cells of bronchiolized

structures

BASCA-expressing

cells were non-ciliated,

lar to those

bronchi

in fetal

ofa fibrosed

non-endocrine

at the pseudoglandular

stage.

by MAb

against

cells process

SCCL

is a

genesis

of the lung.

has additional

that

plays

Therefore,

significance

an important

BASCA

in lung

tumors

Future

studies

expression.

the molecular tumonigenesis.

structure

of BASCA

K:yose

DrH.

Hapkano

(Department

ofPathology,

ChildrenHospital)forpermitting

photographs

were

prepared

usto by Ms

infantlungs.

10.

1. Baylin

11.

McDowell 1987, 2.

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spectrum

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Edinburgh,

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in

roepithelial

Acknowledgments We thank

Lee I, Gould expressed

role in morpho-

expression

as an oncofetal

are necessary to determine lung differentiation and

8.

the lung.

in spatial and temporal pattern in contrast to its consistency in neural tissues. BASCA may be not only a common molecule in SCCL and but also a molecule

endocrine tumor microscopic

H, Th.keichi M: Spatial and temporal expression pattern of N-cadherin cell adhesion molecules correlated with morphogenetic processes ofchicken embryos. Dev Biol 120:215, 1987

It is pos-

molecule expressed in fetal non-neural tissues as well as in adult neural tissues. However, BASCA expression in fetal lungs changes

brain

docnine

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cells, simi-

sible that BASCA may be re-expressed when the constituent change with bronchiolization, i.e. , during the remodeling of the fibrotic lung (7). In conclusion, BASCA

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